Physiology_Levy

Physiology_Levy. raphe nuclei. Similar to the noradrenergic fibers, serotoninergic fibers are distributed throughout most of the brain and spinal cord. Dopaminergic fibers arise from two main brainstem regions: the substantia nigra pars compacta, which projects to the striatum, and the ventral tegmental area, which projects more widely to the neocortex and subcortical areas, including the nucleus accumbens. Histaminergic neurons are located within the tuberomammillary nucleus of the hypothalamus and project diffusely throughout the CNS. Finally, adrenergic neurons are relatively few in number when compared with the other biogenic amine transmitters. They have cell bodies localized to small cell groups in the rostral medulla. The largest group, termed C1, has projections to the locus coeruleus and down to the thoracic and lumbar levels of the spinal cord, where they terminate in the autonomic nuclei of the intermediolateral and intermediomedial cell columns. Thus, these neurons are important for


Physiology_Levy

Physiology_Levy. to the thoracic and lumbar levels of the spinal cord, where they terminate in the autonomic nuclei of the intermediolateral and intermediomedial cell columns. Thus, these neurons are important for autonomic functions, particularly vasomotor ones, such as control of arterial pressure.


Physiology_Levy

Physiology_Levy. The diffuse nature of the projection pattern of most of the amine systems is mirrored in their proposed functions. Activity in the different aminergic systems is believed to be important in setting global brain states. For example, these systems are involved in setting the level of arousal (sleep, waking), attention, and mood. Their involvement in pathways connected with the hypothalamus and other autonomic centers also indicates that they have important homeostatic functions. The role of dopamine in balancing the flow of activity through the basal ganglia pathways and how its loss leads to the motor symptoms observed in Parkinson’s disease are described in


Physiology_Levy

Physiology_Levy. ATP has the potential to act as a transmitter or cotransmitter at synapses in the peripheral and central nervous systems. ATP is found in all synaptic vesicles and thus is co-released during synaptic transmission. ATP has its own receptors, which like standard neurotransmitters, are coupled to ion channels, but it can also modify the action of other neurotransmitters with which it is co-released, including norepinephrine, serotonin, glutamate, dopamine, and GABA. Glial cells may also release ATP after certain types of stimulation. Once released, ATP is broken down by ATPases and 5-nucleotidase to adenosine, which can be taken up again by the presynaptic terminal. Peptide neurotransmitters consist of chains of between 3 and about 40 amino acids. Studies of neuropeptides


Physiology_Levy

Physiology_Levy. Peptide neurotransmitters consist of chains of between 3 and about 40 amino acids. Studies of neuropeptides Hyperactivityofdopaminergicsynapsesmaybeinvolvedinsomeformsofpsychosis.Chlorpromazine andrelatedantipsychoticdrugsinhibitdopaminereceptorsonpostsynapticmembranesandthusdiminishtheeffectsofdopaminereleasedfrompresynapticnerveterminals.Overdosesofsuchantipsychoticdrugscanproduceatemporaryparkinsonian-likestate. focused on the hypothalamus for many years. However, it is now clear that neuropeptides are released by neurons and act on receptors throughout the CNS and thus are a fundamental mechanism of neurotransmission throughout the CNS. To date, more than 100 neuropeptides have been identified. They can be classified into several functional groups, as shown in


Physiology_Levy

Physiology_Levy. Box 6.1 , which lists some of the known neuropeptides. It is now clear that many neurons that release classic neurotransmitters also release neuropeptides. As detailed later, understanding the interaction between coexisting classic and peptide transmitters has become an important area of research. In addition to being co-released with another transmitter, neuropeptides can also function as the sole or primary neurotransmitter at a synapse. In some ways neuropeptides are like the classic neurotransmitters: they are packaged into synaptic vesicles, their release is dependent on Ca++ , and they bind to specific receptors on target neurons. However, there are also significant differences, ones that have led to alternative names for the intercellular communication mediated by neuropeptides, such as nonsynaptic, parasynaptic, and volume transmission. Table 6.1 summarizes some of these differences between classic and peptide neurotransmitters.


Physiology_Levy

Physiology_Levy. Table 6.1 summarizes some of these differences between classic and peptide neurotransmitters. Unlike classic neurotransmitters, which are synthesized at the presynaptic terminal, neuropeptides are synthesized at the cell body and then transported to the terminal (see Fig. 6.2 ). Neuropeptides are packaged into large electron-dense vesicles that are scattered throughout the presynaptic terminal rather than in small electron-lucent vesicles docked at the active zone, where small-molecule transmitters are stored. (In neurons that make multiple neuropeptides, the various peptides are co-stored in the same vesicles.) Neuropeptide receptors are not confined to the synaptic region, and in general, peptide action is not limited by reuptake mechanisms.


Physiology_Levy

Physiology_Levy. Each of these differences has functional implications. For example, the separate storage of peptide and nonpeptide transmitters immediately raises the question of whether the two transmitters are co-released or differentially released in response to particular stimulation patterns.


Physiology_Levy

Physiology_Levy. In fact, differential release of peptide and classic transmitters from the same cell has been demonstrated for several types of neurons and is probably a result of the differences in vesicle storage described earlier. Because of their proximity to the active zones, nonpeptide vesicles can be released rapidly (<1 msec) in response to single action potentials • BOX 6.1 Some Neuroactive Peptides as a result of localized influx of Ca++ . Thus, low-frequency stimulation of the cell causes just the release of nonpeptide transmitter. In contrast, with higher-frequency stimulation of the presynaptic neuron, there is a more global increase in [Ca++] throughout the nerve terminal that leads to release of neuropeptide as well as neurotransmitter.


Physiology_Levy

Physiology_Levy. When neuropeptides are co-released with other transmitters, they may act synergistically or antagonistically. For example, in the spinal cord, tachykinins and calcitonin gene–related peptide (CGRP) act synergistically with glutamate and with substance P to enhance the action of serotonin. Conversely, tachykinins and CGRP antagonize norepinephrine’s action at other synapses. The interactions, however, are not simply a one-to-one synergism or antagonism at a particular synapse because of the differing temporal and spatial profiles of the action of peptides versus classic transmitters. In particular, the slower release and lack of rapid reuptake mean that neuropeptides can act for long durations, diffuse over a region of brain tissue, and affect all cells in that region (that have the appropriate receptors) rather than just acting at the specific synapse at which it was released. In fact, studies have shown that there is often a spatial mismatch between the presynaptic terminals that


Physiology_Levy

Physiology_Levy. receptors) rather than just acting at the specific synapse at which it was released. In fact, studies have shown that there is often a spatial mismatch between the presynaptic terminals that contain a particular neuropeptide and the sites of the receptors for that peptide. In sum, peptides released from a particular synapse probably affect the local neuronal population as a whole, whereas the co-released classic transmitters act in more of a point-to-point manner.


Physiology_Levy

Physiology_Levy. Opiates are drugs derived from the juice of the opium poppy. Compounds that are not derived from the opium poppy but that exert direct effects by binding to opiate receptors are called opioids and form a clinically and functionally important class of neuropeptides. Operationally, opioids are defined as compounds whose effects are stereospecifically antagonized by a morphine derivative called naloxone. The three major classes of endogenous opioid peptides in mammals are enkephalins, endorphins, and dynorphins. Enkephalins are the simplest opioids; they are pentapeptides. Dynorphins and endorphins are somewhat longer peptides that contain one or the other of the enkephalin sequences at their N-terminal ends.


Physiology_Levy

Physiology_Levy. Opioid peptides are widely distributed in neurons of the CNS and intrinsic neurons of the gastrointestinal tract. The endorphins are discretely localized in particular structures of the CNS, whereas the enkephalins and dynorphins are more widely distributed. Opioids inhibit neurons in the brain involved in the perception of pain. Indeed, opioid peptides are among the most potent analgesic (pain-relieving) compounds known, and opiates are used therapeutically as powerful analgesics. They exert their analgesic effect by binding to specific opiate receptors.


Physiology_Levy

Physiology_Levy. Substance P is a peptide consisting of 11 amino acids. It is present in specific neurons in the brain, in primary sensory neurons, and in plexus neurons in the wall of the gastrointestinal tract. The wall of the gastrointestinal tract is richly innervated with neurons that form networks or plexuses (see also ). The intrinsic plexuses of the gastrointestinal tract exert primary control over its motor and secretory activities. These enteric neurons contain many of the neuropeptides, including substance P, that are found in the brain and spinal column. Substance P is involved in pain transmission and has a powerful effect on smooth muscle. Substance P is probably the transmitter used at synapses made by primary sensory neurons (their cell bodies are in the dorsal root ganglia) with spinal interneurons in the dorsal horn of the spinal column, and thus it is an example of a peptide acting as a primary transmitter at a synapse.


Physiology_Levy

Physiology_Levy. Enkephalins act to decrease the release of substance P at these synapses and thereby inhibit the pathway for pain sensation at the first synapse in the pathway.


Physiology_Levy

Physiology_Levy. This is the newest category of neurotransmitter to be defined and stretches the usual definition of synaptic transmission even further than neuropeptides do. Gas neurotransmitters are neither packaged into synaptic vesicles nor released by exocytosis. Instead, gas neurotransmitters are highly permeant and simply diffuse from synaptic terminals to neighboring cells after synthesis, their synthesis being triggered by depolarization of the nerve terminal (the influx of Ca++ activates synthetic enzymes). Moreover, there are no specific reuptake mechanisms, nor do they undergo enzymatic destruction, so their action appears to be ended by diffusion or binding to superoxide anions or various scavenger proteins. Both nitric oxide (NO) and carbon monoxide (CO) are examples of gaseous neurotransmitters. NO is a transmitter at synapses between inhibitory motor neurons of the enteric nervous system and gastrointestinal smooth muscle cells (see ). NO also functions as a neurotransmitter in the


Physiology_Levy

Physiology_Levy. NO is a transmitter at synapses between inhibitory motor neurons of the enteric nervous system and gastrointestinal smooth muscle cells (see ). NO also functions as a neurotransmitter in the CNS. The enzyme NO synthase catalyzes the production of NO as a product of the oxidation of arginine to citrulline. This enzyme is stimulated by an increase in cytosolic [Ca++].


Physiology_Levy

Physiology_Levy. In addition to serving as a neurotransmitter, NO functions as a cellular signal transduction molecule both in neurons and in nonneuronal cells (e.g., vascular smooth muscle; see Chapter 14). One way that NO functions as a signal transduction molecule is by regulating guanylyl cyclase, the enzyme that produces cGMP from GTP. NO binds to a heme group in soluble guanylyl cyclase and potently stimulates the enzyme. Stimulation of this enzyme leads to an elevation in cGMP in the target cell. The cGMP can then influence multiple cellular processes.


Physiology_Levy

Physiology_Levy. The multitude of neurotransmitters used in the nervous system provides it with a specific and flexible interneuronal communications system. These characteristics are even further enhanced by the variety of receptors for each neurotransmitter. Receptors for a particular neurotransmitter were traditionally distinguished primarily by pharmacological differences in their sensitivity to particular agonists and antagonists. For example, acetylcholine receptors were split into muscarinic and nicotinic classes, depending on whether they bind muscarine or nicotine. Similarly, glutamate receptors were split into three main groups according to their sensitivity to the agonists NMDA, kainic acid, or AMPA. Though useful, this classification scheme has several limitations: some receptors fail to be activated by agonists, and it fails to disclose all the various receptor subtypes for a particular transmitter. Over the past 15 years or so, molecular biological approaches have been used to identify


Physiology_Levy

Physiology_Levy. by agonists, and it fails to disclose all the various receptor subtypes for a particular transmitter. Over the past 15 years or so, molecular biological approaches have been used to identify and sequence the receptor genes for many of the known neurotransmitters. It is thought that we now have a relatively complete catalog of the genes for these receptors. What this work has revealed is that there is a tremendous diversity of actual and potential receptor subtypes that are or could be used by the nervous system. Moreover, knowledge of the gene sequences has enabled an understanding of the relationship of different receptor proteins to each other and to other important proteins. This knowledge, combined with the results of biochemical, crystallographic, and other types of studies, has led to a much deeper understanding of the structural and functional workings of receptor proteins. In particular, various receptors can be grouped into families based on gene sequences, and members of


Physiology_Levy

Physiology_Levy. to a much deeper understanding of the structural and functional workings of receptor proteins. In particular, various receptors can be grouped into families based on gene sequences, and members of each family share various structural and functional features.


Physiology_Levy

Physiology_Levy. Neurotransmitter receptors are members of one of two large groups or families of proteins: ligand-gated ion channels, also known as ionotropic receptors, and G protein– coupled receptors, also referred to as metabotropic receptors (


Physiology_Levy

Physiology_Levy. Fig. 6.12A–B ). Almost all classic neurotransmitters and neuropeptides have at least one metabotropic-type receptor. Many of the classic neurotransmitters also have at least one ionotropic receptor. Ionotropic receptors are protein complexes that both have an extracellular binding site for the transmitter and form an ion channel (pore) through the cell membrane. The receptor is made up of several protein subunits, usually three to five, each of which typically has a series of membrane-spanning domains, some of which contribute to the wall of the ion channel. Binding of the neurotransmitter alters (usually increases) the probability of the ion channel being in the open state and thus typically results in postsynaptic events that are rapid in both onset and decay, with a duration of several milliseconds. Ionotropic receptors underlie fast synaptic EPSPs and IPSPs, as described earlier.


Physiology_Levy


Physiology_Levy

Physiology_Levy. IonotropicglutamateandATPreceptorsformtwootherionotropicreceptorsuperfamilies;thedetailsforeacharegiveninthelatercorrespondingsections.Transientreceptorpotential(TRP)channels,whichareimportantfortransductionofpainandthermalsensations,formyetanotherfamily(see 1. Neurotransmitter Neurotransmitter Ions binds 1. Neurotransmitter binds 2. Channel opens 5. Ions flow across membrane 4. Ion 3. Ions flow Ions across membrane 2. G protein is 3. G protein subunits or • Fig.


Physiology_Levy

Physiology_Levy. binds 2. Channel opens 5. Ions flow across membrane 4. Ion 3. Ions flow Ions across membrane 2. G protein is 3. G protein subunits or • Fig. 6.12 Neurotransmitter receptors. The basic structure and mechanism of action are shown for ligand-gated ion channels (ionotropic receptors) (A) and G protein–coupled (metabotropic) receptors (B). Detailed structures of cys-loop and glutamate ionotropic receptors are shown in C and D, respectively. Cys-loop receptors include ionotropic receptors for GABA, glycine, serotonin, and acetylcholine. Note the differing membrane topologies of the individual subunits of these two classes of receptors: four transmembrane domains for cys-loop receptors and three plus a pore loop for glutamate receptors. Pore loops form the internal wall of the glutamate channel, whereas transmembrane domain 2 forms the internal wall of cys-loop receptors. (A and B, From Purves D, Augustine GJ, Fitzpatrick D. Neuroscience. 2nd ed. Sunderland, MA: Sinauer Associates; 2001.)


Physiology_Levy

Physiology_Levy. Metabotropic receptors are not ion channels. Instead, they are protein monomers that have an extracellular binding site for a particular transmitter and an intracellular site for binding a G protein. Binding of the receptor leads to activation of a G protein, which is the first step in a signal transduction cascade that alters the function of an ion channel in the postsynaptic membrane. In contrast to ionotropic receptors, metabotropic receptors mediate post-synaptic phenomena that have a slow onset and that may persist from hundreds of milliseconds to minutes. Because of the various biochemical cascades they initiate, they have great potential to cause changes in the neuron beyond just generating a postsynaptic potential.


Physiology_Levy

Physiology_Levy. Acetylcholine receptors were originally classified on a pharmacological basis (being sensitive to nicotine or muscarine) into two major groups. This grouping corresponds to groupings based on structural and molecular biological studies. Nicotinic receptors are members of the ionotropic cys-loop family, and muscarinic receptors are part of the metabotropic family of receptor proteins.


Physiology_Levy

Physiology_Levy. The nicotinic receptors mediate synaptic transmission at the neuromuscular junction as described earlier; however, nicotinic receptors are also present within the CNS. The nicotinic receptor contains a relatively nonselective cationic channel, so binding of acetylcholine produces an EPSP. Being members of the cys-loop family, acetylcholine receptors are pentamers constructed from a series of subunit types called α, β, γ, δ, ε, some of which contain multiple members. At the neuromuscular junction the channel is constructed from 2α, β, δ, ε, whereas in the CNS the composition is typically 3α, 2β. Furthermore, the junctional receptors all use the α1 subunit, whereas centrally located receptors use one of the α subunits between α2 and α10. As noted, the differing subunits result in receptors with differing pharmacological sensitivities and channel kinetics and selectivity.


Physiology_Levy

Physiology_Levy. There are five known muscarinic subtypes of acetylcholine receptors (M1 to M5). All are metabotropic receptors; however, they are coupled to different G proteins and can thus have distinct effects on the cell. M1, M3, and M5 are coupled to pertussis toxin–insensitive G proteins, whereas M2 and M4 are coupled to pertussis toxin–sensitive G proteins. Each set of G proteins is coupled to different enzymes and second messenger pathways (see for details of these pathways). Inhibitory Amino Acid Receptors: GABA and Glycine As noted, the most common inhibitory synapses in the CNS use either glycine or GABA as their transmitter. Glycine-mediated inhibitory synapses are common in the spinal cord, whereas GABAergic synapses make up the majority of inhibitory synapses in the brain.


Physiology_Levy

Physiology_Levy. Both glycine and GABA have ionotropic receptors that are members of the cys-loop family, thus sharing a number of characteristics as already described. In addition, each of these receptors has a Cl− channel, which opens while the receptor portion is bound. Therefore, the probability of these channels opening and the average time a channel stays open are controlled by the concentration of the neurotransmitter for which the receptor is specific.


Physiology_Levy

Physiology_Levy. Glycine receptors are pentamers and may be heteromers of α and β subunits (3:2 ratio) or homomers. Interestingly, the molecular composition appears to be related to its cellular location, with heteromers located postsynaptically and homomers located extrasynaptically. The β subunit seems to bind to an intracellular scaffold protein called gephyrin that appears to help localize receptors to the postsynaptic site. The α subunit contains the glycine binding site, and there are four genes coding for distinct α subunits (and splice variants of each). Each variant results in a receptor having distinct conductance, kinetics, agonist and antagonist affinity, and modulatory sites. Intriguingly, subunit variants are differentially expressed during development and in different brain regions.


Physiology_Levy

Physiology_Levy. GABA has two separate ionotropic receptors (GABAA and GABAC) coded for by distinct sets of genes. Like glycine receptors, both control a Cl− channel. GABAA receptors are heteromers generated from seven classes of subunits, three of which have multiple members. The most common configuration is α1, β2, γ2 in a 2:2:1 stoichiometry, which may account for 80% of the receptors; however, many other heteromers are found in the brain. As with glycine, different subunits confer distinct properties on the receptor. For example, GABAA receptors are the targets of two major classes of drugs: benzodiazepines and barbiturates. Benzodiazepines (e.g., diazepam) are widely used antianxiety and relaxant drugs. Barbiturates are used as sedatives and anticonvulsants. Both classes of drugs bind to distinct sites on the α subunits of GABAA receptors and enhance opening of the receptors’ Cl− channels in response to GABA. The sedative and anticonvulsant actions of benzodiazepines appear to be mediated by


Physiology_Levy

Physiology_Levy. sites on the α subunits of GABAA receptors and enhance opening of the receptors’ Cl− channels in response to GABA. The sedative and anticonvulsant actions of benzodiazepines appear to be mediated by receptors with the α1 subunit, whereas the anxiolytic effects reflect binding to receptors with the α2 subunit. GABAC receptors are structurally similar to GABAA receptors but have a distinct pharmacological profile (e.g., they are not affected by benzodiazepines) and are coded for by a separate set of genes (ρ1, ρ2, and ρ3).


Physiology_Levy

Physiology_Levy. The GABAB receptor is a metabotropic receptor. Binding of GABA to this receptor activates a heterotrimeric GTP-binding protein (G protein; see ), which leads to activation of K+ channels and hence hyperpolarization of the postsynaptic cell, as well as inhibition of Ca++ channels (when located presynaptically) and thus a reduction in release of transmitter. Excitatory Amino Acid Receptors: Glutamate


Physiology_Levy

Physiology_Levy. Glutamate has both ionotropic and metabotropic receptors. Based on pharmacological properties and subunit composition, several distinct ionotropic receptor subtypes are recognized: AMPA, kainate, and NMDA. Overall, there are 18 known genes that code for glutamate subunits for the ionotropic glutamate receptors. The genes are divided into several families (AMPA, kainate, NMDA, and δ) that essentially correspond to the pharmacological subtypes of receptors. Each glutamate receptor is a tetramer. Thus, there is a certain correspondence between the genes and the receptor types that are formed. For example, AMPA receptors are formed from GluR1 to GluR4 subunits, kainate receptors require either KA1 or KA2 and GluR5 to GluR7 subunits, and NMDA receptors all have NR1 subunits plus some combination of NR2 and NR3 subunits. As was mentioned for the other receptors, the receptor properties vary with subunit composition. Ionotropic glutamate receptors are excitatory and contain a


Physiology_Levy

Physiology_Levy. some combination of NR2 and NR3 subunits. As was mentioned for the other receptors, the receptor properties vary with subunit composition. Ionotropic glutamate receptors are excitatory and contain a cationic-selective channel. Thus, all the channels are permeable to Na+ and K+ , but only a subset allow Ca++ to pass.


Physiology_Levy

Physiology_Levy. AMPA and kainate receptors behave as classic ligand-gated channels as already discussed; on binding of glutamate to the receptor, the channel opens and allows current to flow, thereby generating an EPSP. NMDA channels are different. First, they require binding of both glutamate and glycine to open. Second, they display voltage sensitivity as a result of Mg++ blockade of the channel. That is, at resting (or more negative) membrane potentials, a Mg++ ion blocks the entrance to the channel so that even when glutamate and glycine are bound, no current flows through the channel. However, if the cell is depolarized (either experimentally by injection of current through an electrode or by other EPSPs), the Mg++ block is relieved and current can flow through the channel. A further interesting feature of NMDA channels is that they are generally permeable to Ca++, which can act as a second messenger. The combination of voltage sensitivity and Ca++ permeability of the NMDA channels has led to


Physiology_Levy

Physiology_Levy. of NMDA channels is that they are generally permeable to Ca++, which can act as a second messenger. The combination of voltage sensitivity and Ca++ permeability of the NMDA channels has led to hypotheses concerning their role in learning and memory-related functions (see


Physiology_Levy

Physiology_Levy. Eight genes coding for metabotropic glutamate receptors have been identified and classified into three groups. Group I receptors are found postsynaptically, whereas groups II and III are found presynaptically. These receptors generate slow EPSPs, but probably at least as importantly, they trigger second messenger cascades (see


Physiology_Levy

Physiology_Levy. Purines have two receptor families: an ionotropic (P2X) and a metabotropic (P2Y) family. There are seven identified P2X subunit types that form channels, and they represent their own superfamily of ligand-gated channels. Each subunit has only two transmembrane domains, with the loop between these two domains located extracellularly and containing the ATP binding site. The receptors are heterotrimers or homotrimers or hexamers. In general, these receptors form a cationic channel that is permeable to Na+ , K+ , and Ca++ . The distribution of subunits in the brain varies significantly, with some subunits having a widespread distribution (P2X2) and others being quite limited (P2X3 is present mostly on cells involved in pain-related pathways).


Physiology_Levy

Physiology_Levy. Metabotropic purine receptors are coded for by 10 genes, but only 6 are expressed in the human CNS. They have the typical features of G protein–coupled receptors and are known to activate K+ currents and modulate both NMDA and voltage-gated Ca++ currents. An interesting localization distinction between P2X and P2Y receptors is that although both are present on neurons, the latter dominates on astrocytes. Finally, in addition to the P2X and P2Y receptors, which respond to ATP, there are adenosine receptors that respond to the adenosine that is released after the enzymatic breakdown of ATP. These receptors are located presynaptically and act to inhibit synaptic transmission by inhibiting influx of Ca++ . Biogenic Amine Receptors: Serotonin, Dopamine, Noradrenaline, Adrenaline, Histamine


Physiology_Levy

Physiology_Levy. Biogenic Amine Receptors: Serotonin, Dopamine, Noradrenaline, Adrenaline, Histamine With the exception of one class of serotonin receptors (5-HT3) that are part of the cys-loop ionotropic family, receptors for the various biogenic amines are all metabotropic-type receptors. Thus, these neurotransmitters tend to act on relatively long time scales by generating slow synaptic potentials and by initiating second messenger cascades. Agonists and blockers of many of these receptors are important clinical tools for treating various neurological and psychiatric disorders. The role of different dopamine receptors in basal ganglia disorders will be covered in the motor systems (see


Physiology_Levy

Physiology_Levy. As is the case with the biogenic amines, receptors for the various peptides are essentially all of the metabotropic type and are coupled to G proteins that mediate effects via second messenger cascades. It is worth mentioning again that studies consistently show a mismatch between the locations of terminals containing a particular peptide and the receptors for it. Thus, these receptors are often activated by neurotransmitter diffusing through the extracellular space rather than at synapses. This implies that these receptors will experience much lower concentrations of agonist, and indeed, they are very sensitive to their agonists.


Physiology_Levy

Physiology_Levy. Unlike the other neurotransmitters that were covered, NO and CO do not bind to receptors. One way they do affect cell activity is to activate enzymes involved in second messenger cascades, such as guanylyl cyclase. In addition, NO has been shown to modify the activity of other proteins, such as NMDA receptors and the Na+,K+-ATPase pump, by nitrosylating them. 1. Both electrical and chemical synapses are important means of cellular communication in the mammalian nervous system. 2. Electrical synapses directly connect the cytosol of two neurons and allow rapid bidirectional current flow between neurons. They act as low-pass filters. 3. Gap junctions are the morphological correlate of electrical synapses. Gap junctions contain channels formed by hemichannels called connexons. Connexons are formed by proteins called connexins. 4.


Physiology_Levy

Physiology_Levy. Gap junctions are the morphological correlate of electrical synapses. Gap junctions contain channels formed by hemichannels called connexons. Connexons are formed by proteins called connexins. 4. Standard chemical synaptic transmission involves the release of transmitter from a presynaptic terminal, diffusion of transmitter across a synaptic cleft, and binding of the transmitter to receptors on the apposed postsynaptic membrane. 5. Entry of calcium into the presynaptic terminal triggers the release of neurotransmitter. Release of neurotransmitter is quantal, as first demonstrated by the recording of mEPPs at the frog neuromuscular junction. 6. Transmitter is packaged into synaptic vesicles in the presynaptic terminal. The vesicles are the quantal elements. That is, the release of transmitter from one vesicle causes a mEPP at the neuromuscular junction or, equivalently, one mPSP at a central synapse. 7.


Physiology_Levy

Physiology_Levy. 7. Many proteins are involved in priming, docking, and fusion of synaptic vesicles. Synaptotagmin is the Ca++ sensor for triggering vesicle fusion. 8. Excitatory and inhibitory synapses increase or decrease, respectively, the probability that the postsynaptic neuron will spike. 9. The reversal potential is the membrane potential at which net current flow through a ligand-gated channel reverses. Excitatory synapses generate depolarizing potentials (EPSPs) that have reversal potentials positive to the spike threshold, most often as a result of the opening of nonselective cation channels. 10. Inhibitory synapses generate IPSPs that have reversal potentials more negative than the spike threshold but not necessarily negative to the resting potential. Inhibitory synapses can decrease spike probability by two mechanisms: hyperpolarization of the membrane and a decrease in the input resistance of the neuron, leading to a shunt of synaptic currents.


Physiology_Levy

Physiology_Levy. Alabi AA, Tsien RW. Perspectives on kiss-and-run: role in exocytosis, endocytosis, and neurotransmission. Annu Rev Physiol. 2013;75:393-422. 11. The process by which a neuron decides to fire an action potential as a result of its inputs is referred to as synaptic integration. The summation of EPSPs and IPSPs can be highly nonlinear and depends on many factors, including the geometry of the dendritic tree, location of the synaptic inputs relative to the initial segment, and the passive (RC) and active membrane properties of the cell. 12. The efficacy of synaptic transmission depends on the timing and frequency of action potentials in the presynaptic neuron. Facilitation, posttetanic potentiation, and long-term potentiation are examples of increased efficacy of synaptic transmission in response to previous multiple stimulations of a synapse. Long-term depression is an example of reduced efficacy resulting from previous activation of the synapse. 13.


Physiology_Levy

Physiology_Levy. 13. The nervous system uses hundreds of neurotransmitters. Neurotransmitters can be subdivided into a few broad functional classes: small-molecule transmitters (acetylcholine, amino acids, biogenic amines, and purines), peptides, and gases (CO, NO). The action of a neurotransmitter depends on its postsynaptic receptors. Most nongaseous transmitters have both ionotropic and metabotropic receptors. 14. Small-molecule transmitters act locally, mainly across a single synapse, and their duration of action is limited by reuptake and enzymatic degradation. Peptides can diffuse from their presynaptic release site and thus have the potential to affect all cells within a local region. Gaseous transmitters are free to diffuse from their release site. 15. Ionotropic receptors contain an ion channel whose state (open versus closed) is gated by the binding of neurotransmitter to the receptor. Metabotropic receptors activate second messengers on binding neurotransmitter. 16.


Physiology_Levy

Physiology_Levy. 16. Many synapses can release multiple types of transmitters, and which ones they release depends on the activity pattern of the terminal. Co-released transmitters may function independently or act synergistically or antagonistically. Fain GL. Molecular and Cellular Physiology of Neurons. 2nd ed. Cambridge, MA: Harvard University Press; 2014. Hille B. Ion Channels of Excitable Membranes. 3rd ed. Sunderland, MA: Sinauer Associates; 2001. Upon completion of this chapter the student should be able to answer the following questions: 1. What are the major modalities of somatosensory information, and what are the corresponding pathways that convey each from the periphery to the primary somatosensory cortex? 2. What body regions and categories of information are the exteroceptive, proprioceptive, and enteroceptive divisions of the somatosensory system associated with? 3. What are the main receptors for fine/discriminatory touch sensations? 4.


Physiology_Levy

Physiology_Levy. 3. What are the main receptors for fine/discriminatory touch sensations? 4. What types of somatosensory information does the cerebellum receive? 5. What are the main receptors for pain and temperature touch sensations? 6. What is the phenomenon of referred pain? 7. What proteins are involved in transducing different categories of somatosensory information? 8. How do descending pathways act to regulate the flow of activity in ascending somatosensory pathways?


Physiology_Levy

Physiology_Levy. What proteins are involved in transducing different categories of somatosensory information? 8. How do descending pathways act to regulate the flow of activity in ascending somatosensory pathways? he somatosensory system provides information to the central nervous system (CNS) about the state of the body and its contact with the world. It does so by using a variety of sensory receptors that transduce mechanical (pressure, stretch, and vibrations) and thermal energies into electrical signals. These electrical signals are called generator or receptor potentials and occur in the distal ends of axons of first-order somatosensory neurons, where they trigger action potential trains that reflect information about the characteristics of the stimulus. The cell bodies of these neurons are located in dorsal root ( Fig. 7.1A Fig. 4.8 ) and cranial nerve ganglia.


Physiology_Levy

Physiology_Levy. Fig. 7.1A Fig. 4.8 ) and cranial nerve ganglia. Each ganglion cell gives off an axon that after a short distance divides into a peripheral process and a central process. The peripheral processes of the ganglion cells coalesce to form peripheral nerves. A purely sensory nerve will have only axons from such ganglion cells; however, mixed nerves, which innervate muscles, will contain both afferent (sensory) fibers and efferent (motor) fibers. At the target organ the peripheral process of an afferent axon divides repeatedly, with each terminal branch ending as a sensory receptor. In most cases the free nerve ending by itself forms a functional receptor, but in some the nerve ending is encapsulated by accessory cells and the entire structure (axon terminal plus accessory cells) forms the receptor.


Physiology_Levy

Physiology_Levy. The central axonal process of the ganglion cell either enters the spinal cord via a dorsal root or enters the brainstem via a cranial nerve. A central process typically gives rise to numerous branches that may synapse with a variety of cell types, including second-order neurons of the somatosensory pathways. The terminal location of these central branches varies depending on the type of information being transmitted. Some terminate at or near the segmental level of entry, whereas others project to brainstem nuclei.


Physiology_Levy

Physiology_Levy. Second-order neurons that are part of the pathway for the perception of somatosensory information project to specific thalamic nuclei where the third-order neurons reside. These neurons in turn project to the primary somatosensory cortex (S-I). Within the cortex, somatosensory information is processed in S-I and in numerous higher-order cortical areas. Somatosensory information is also transmitted by other second-order neurons to the cerebellum for use in its motor coordination function. The organization of the somatosensory system is quite distinct from that of the other senses, which has both experimental and clinical implications. In particular, other sensory systems have their receptors localized to a single organ, where they are present at high density (e.g., the eye for the visual system). In contrast, somatosensory receptors are distributed throughout the body (and head). Subdivisions of the Somatosensory System


Physiology_Levy

Physiology_Levy. Subdivisions of the Somatosensory System The somatosensory system receives three broad categories of information based on the distribution of its receptors. Its exteroceptive division is responsible for providing information about contact of the skin with objects in the external world, and a variety of cutaneous mechanoceptive, nociceptive (pain), and thermal receptors are used for this purpose. Understanding this division will be the main focus of this chapter. The proprioceptive component provides information about body and limb position and movement and relies primarily on receptors found in joints, muscles, and tendons. The ascending central pathways that originate CHAPTER 7 The Somatosensory System 109


Physiology_Levy

Pain, temperature, crude touch 7 • Fig.

Physiology_Levy. Pain, temperature, crude touch 7 • Fig.


Physiology_Levy

Physiology_Levy. 7.1 Ascending somatosensory pathways from the body. A, First-, second-, and third-order neurons are shown for the two main pathways conveying cutaneous information from the body to the cerebral cortex: the dorsal column/medial lemniscal and the spinothalamic pathways. Note that the axon of the second-order neuron crosses the midline in both cases, so sensory information from one side of the body is transmitted to the opposite side of the brain, but the levels in the neuraxis at which this takes place are distinct for each pathway. Homologous central pathways for the head originate in the trigeminal nucleus and are described in text, but they are not illustrated for clarity. B, Major spinocerebellar pathways carrying tactile and proprioceptive information to the cerebellum from the upper and lower parts of the body. Again, pathways from the head originate in the trigeminal nuclei but are not shown for clarity. A midsagittal view of the nervous system shows the levels of the spinal and


Physiology_Levy

Physiology_Levy. nd lower parts of the body. Again, pathways from the head originate in the trigeminal nuclei but are not shown for clarity. A midsagittal view of the nervous system shows the levels of the spinal and brainstem cross sections in panels A and B.


Physiology_Levy

Physiology_Levy. with them and that underlie conscious and unconscious proprioceptive functions will be covered in this chapter. However, because these receptors also initiate pathways that are intimately involved in the control of movement, they will be discussed again in . Finally, the enteroceptive division has receptors for monitoring the internal state of the body and includes mechanoreceptors that detect distention of the gut or fullness of the bladder. Aspects of enteroceptive division are also covered in as they are related to autonomic functions.


Physiology_Levy

Physiology_Levy. The somatosensory pathways can also be classified by the type of information they carry. Two broad functional categories are recognized, each of which subsumes several somatosensory submodalities. Fine discriminatory touch sensations include light touch, pressure, vibration, flutter (low-frequency vibration), and stretch or tension. The second major functional group of sensations is that of pain and temperature. Submodalities here include both noxious and innocuous cold and warm sensations and mechanical and chemical pain. Itch is also closely related to pain and appears to be carried by particular fibers associated with the pain system.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Of great importance experimentally, the afferent fibers that convey these somatosensory submodalities to the CNS are different sizes. Recall that the compound action potential recorded from a peripheral nerve (see 5.1 ) consists of a series of peaks, thus implying that the diameters of axons in a nerve are grouped rather than being uniformly distributed. Information about tactile sensations is carried primarily by large-diameter myelinated fibers in the Aβ class, whereas pain and temperature information travels via small-diameter, lightly myelinated (Aδ) and unmyelinated (C) fibers. It is possible to block or stimulate selectively a class of axons of particular size, thereby allowing study of the different somatosensory submodalities in isolation. Innervation of the Skin


Physiology_Levy

Physiology_Levy. Innervation of the Skin The skin is an important sensory organ and not surprisingly is richly innervated with a variety of afferents. We first consider the afferent types related to fine or discriminatory touch sensations. These afferents are related to what are called low-threshold mechanoreceptors. Nociceptor and thermoceptor innervation will be considered separately in a later section of this chapter. To study the responsiveness of tactile receptors, a small-diameter rod or wire is used to press on a localized region of skin. With this technique, two basic types of responses may be seen when recording sensory afferent fibers: fast-adapting (FA) and slow-adapting (SA) responses (


Physiology_Levy

Physiology_Levy. Fig. 7.2). They are present in similar quantities. FA fibers will show a short burst of action potentials when the rod first pushes down on the skin, but then they will cease firing despite continued application of the rod. They may also burst at the cessation of the stimulus (i.e., when the rod is lifted off). In contrast, SA units will start firing action potentials (or increase their firing rate) at the onset of the stimulus and continue to fire until the stimulus ends.


Physiology_Levy

Physiology_Levy. Both the FA and SA afferent classes can be subdivided on the basis of other aspects of their receptive fields, where receptive field is defined as the region of skin from which stimuli can evoke a response (i.e., change the firing of the afferent axon). Type 1 units have small receptive fields with well-defined borders. Particularly for glabrous skin (i.e., hairless skin, such as on the palms of the hands and soles of the feet), the receptive field has a circular or ovoid shape within which there is relatively uniform and high sensitivity to stimuli that decreases sharply at the border ( Fig. 7.3). Type 1 units, particularly SA1 units, respond best to edges. That is, a larger response is elicited from them when the edge of a stimulus cuts through their receptive field than when the entire receptive field is indented by the stimulus.


Physiology_Levy

Physiology_Levy. Type 2 units have wider receptive fields with poorly defined borders and only a single point of maximal sensitivity, from which there is a gradual reduction in sensitivity with distance (see Fig. 7.3 ). For comparison a type 1 unit’s receptive field typically will cover approximately four papillary ridges in the fingertip, whereas a type 2 unit will have a receptive field that covers most or all of a finger. Thus, four main classes of low-threshold mechanosensitive afferents have been identified physiologically (FA1, FA2, SA1, and SA2). Peripherally these axons may terminate either as free nerve endings, associated with a hair follicle, or within a specialized receptor structure made up of supporting cells. For glabrous skin the four afferent classes have been associated with four specific types of histologically identified receptor structures whose locations and physical


Physiology_Levy

Physiology_Levy. CHAPTER 7 The Somatosensory System •Fig. 7.2 Cutaneousmechanoreceptorsandtheresponsepatternsofassociatedafferentfibers.A,Schematicviewsofglabrous(hairless)andhairyskinshowingthearrangementofthevariousmajormechanoreceptors.B,Firingpatternsofthedifferentcutaneouslow-thresholdmechanosensitiveafferentfibersthatinnervatethevariousencapsulatedreceptorsoftheskin.(TracesinBarebasedondatafromJohanssonRS,VallboÅB.Trends Neurosci 1983;6:27.) •Fig. 7.3 Receptivefieldcharacteristicsfortype1andtype2sensoryafferents.Plotsinthetoprowshowthethresholdlevelofforceneededtoevokearesponseasafunctionofthedistanceacrossthereceptivefield.Receptivefieldsizeisshownonthehandbeloweachplot.(DatafromJohanssonRS,VallboÅB.Trends Neurosci 1983;6:27.) characteristics help explain the firing properties of these sensory afferents. FA1 afferents terminate in Meissner’s corpuscles, whereas SA1 afferents terminate in Merkel’s disks. In both cases the receptor is located relatively superficially, either in the basal


Physiology_Levy

Physiology_Levy. afferents. FA1 afferents terminate in Meissner’s corpuscles, whereas SA1 afferents terminate in Merkel’s disks. In both cases the receptor is located relatively superficially, either in the basal epidermis (Merkel) or just below the epidermis (Meissner) (see


Physiology_Levy

Physiology_Levy. Fig. 7.2 ). These receptors are small and oriented to detect stimuli pressing down on the skin surface just above them, thus allowing SA1 and FA1 afferents to have small receptive fields. For glabrous skin, SA2 afferents terminate in Ruffini endings and FA2 afferents end in Pacinian corpuscles. Both of these receptors lie deeper in the dermis and connective tissue and therefore are sensitive to stimuli applied over much larger territory. The capsules of both Pacinian and Meissner receptors act to filter out slowly changing or steady stimuli, thus making these afferents selectively sensitive to changing stimuli.


Physiology_Levy

Physiology_Levy. For hairy skin, the relationship between receptors and afferent classes is similar to that of glabrous skin. SA1 and SA2 fibers connect to Merkel and Ruffini endings, the same as for glabrous skin. Pacinian corpuscles also underlie the properties of FA2 afferents; however, they are not found in hairy skin but instead are located in deep tissues surrounding muscles and blood vessels. There is not an exact analogue to the FA1 afferents. Rather there are hair units, which are afferents whose free endings wrap around hair follicles (see Fig. 7.2 ). Each such hair unit will connect with about 20 hairs to produce a large ovoid or irregularly shaped receptive field. These units are extremely sensitive to movement of even a single hair. There are also field units that respond to touch of the skin, but unlike FA1 units, they have large receptive fields.


Physiology_Levy

Physiology_Levy. Several psychophysical and neural coding questions can be related to the receptive field properties and sensitivities of the various categories of afferents. For example, is the threshold of perception of tactile stimuli due to the sensitivity of the peripheral receptors or to central processes? In fact, by using microneurography it is possible to show that a single spike in an FA1 afferent from the finger can be perceived, thus indicating that the receptors limit the sensitivity; however, for other skin regions, perception is more dependent on central factors such as attention.


Physiology_Levy

Physiology_Levy. An important behavioral and clinical measure of somatosensory function is spatial acuity or two-point discrimination. Clinically a doctor will apply two needle-like points simultaneously to the skin of a patient. The patient will generally perceive the points as two distinct stimuli as long as they are farther apart than some threshold distance, which varies across the body. The best discrimination (shortest threshold distance) is at the fingertips. Type 1 units underlie spatial acuity, which is not surprising given the smaller receptive fields of type 1 units than type 2 units. Moreover, the threshold distance for a region of skin is most closely related to its density of type 1 units because these units have similarly sized receptive fields throughout the glabrous skin, but their density falls off from fingertip to palm to forearm, and this fall-off correlates with the rise in threshold distance. Note that this variation in innervation density also matches the overall sensitivity of


Physiology_Levy

Physiology_Levy. falls off from fingertip to palm to forearm, and this fall-off correlates with the rise in threshold distance. Note that this variation in innervation density also matches the overall sensitivity of different skin regions to cutaneous stimuli.


Physiology_Levy

Physiology_Levy. The relationship of the firing rates in the various afferent classes to perceived stimulus quality is another important issue that has been addressed with microneurographic techniques. When a single SA fiber is stimulated with brief current pulses such that each pulse triggers a spike, a sensation of steady pressure is felt at the receptive field area of that fiber. As pulse frequency is increased a concurrent increase in pressure is perceived. Thus the firing rate in SA fibers codes for the force of the tactile stimulus. As another example, when an FA fiber is repetitively stimulated, a sensation of tapping results first, and as the frequency of the stimulus is increased, the sensation turns to one of vibration. Interestingly, in neither case does the stimulus change its qualitative character—for example, to a feeling of pain—so long as the stimulus activates only a particular fiber class. This is evidence that pain is a distinct submodality that uses a set of fibers distinct from


Physiology_Levy

Physiology_Levy. example, to a feeling of pain—so long as the stimulus activates only a particular fiber class. This is evidence that pain is a distinct submodality that uses a set of fibers distinct from those used by low-threshold mechanoreceptors.


Physiology_Levy

Physiology_Levy. These findings illustrate an important principle of sensory systems called labeled line. The idea is that the quality (i.e., modality) of a particular sensation results from the fact that it is conveyed to the CNS by a specific set of afferents that have a distinct set of targets in the nervous system. Alterations in activity in these afferents will therefore change only quantitative aspects of the sensation. As will be seen in more detail later, the various somatosensory submodalities (i.e., information arising from FA and SA mechanoreceptors, proprioceptors, and nociceptors) appear to use relatively separate dedicated cell populations even at relatively high levels of the CNS such as the thalamus and primary somatosensory cortex. Innervation of the Body


Physiology_Levy

Physiology_Levy. Innervation of the Body Axons of the peripheral nervous system (PNS) enter or leave the CNS through the spinal roots (or through cranial nerves). The dorsal root of a given spinal segment is composed entirely of the central processes of its associated dorsal root ganglion cells. The ventral root consists chiefly of motor axons, including α and γ motor neuron axons (see ), and at certain segmental levels, autonomic preganglionic axons (see CHAPTER 7 The Somatosensory System The pattern of innervation is determined during embryo-logical development. In adults a given dorsal root ganglion supplies a specific cutaneous region called a dermatome. Many dermatomes become distorted during development, chiefly because of rotation of the upper and lower extremities as they are formed, but also because humans maintain an upright posture. However, the sequence of dermatomes can readily be understood if depicted on the body of a person in a quadrupedal position ( Fig. 7.4).


Physiology_Levy

Physiology_Levy. Fig. 7.4). Although a dermatome receives its densest innervation from the corresponding spinal cord segment, collaterals of afferent fibers from the adjacent spinal segments also supply the dermatome. Thus transection of a single dorsal root causes little sensory loss in the corresponding dermatome. Anesthesia of any given dermatome requires interruption of several adjacent dorsal roots. Acommondiseasethatillustratesthedermatomalorganizationofthedorsalrootsisshingles. Shinglesistheresultofreactivationoftheherpeszostervirus,whichtypicallycauseschickenpoxduringtheinitialinfection.Duringtheinitialinfectionthevirusinfectsdorsalroot(andcranialnerve)ganglioncells,whereitcanremainlatentforyearstodecades.Whenthevirusreactivates,thecellsofthatparticulardorsalrootganglionbecomeinfected,andthevirustravelsalongtheperipheralaxonbranchesandgivesrisetoapainfuloritchyrashthatisconfinedtoonesideofthebody(endsatthemidline)inadermatomal,belt-likedistributionortothedistributionofacranialnerve.


Physiology_Levy

Physiology_Levy. Within the dorsal roots, fibers are not randomly distributed. Rather the large myelinated primary afferent fibers assume a medial position in the dorsal root, whereas the small myelinated and unmyelinated fibers are more lateral. The large medially placed afferent fibers enter the dorsal column, where they bifurcate into rostrally and caudally directed branches. These branches give off collaterals that terminate in several neighboring segments. The rostral branch also ascends to the medulla as part of the dorsal column–medial lemniscus pathway. The axonal branches that terminate locally in the spinal cord gray matter transmit sensory information to neurons in the dorsal horn and also provide the afferent limb of reflex pathways (see Chapter 9). Innervation of the Face


Physiology_Levy

Physiology_Levy. Chapter 9). Innervation of the Face The arrangement of primary afferent fibers that supply the face is comparable to that of fibers that supply the body and is provided for primarily by fibers of the trigeminal nerve. Peripheral processes of neurons in the trigeminal ganglion (also called the gasserian or semilunar ganglion) pass through the ophthalmic, maxillary, and mandibular divisions of the trigeminal nerve to innervate dermatome-like regions of the face. These fibers carry both tactile information and pain and temperature information. The trigeminal nerve •Fig. 7.4 A,Dermatomesrepresentedonadrawingofapersonassumingaquadrupedalposition.NotenerveC1generallyhaslittleornosensorycomponent,andtheunlabeledportionoftheheadandthefaceareinnervatedbysensoryfibersofthecranialnerves,primarilythetrigeminalnerve.B,SagittalviewofthespinalcordshowingtheoriginofnervescorrespondingtoeachofthedermatomesshowninA.


Physiology_Levy

Physiology_Levy. Thetrigeminalnuclearcomplexconsistsoffourmaindivisions,threeofwhicharesensory.Thethreesensorydivisions(fromrostraltocaudal)arethemesencephalic, chief (ormain)sensory, anddescending (orspinal)trigeminal nuclei. Thelattertwoaretypicalsensorynucleiinthatthecellbodiescontainedinthemaresecond-orderneurons.Themesencephalicnucleusactuallycontainsfirst-orderneuronsandthusisanalogoustoadorsalrootganglion.Thefourthdivisionofthetrigeminalcomplexisthemotornucleusofthetrigeminalnerve,whosemotorneuronsprojecttoskeletalmusclesoftheheadviathetrigeminalnerve(see Fig.4.6D–E also innervates the teeth, the oral and nasal cavities, and the cranial dura mater.


Physiology_Levy

Physiology_Levy. Fig.4.6D–E also innervates the teeth, the oral and nasal cavities, and the cranial dura mater. The central processes of trigeminal ganglion cells enter the brainstem at the midpontine level, which also corresponds to the level of the chief sensory trigeminal nucleus (nucleus of cranial nerve V). Some axons terminate in this nucleus (primarily large-caliber axons carrying the information needed for fine discriminative touch), whereas others (intermediateand small-caliber axons that carry information about touch as well as pain and temperature) form the descending trigeminal tract, which descends through the medulla just lateral to the descending trigeminal nucleus. As the tract descends, axons peel off and synapse in this nucleus.


Physiology_Levy

Physiology_Levy. Proprioceptive information is also conveyed via the trigeminal nerve; however, in this unique case the cell bodies of the first-order fibers are located within the CNS in the mesencephalic portion of the trigeminal nucleus. The central processes of these neurons terminate in the motor trigeminal nucleus (to subserve segmental reflexes equivalent to the segmental spinal cord reflexes [see ]), the reticular formation, and the chief sensory trigeminal nucleus.


Physiology_Levy

Physiology_Levy. As may already be clear, information related to the different somatosensory submodalities travels to a large extent into the CNS via distinct sets of axons and targets different structures in the spinal cord and brainstem. Within the CNS this segregation continues as the information travels via separate pathways up the spinal cord and brainstem. For example, from the body, fine discriminatory touch information is conveyed by the dorsal column–medial lemniscus pathway, whereas pain, temperature, and crude touch information is conveyed by the anterolateral system.


Physiology_Levy

Physiology_Levy. Proprioceptive information is transmitted by yet another route that partially overlaps with the dorsal column–medial lemniscal pathway. Note, however, that this functional segregation is not absolute, so, for example, there can be some recovery of discriminative touch ability after a lesion of the dorsal columns. The anterolateral system will be discussed in the section on pain because it is the critical pathway for that information. Here, the central pathways CHAPTER 7 The Somatosensory System for discriminatory touch and proprioception are considered in detail. This pathway is shown in its entirety in Fig. 7.1A.


Physiology_Levy

Physiology_Levy. Fig. 7.1A. The dorsal columns are formed by ascending branches of the large myelinated axons of dorsal root ganglion cells (the first-order neurons). These axons enter at each spinal segmental level and travel rostrally up to the caudal medulla to synapse in one of the dorsal column nuclei: the nucleus gracilis, which receives information from the lower part of the body and leg, and the nucleus cuneatus, which receives information from the upper part of the body and arm. Note that across the dorsal columns and across the dorsal column nuclei there is a somatotopic representation of the body, with the legs represented most medially, followed by the trunk and then the upper limb. This somatotopy is a consequence of newly entering afferents being added to the lateral border of the dorsal funiculus as the spinal cord is ascended. Such somatotopic maps are present at all levels in the somatosensory system, at least through the primary sensory cortices.


Physiology_Levy

Physiology_Levy. The dorsal column nuclei are located in the medulla and contain the second-order neurons of the pathway for discriminatory touch sensation. These cells respond similarly to the primary afferent fibers that synapse on them (see the earlier description of afferent types). The main differences between the responses of dorsal column neurons and primary afferent neurons are as follows: (1) dorsal column neurons have larger receptive fields because multiple primary afferent fibers synapse on a given dorsal column neuron, (2) dorsal column neurons sometimes respond to more than one class of sensory receptor because of the convergence of several different types of primary afferent fibers on the second-order neurons, and (3) dorsal column neurons often have inhibitory receptive fields that are mediated through local interneurons.


Physiology_Levy

Physiology_Levy. The axons of dorsal column nuclear projection neurons exit the nuclei and are referred to as the internal arcuate fibers as they sweep ventrally and then medially to cross the midline at the same medullary level as the nuclei. Immediately after crossing the midline, these fibers form the medial lemniscus (see Fig. 4.6C–E ), which projects rostrally to the thalamus. Knowledge of the level of this decussation is clinically important because damage to the dorsal column–medial lemniscal pathway below this level, which includes all of the spinal cord, will produce loss of fine somatosensory discriminatory abilities on the same, or ipsilateral, side of the lesion, whereas lesions above this level will produce contralateral deficits. Moreover, because there is a clear somatotopic arrangement of fibers in the medial lemniscus, localized lesions cause selective loss of fine-touch sensations limited to specific body regions.


Physiology_Levy

Physiology_Levy. The third-order neurons of the pathway are located in the ventral posterior lateral (VPL) nucleus of the thalamus and project to somatosensory areas of the cerebral cortex ( Fig. 7.5 •Fig. 7.5 Diagramofconnectionsfromthesomatosensoryreceivingnucleiofthethalamustothesomatosensorycortexoftheparietallobe.Notetheparallelflowofdifferenttypesofsomatosensoryinformationthroughthethalamusandontothecortex.CS,centralsulcus;S1andS2areprimaryandsecondarysomatosensoryareas,respectively.Note:collectively,areas3a,3b,1,and2arereferredtoasS1.


Physiology_Levy

Physiology_Levy. The dorsal column–medial lemniscus pathway conveys information about fine-touch and vibratory sensations. This information is critical for many of the discriminatory tactile abilities we have. For example, spatial acuity is lowered by damage to this pathway, and the ability to identify objects by their shape and texture can be lost by damage to this pathway. Clinically, one may test for impaired graphesthesia, or the ability to recognize letters or numbers traced on the skin, or for loss of the ability to tell the direction of a line drawn across the skin. Importantly, some tactile function remains even after complete loss of the dorsal columns, and awareness and localization of nonnoxious tactile stimuli can still occur. Thus at least some of the information carried by the dorsal column pathway is also conveyed by additional ascending pathways. In contrast to the severe deficits in discriminatory touch sensation, cutaneous pain and temperature sensations are unaffected by lesions of


Physiology_Levy

Physiology_Levy. pathway is also conveyed by additional ascending pathways. In contrast to the severe deficits in discriminatory touch sensation, cutaneous pain and temperature sensations are unaffected by lesions of the dorsal columns. However, visceral pain is substantially diminished by damage to the dorsal columns.


Physiology_Levy

Physiology_Levy. Trigeminal Pathway for Fine-Touch Sensation From the Face Primary afferent fibers that supply the face, teeth, oral and nasal cavities, and cranial meninges synapse in several brainstem nuclei, including the main sensory nucleus and the descending nucleus of the trigeminal nerve. The pathway through the main sensory nucleus resembles the dorsal column–medial lemniscus pathway. This sensory nucleus relays tactile information to the contralateral ventral posterior medial (VPM) thalamic nucleus by way of the trigeminothalamic tract. Third-order neurons in the VPM nucleus project to the facial area of the somatosensory cortex. Proprioceptors provide information about the positions and movement of parts of the body. In addition to being used for local reflexes (see


Physiology_Levy

Physiology_Levy. Proprioceptors provide information about the positions and movement of parts of the body. In addition to being used for local reflexes (see Chapter 9), this information has two main targets, the cerebellum and the cerebral cortex. The cerebellum uses this information for its motor coordination functions. The information sent to the cerebral cortex is the basis for conscious awareness of our body parts (e.g., position of our hand), which is referred to as kinesthesia. The major pathways by which somatosensory information is brought to the cerebellum are shown in


Physiology_Levy

Physiology_Levy. The major pathways by which somatosensory information is brought to the cerebellum are shown in Fig. 7.1B . These pathways carry both cutaneous and proprioceptive information to the cerebellum. For the trunk and lower limb, the pathway starts with dorsal root ganglion cells whose axons synapse in Clarke’s column (nucleus dorsalis). The cells of Clarke’s column send their axons into the ipsilateral lateral funiculus to form the dorsal spinocerebellar tract, which enters the cerebellum via the inferior cerebellar peduncle. The ventral spinocerebellar tract also provides somatosensory input from the lower limb to the cerebellum. Note the double decussation of the ventral spinocerebellar pathway (one decussation at the spinal cord levels and a second one in the cerebellar white matter). This double crossing highlights the general rule that each half of the cerebellum is functionally related to the ipsilateral side of the body.


Physiology_Levy

Physiology_Levy. To provide proprioceptive information from the lower limb to the cerebral cortex, the main axons of the dorsal spinocerebellar tract give off a branch in the medulla that terminates in nucleus z, which is just rostral to the nucleus gracilis. The axons of cells from nucleus z then form part of the internal arcuate fibers and medial lemniscus and ascend to the VPL nucleus of the thalamus. The ascending somatosensory pathways to the cerebellum for the upper limb are simpler than those from the lower limb (see Fig. 7.1B ). The route to the cerebellum starts with dorsal root ganglion fibers from the cervical spinal levels that ascend in the cuneate fasciculus to the external cuneate nucleus. The axons of the external cuneate nucleus then form the cuneocerebellar tract, which enters the cerebellum via its inferior peduncle.


Physiology_Levy

Physiology_Levy. The route to the cerebral cortex for proprioceptive information from the upper limb is identical to that for discriminative touch: the dorsal column–medial lemniscal pathway, with a synapse in the cuneate nucleus and then in the VPL nucleus of the thalamus. For the head, proprioceptive input is carried by cells of the mesencephalic nucleus of the trigeminal nerve. Recall that the neurons in this nucleus are actually the cell bodies of the primary afferents that innervate stretch receptors in the muscles of mastication (muscles that move the jaw) and in other muscles of the head. The central processes of these neurons project to the trigeminal motor nucleus for local reflexes or to the nearby reticular formation. Axons from these reticular formation neurons join the trigeminothalamic tract, which terminates in the VPM of the thalamus. There are also trigeminocerebellar pathways for conveying somatosensory (tactile and proprioceptive) information from the head to the cerebellum.


Physiology_Levy

Physiology_Levy. The ventroposterior nuclear complex of the thalamus represents the main termination site for ascending somatosensory information in the diencephalon. It consists of two major nuclei, the VPL and VPM, and a smaller nucleus called the ventral posterior inferior (VPI) (see Fig. 7.5 ). The medial lemniscus forms the main input to the VPL nucleus, and the equivalent trigeminothalamic tract from the main sensory nucleus of the trigeminal nerve forms the main input to the VPM nucleus. These nuclei also receive input conveying pain and temperature information from the spinothalamic or equivalent trigeminothalamic tracts, respectively. The VPI nucleus receives input from the spinothalamic tract. In addition, the spinothalamic tract terminates in parts of the posterior nuclear complex and several other thalamic nuclei.


Physiology_Levy

Physiology_Levy. Single-unit recordings from the ventroposterior complex of nuclei have shown that the responses of many of the neurons in these nuclei to stimuli resemble those of firstand second-order neurons in the ascending tracts. The receptive fields of thalamic cells are small but somewhat larger than those of primary afferent fibers. Moreover, the responses may be dominated by a particular type of sensory receptor. For example, VPL and VPM nuclei have cells whose receptive fields typically reflect input either from one type of cutaneous receptor (FA or SA) or from proprioceptive receptors, as expected from their medial lemniscal input. In contrast, cells of the VPI and posterior nuclei show responses to activation of nociceptors, the main input to the spinothalamic pathway.


Physiology_Levy

Physiology_Levy. Thalamic neurons often have inhibitory as well as excitatory receptive fields. The inhibition may actually take place in the dorsal column nuclei or in the dorsal horn of the spinal cord. However, inhibitory circuits are also situated within the thalamus. For example, the VPL and VPM nuclei contain GABAergic inhibitory interneurons (in primates but not in rodents), and GABAergic inhibitory interneurons in the reticular nucleus of the thalamus project into the VPL and VPM nuclei. (The reticular nucleus of the thalamus is a thin shell of neurons that surrounds much of the thalamus. Thalamocortical and corticothalamic neurons both send axon collaterals to the reticular nucleus, whose neurons then respectively complete feedback and/ or feed-forward inhibitory circuits with neurons in other thalamic nuclei.)


Physiology_Levy

Physiology_Levy. One difference between neurons in the VPL and VPM nuclei and sensory neurons at lower levels of the somatosensory system is that thalamic neuron excitability depends on the stage of the sleep/wake cycle and on the presence or absence of anesthesia. During a state of drowsiness or during barbiturate anesthesia, thalamic neurons tend to undergo an alternating sequence of excitatory and inhibitory postsynaptic potentials. The alternating bursts of discharges in turn intermittently excite neurons in the cerebral cortex. Such patterns of excitation and inhibition result in an α rhythm or in spindling on the electroencephalogram. This alternation of excitatory and inhibitory postsynaptic potentials during these two states may reflect the level of excitation of thalamic neurons by excitatory amino acids that act at NMDA and non-NMDA receptors. It may also reflect inhibition of the thalamic neurons by recurrent pathways through the reticular nucleus.


Physiology_Levy

Physiology_Levy. Thalamic neuron receptive fields are on the side of the body contralateral to the neuron, and the receptive field locations vary systematically across the ventroposterior nuclear complex. That is, the VPL and VPM nuclei are somatotopically organized such that the lower limb is represented most laterally and the upper limb most medially in the VPL nucleus, and the head is represented even more medially in the VPM nucleus. Moreover, the fact that thalamic neurons often receive input from only one class of receptor suggests that there are multiple somatotopic maps laid out across the ventroposterior nuclear complex. That is, there appear to be separate somatotopic maps for SA, FA, and proprioceptive and pain sensations laid out across the ventroposterior nuclear complex.


Physiology_Levy

Physiology_Levy. These maps are not randomly interspersed. As already mentioned, pain sensation is largely mapped across the VPI nucleus. In addition, the cutaneous receptors appear to drive cells located in a central “core” region of the VPL-VPM complex, whereas proprioceptive information is directed to cells that form a “shell” (VPS) around this core. This parallel flow of information into thalamus and then onto the cortex is diagramed in Fig. 7.5 The spinothalamic tract also projects to other thalamic regions, including the posterior nucleus and the central lateral nucleus of the intralaminar complex of the thalamus. The intralaminar nuclei of the thalamus are not somatotopically organized, and they project diffusely to the cerebral cortex as well as to the basal ganglia (see ). The projection of the central lateral nucleus to the S-I cortex may be involved in arousal of this part of the cortex and in selective attention.


Physiology_Levy

Physiology_Levy. Third-order sensory neurons in the thalamus project to the somatosensory cortex. The details of this projection pattern are shown in Fig. 7.5 . The main somatosensory receiving CHAPTER 7 The Somatosensory System areas of the cortex are called the S-I and S-II areas. The S-I cortex (or primary somatosensory cortex) is located on the postcentral gyrus, and the S-II cortex (secondary somatosensory cortex) is in the superior bank of the lateral fissure (see Fig. 7.5


Physiology_Levy

Physiology_Levy. Fig. 7.5 As previously discussed, the S-I cortex, like the somatosensory thalamus, has a somatotopic organization. The S-II cortex also contains a somatotopic map, as do several other less understood areas of the cortex. In the S-I cortex the face is represented in the lateral part of the postcentral gyrus, above the lateral fissure. The hand and the rest of the upper extremity are represented in the dorsolateral part of the postcentral gyrus, and the lower extremity on the medial surface of the hemisphere. A map of the surface of the body and face of a human on the postcentral gyrus is called a sensory homunculus. The map is distorted because the volume of neural tissue devoted to a body region is proportional to the density of its innervation. Thus in humans, the perioral area, the thumb, and other digits take up a disproportionately large expanse of cortex relative to their size.


Physiology_Levy

Physiology_Levy. The sensory homunculus is an expression of place coding of somatosensory information. A locus in the S-I cortex encodes the location of a somatosensory stimulus on the surface of the body or face. For example, the brain knows that a certain part of the body has been stimulated because certain neurons in the postcentral gyrus are activated. The S-I cortex has several morphological and functional subdivisions, and each subdivision has a somatotopic map. These subdivisions were originally described by Brodmann, and they were based on the arrangements of neurons in the various layers of the cortex, as seen in Nissl-stained preparations. The subdivisions are therefore known as Brodmann areas 3a, 3b, 1, and 2 (see ). Cutaneous input dominates in areas 3b and 1, whereas muscle and joint input (proprioceptive) dominates in areas 3a and 2. Thus separate cortical zones are specialized for processing tactile and proprioceptive information (see Fig. 7.5


Physiology_Levy

Physiology_Levy. Fig. 7.5 Within any particular area of the S-I cortex, all the neurons along a line perpendicular to the cortical surface have similar response properties and receptive fields. The S-I cortex is thus said to have a columnar organization. A comparable columnar organization has also been demonstrated for other primary sensory receiving areas, including the primary visual and auditory cortices (see ). Nearby cortical columns in the S-I cortex may process information for different sensory modalities. For example, the cutaneous information that reaches one cortical column in area 3b may come from FA mechanoreceptors, whereas the information that reaches a neighboring column might originate from SA mechanoreceptors.


Physiology_Levy

Physiology_Levy. Besides being responsible for the initial processing of somatosensory information, the S-I cortex also begins higher-order processing such as feature extraction. For example, certain neurons in area 1 respond preferentially to a stimulus that moves in one direction across the receptive field but not in the opposite direction (Fig. 7.6 ). Such neurons presumably contribute to the perceptual ability to recognize the direction of an applied stimulus and could help detect slippage of an object being grasped by the hand. 118 SECTION2Berne & Levy Physiology •Fig. 7.6 Featureextractionbycorticalneurons.Theresponseswererecordedfromaneuroninthesomatosensorycortexofamonkey.Thedirectionofastimuluswasvaried,asshownbythearrowsinthedrawing.NotethattheresponsesweregreatestwhenthestimulusmovedinthedirectionfromUWtoRFandleastfromRWtoUF.F,fingers;R,radialside;U,ulnarside;W,wrist.(FromCostanzoRM,GardnerEP.J Neurophysiol 1980;43:1319.)R W F UW RF RW UF U R U R F U W UF RW F W RF UW 1 second


Physiology_Levy

Physiology_Levy. Effects of Lesions of the Somatosensory Cortex A lesion of the S-I cortex in humans produces sensory changes similar to those produced by a lesion of the somatosensory thalamus. However, usually only a part of the cortex is involved, and thus the sensory loss may be confined, for example, to the face or to the leg, depending on the location of the lesion with respect to the sensory homunculus. The sensory modalities most affected are discriminative touch and position sense. Graphesthesia and stereognosis (i.e., the ability to recognize objects such as coins and keys as they are handled) are particularly disturbed. Pain and thermal sensation may be relatively unaffected, although loss of pain sensation may follow cortical lesions. Conversely, cortical lesions can result in a central pain state that resembles thalamic pain (see “ Effects of Interruption of the Spinotha lamic Tract and Lesions of the Thalamus on Somatosensory


Physiology_Levy

Physiology_Levy. Effects of Interruption of the Spinotha lamic Tract and Lesions of the Thalamus on Somatosensory The sensations of pain and temperature are related and often grouped together because they are mediated by overlapping sets of receptors and are conveyed by the same types of fibers in the PNS and the same pathways in the CNS. One consequence of these labeled lines is that pain sensations in particular are not due to stronger activation of touch pathways, as might naively be thought. This difference is borne out experimentally because if SA afferents, for example, are stimulated more and more frequently, the sensation of tactile pressure becomes stronger but not painful. The axons that carry painful and thermal sensations are members of the relatively slowly conducting Aδ and C classes. However, not all Aδ and C axons carry pain and temperature information; some respond to light touch in a manner similar to what was described for low-threshold mechanoreceptors.


Physiology_Levy

Physiology_Levy. Unlike the case for low-threshold mechanoreceptors in which morphologically distinct receptors correspond to response properties, the Aδ and C axons conveying pain and temperature information appear to originate mostly as “free nerve endings.” (This description is not entirely accurate; the endings are mostly but not entirely covered by Schwann cells.) Despite the lack of distinct morphological specialization associated with their endings, Aδ and C axons constitute a heterogeneous population that is differentially sensitive to a variety of tissue-damaging or thermal stimuli (or both). This ability to sense tissue-damaging stimuli (mechanical, thermal, or chemical) is mediated by what are called nociceptors. These receptors share some features with low-threshold mechanoreceptors but are distinct in many ways, such as the ability to become sensitized (see later). Indeed, there appear to be a significant number of C fibers that are silent or unresponsive to any stimuli until first


Physiology_Levy

Physiology_Levy. are distinct in many ways, such as the ability to become sensitized (see later). Indeed, there appear to be a significant number of C fibers that are silent or unresponsive to any stimuli until first sensitized.


Physiology_Levy

Physiology_Levy. The first functional distinction that may be made in the pain system is between Aδ and C axons. Aδ axons conduct signals faster than C fibers do and are thought to underlie what is called first pain, whereas C fibers are responsible for second pain. Thus after a damaging stimulus, one first feels an initial sharp, pricking, highly localized sensation (first pain) followed by a duller, more diffuse, burning sensation (second pain). Experiments in which Aδ or C fibers were selectively activated demonstrated that activity in Aδ fibers produces sensations similar to first pain and that activity in C fibers produces second pain–like sensations.


Physiology_Levy

Physiology_Levy. Each fiber class in turn forms a heterogeneous group with regard to sensitivity to stimuli. Thus afferents are classified according to both size and their sensitivity to mechanical, thermal, and chemical stimuli. Fibers may have a low or high threshold to mechanical stimulation or be completely insensitive to it. Thermal sensitivity has been classified as responsiveness to warmth, noxious heat, cool, and noxious cold. Note that 43°C and 15°C are the approximate limits above and below which, respectively, thermal stimuli are sensed as painful. Chemical sensitivity to a variety of irritating compounds has been tested, including capsaicin (found in chili peppers), mustard oil, and acids.


Physiology_Levy

Physiology_Levy. Afferent fibers may be sensitive to one or more types of stimuli and have been named accordingly. For example, C fibers sensitive only to high-intensity (damaging) mechanical stimuli are called C mechanosensitive fibers, whereas those sensitive to heat and mechanical stimuli are labeled C mechanoheat-sensitive fibers (also called polymodal fibers). Other identified fiber types include Aδ and C cold-sensitive, Aδ mechanosensitive, and mechanoheat-sensitive fibers. Thus there is quite a variety of afferent types; however, the most common afferent type is the C polymodal fiber, which accounts for nearly half of the cutaneous C fibers. Surprisingly the second most common type is the mechanoheatinsensitive afferent (i.e., an afferent that is not sensitive to noxious stimuli until sensitized—see later).


Physiology_Levy

Physiology_Levy. The central portion of the Aδ and C axons carrying pain and temperature information from the body terminates in the dorsal horn of the spinal cord. The Aδ fibers target lamina I (dorsalmost part of dorsal horn), V (base of dorsal horn), and X (area surrounding central canal) of the gray matter, whereas the C fibers terminate in lamina I and II. The distinct termination patterns of the Aδ and C fibers in the spinal cord suggest that the messages they are carrying to the CNS are kept separated, and this is consistent with our ability to feel two distinct types of pain. The primary afferent termination patterns in the spinal cord are also important because they may help determine the possible interactions pain fibers can have with other afferents and with descending control systems (see later). Indeed, the gate control theory of pain refers to the phenomenon that


Physiology_Levy

Physiology_Levy. CHAPTER 7 The Somatosensory System innocuous stimuli, such as rubbing a hurt area, can block or reduce painful sensations. Such stimulation activates the large-diameter (Aα and Aβ) fibers, and their activity leads to release of GABA and other neurotransmitters by inter-neurons within the dorsal horn. GABA then acts by both presynaptic and postsynaptic mechanisms to shut down the activity of spinothalamic tract cells. Presynaptically, GABA activates both GABAA and GABAB receptors, which leads to partial depolarization of the presynaptic terminal and blocking of Ca++ channels, respectively. Both actions will decrease release of transmitter by the afferent terminal and thereby lessen excitation of the tract cell (see section on presynaptic inhibition).


Physiology_Levy

Physiology_Levy. Nociceptive and thermoreceptive information that originates from regions of the head is processed in a fashion similar to that for the trunk and limbs. The primary afferent fibers of nociceptors and thermoreceptors in the head enter the brainstem through the trigeminal nerve (some also enter through the facial, glossopharyngeal, and vagus nerves). Of note, the trigeminal distribution includes both tooth and headache pain. These fibers then descend through the brainstem as far as the upper cervical spinal cord via the descending tract of the trigeminal nerve. Some mechanoreceptive afferent fibers also join the descending tract of the trigeminal nerve. Axons in the descending tract synapse on second-order neurons in the descending nucleus of the trigeminal nerve.


Physiology_Levy

Physiology_Levy. Elderlypeoplearesometimessusceptibletoaconditionofchronicpainknownastrigeminal neuralgia. Peoplewiththisconditionexperiencespontaneousepisodesofsevere,oftenlancinatingpaininthedistributionofoneormorebranchesofthetrigeminalnerve.Frequentlythepainistriggeredbyweakmechanicalstimulationinthesameregion.Amajorcontributingfactortothispainfulstateappearstobemechanicaldamagetothetrigeminalganglionbyanarterythatimpingesontheganglion.Surgicaldisplacementofthearterycanoftenresolvethecondition. The central pain pathways include the spinothalamic, spinoreticular, and spinomesencephalic tracts. The spinothalamic tract is the most important sensory pathway for somatic pain and thermal sensations from the body (see


Physiology_Levy

Physiology_Levy. Fig. 7.1A ). It also contributes to tactile sensation. The spinothalamic tract originates from second-order neurons located in the spinal cord (primarily laminae I and IV to VI). The axons of these cells cross to the opposite side of the cord at or near to their level of origin. They then ascend to the brain in the ventral part of the lateral funiculus and subsequently through the brainstem to the thalamus, where they terminate on third-order neurons (thalamocortical neurons), as described earlier. Spinothalamic cells conveying pain and temperature target the VPI portion of the ventroposterior complex (although some also end in the


Physiology_Levy

Physiology_Levy. Multireceptive spinothalamic VPL), the posterior nucleus, and the intralaminar nuclei tract cells of the thalamus. Nociceptive signals are then forwarded to 120 several cortical areas, including not only the somatosensory cortex but also cortical areas that are involved in affective responses, such as the cingulate gyrus and the insula, which have limbic system functions (see Fig. 7.5 Most spinothalamic tract cells receive excitatory input from nociceptors in the skin, but many can also be excited by noxious stimulation of muscle, joints, or viscera. Few receive input only from viscera. Effective cutaneous stimuli include noxious mechanical, thermal (hot or cold), and chemical stimuli. Thus different spinothalamic tract cells respond in a manner appropriate for signaling noxious, thermal, or mechanical events. A Some nociceptive spinothalamic tract cells receive convergent excitatory input from several different classes of cutaneous sensory receptors. For example, a given spino


Physiology_Levy

Physiology_Levy. Some nociceptive spinothalamic tract cells receive convergent excitatory input from several different classes of cutaneous sensory receptors. For example, a given spino Fig. 7.7A ). Such neurons are called wide–dynamic range cells or multirecep-120 tive cells because they are activated by stimuli with a wide range of intensities. Wide–dynamic range neurons signal mainly noxious events; weak responses to tactile stimuli appear to be ignored by the higher centers. However, in certain pathological conditions, these neurons may be suf ficiently activated by tactile stimuli to evoke a sensation of pain, possibly as a result of activity in sensitized afferents that were previously silent. This would explain some pain states in which activation of mechanoreceptors causes pain (mechanical allodynia). Other spinothalamic tract cells are activated only by noxious stimuli. Such neurons are often called high-threshold or nociceptive-specific cells (see Fig. 7.7B


Physiology_Levy

Physiology_Levy. Fig. 7.7B Because cells signaling visceral input also typically convey information from cutaneous receptors, the brain may misidentify the source of the pain. This phenomenon is called referred pain. A typical example is when the heart muscle becomes ischemic and pain is felt in the chest wall and left arm.


Physiology_Levy

Physiology_Levy. Neurotransmitters released by nociceptive afferents that activate spinothalamic tract cells include the excitatory amino acid glutamate and any of several peptides, such as SP, CGRP, and vasoactive intestinal polypeptide (VIP). Glutamate appears to act as a fast transmitter by its action on non-NMDA excitatory amino acid receptors. However, with repetitive stimulation, glutamate can also act through NMDA receptors. Peptides appear to act as neuromodulators. For example, through a combined action with an excitatory amino acid such as glutamate, SP can produce a long-lasting increase in the responses of spinothalamic tract cells; this enhanced responsiveness is called central sensitization. CGRP seems to increase release of SP and prolong the action of SP by inhibiting its enzymatic degradation.


Physiology_Levy

Physiology_Levy. Spinothalamic tract cells often have inhibitory receptive fields. Inhibition may result from weak mechanical stimuli, but usually the most effective inhibitory stimuli •Fig. 7.7 A,Responsesofawide–dynamicrangeormultireceptivespinothalamictractcell.B,Responsesofahigh-thresholdspinothalamictractcell.Graphsshowresponsestogradedintensitiesofmechanicalstimulation.Brushstimulusisacamel’shairbrushrepeatedlystrokedacrossthereceptivefield.Pressureisappliedbyattachmentofanarterialcliptotheskin.Thisisamarginallypainfulstimulustoahuman.Pinchisachievedbyattachmentofastiffarterialcliptotheskinandisdistinctlypainful.Squeezeisappliedbycompressingafoldofskinwithforcepsandisdamagingtotheskin.


Physiology_Levy

Physiology_Levy. are noxious ones. The nociceptive inhibitory receptive fields may be very large and may include most of the body and face. Such receptive fields may account for the ability of various physical manipulations, including transcutaneous electrical nerve stimulation and acupuncture, to suppress pain. Neurotransmitters that can inhibit spinothalamic tract cells include the inhibitory amino acids GABA and glycine, as well as monoamines and the endogenous opioid peptides. Spinoreticular tract neurons frequently have large, sometimes bilateral receptive fields, and effective stimuli include noxious ones. These dorsal horn neurons target multiple regions in the medullary and pontine reticular formation. The reticular formation, which projects to the intralaminar complex of the thalamus and thereby to wide areas of the cerebral cortex, is involved in attentional mechanisms and arousal (see Chapter 10).


Physiology_Levy

Physiology_Levy. Chapter 10). The reticular formation also gives rise to descending reticulospinal projections, which contribute to the descending systems that control transmission of pain. Many cells of the spinomesencephalic tract respond to noxious stimuli, and the receptive fields may be small or large. The terminations of this tract are in several midbrain nuclei, including the periaqueductal gray, which is an important component of the endogenous analgesia system. Motivational responses may also result from activation of the periaqueductal gray matter. For example, stimulation in the periaqueductal gray matter can cause vocalization and aversive behavior. Information from the midbrain is relayed not only to the thalamus but also to the amygdala. This provides one of several pathways by which noxious stimuli can trigger emotional responses.


Physiology_Levy

Physiology_Levy. Pain and temperature information originating from the face and head is conveyed along analogous ascending central pathways, as is such information from the body. Neurons in the descending trigeminal nucleus transmit pain and temperature information to specific nuclei (VPM, VPI) of the contralateral thalamus via the ventral trigeminothalamic tract, which runs in close association with the medial lemniscus. The descending nucleus also projects to the intralaminar complex and other thalamic nuclei in a fashion similar to that of the spinothalamic tract. The thalamic nuclei in turn project to the somatosensory cerebral cortex for sensory discrimination of pain and temperature and to other cortical regions responsible for motivational-affective responses. Effects of Interruption of the Spinothalamic Tract and Lesions of the Thalamus on Somatosensory Sensation


Physiology_Levy

Physiology_Levy. When the spinothalamic tract and accompanying ventral spinal cord pathways are interrupted, both the sensory-discriminative and the motivational-affective components of pain are lost on the contralateral side of the body. This result motivated development of the surgical procedure known as anterolateral cordotomy, which was used to treat pain in many individuals, especially those suffering from cancer. This operation is now used infrequently because of improvements in drug therapy and because pain often returns months to years after an initially successful cordotomy. Return of pain may reflect either extension of the disease or development of a central pain state. In addition to loss of pain sensation, anterolateral cordotomy produces loss of cold and warmth sensation on the contralateral side of the body. Careful testing may reveal a minimal tactile deficit as well, but the intact sensory pathways of the dorsal part of the spinal cord provide sufficient tactile information that any


Physiology_Levy

Physiology_Levy. side of the body. Careful testing may reveal a minimal tactile deficit as well, but the intact sensory pathways of the dorsal part of the spinal cord provide sufficient tactile information that any loss caused by interruption of the spinothalamic tract is insignificant.


Physiology_Levy

Physiology_Levy. Destruction of the VPL or VPM nuclei diminishes sensation on the contralateral side of the body or face. The sensory qualities that are lost reflect those that are


Physiology_Levy

Physiology_Levy. CHAPTER 7 The Somatosensory System transmitted mainly by the dorsal column–medial lemniscus pathway and its trigeminal equivalent. The sensory-discriminative component of pain sensation is also lost. However, the motivational-affective component of pain is still present if the medial thalamus is intact. Presumably, pain persists because of the spinothalamic and spinoreticulothalamic projections to this part of the thalamus. In some individuals a lesion of the somatosensory thalamus results in a central pain state known as thalamic pain. Patients with thalamic pain report that even the slightest touch feels painful, although the intensity of the touch is lower than the threshold of any pain receptor. It is thought that their pain sensitivity is due to a post-lesion sprouting of low-threshold dorsal column system fibers that synapse onto surviving thalamic neurons that normally mediate only pain. Pain that is indistinguishable from thalamic pain can also be produced by lesions in the


Physiology_Levy

Physiology_Levy. dorsal column system fibers that synapse onto surviving thalamic neurons that normally mediate only pain. Pain that is indistinguishable from thalamic pain can also be produced by lesions in the brainstem or cortex.


Physiology_Levy

Physiology_Levy. Pain sometimes occurs in the absence of nociceptor stimulation. This type of pain is most likely to occur after damage to peripheral nerves or to parts of the CNS that are involved in transmitting nociceptive information. Pain caused by damage to neural structures is called neuropathic pain. Neuropathic pain states include peripheral neuropathic pain, which may follow damage to a peripheral nerve, and central neuropathic pain, which sometimes occurs after damage to CNS structures.


Physiology_Levy

Physiology_Levy. Examples of pain secondary to damage to a peripheral nerve are causalgia and phantom limb pain. Causalgia may develop after traumatic damage to a peripheral nerve. Even though evoked pain is reduced, severe pain may develop in the area innervated by the damaged nerve. This pain may be very difficult to treat, even with strong analgesic drugs. The pain is caused in part by spontaneous activity that develops in dorsal root ganglion cells; such activity may be attributed to upregulation of Na+ channels. In some cases the pain seems to be maintained by sympathetic neural activity, because a sympathetic nerve block may alleviate the pain. Sympathetic involvement may relate to the sprouting of damaged sympathic postganglionic axons into the dorsal root ganglia, and it may be accompanied by upregulation of adrenoreceptors in primary afferent neurons. Phantom limb pain follows traumatic amputation in some individuals. Such phantom pain is clearly not caused by activation of nociceptors in the