Psychopharmacology of Opioids



Opiate drugs are compounds that are extracted from the poppy seed. These drugs opened the way to the discovery of the endogenous opioid system in the brain (Brownstein, 1993). The term “opioids” includes “opiates” as well as semisynthetic and synthetic compounds with similar properties. Evidence for the existence of opioid receptors was based on the observation that opiates (e.g. heroin and morphine) interact with specific binding sites in the brain.

In 1976, the first evidence for the existence of multiple opioid receptors was reported (Martin et al., 1976) and pharmacological studies led to the classification of opioid binding sites into three receptor classes referred to as mu, delta and kappa receptors. Later, studies revealed that several subtypes of each receptor class exists (Pasternak, 1993).

The existence of opioid receptors suggested that these receptor sites might be the targets for opiate-like molecules that exist naturally in the brain. In 1975, two peptides that act at opiate receptors were discovered, Leuenkephalin and Met-enkephalin (Hughes et al., 1975). Shortly after, other endogenous peptides were identified and more than 20 distinct opiate peptides are known today (Akil et al., 1997).

Behavioural effects

Intravenous injection of opioids produces a warm flushing of the skin and sensations described by users as a “rush”; however, the first experience with opiates can also be unpleasant, and can involve nausea and vomiting (Jaffe, 1990). Opioids have euphorogenic, analgesic, sedative, and respiratory depressant effects.

Numerous animal experiments using selective opioid compounds have shown that agonists of the mu receptor subtype, injected either peripherally or directly into the brain, have reinforcing properties. Delta agonists, as well as endogenous enkephalins, seem to produce reward, although to a lesser extent than mu agonists. Reinforcement by mu and delta agonists has been shown in several behavioural models, including drug self- administration, intracranial self-stimulation and conditioned place preference paradigms, and has been reviewed extensively (Van Ree, Gerrits & Vanderschuren, 1999).

Pharmacological studies, therefore, have proposed that activation of  both mu and delta receptors is reinforcing. It is also significant that the genetic inactivation of mu receptors abolished both the dependence-producing and analgesic effects of morphine, as well as actions of other clinically used opioid drugs. This demonstrated that mu receptors are critical for all the beneficial as well as detrimental effects of clinically relevant opiate drugs (Kieffer, 1999). Molecular studies, therefore, have highlighted mu receptors as the gate for opioid analgesia, tolerance and dependence.

Kappa receptors, however, appear to have an opposing effect on reward.The hypothesis of a mu/kappa control of mesolimbic dopaminergic neurons is best documented. It is important to note the observation that heroin is also self-administered in animals in the absence of these neurons, suggesting the existence of dopamine-independent mechanisms in opioid reinforcement(Leshner & Koob, 1999).

Mechanism of Action

The three opioid receptors (mu, delta and kappa receptors) mediate activities of both exogenous opioids (drugs) and endogenous opioid peptides, and therefore represent the key players in the understanding of opioid-controlled behaviours. Opioid receptors belong to the superfamily of G protein-coupled receptors. Agonist binding to these receptors ultimately causes inhibition of neuronal activity.

Opioid receptors and peptides are strongly expressed in the central nervous system (Mansour et al., 1995; Mansour & Watson, 1993). In addition to its involvement in pain pathways, the opioid system is largely represented in brain areas involved in responses to psychoactive substances, such as the VTA and nucleus accumbens shell (Akil et al., 1997). Opioid peptides are involved in a wide variety of functions regulating stress responses, feeding, mood, learning, memory, and immune functions (for review, see Vaccarino & Kastin, 2001).

Tolerance and Withdrawal

With repeated administration of opioid drugs, adaptive mechanisms change the functioning of opioid-sensitive neurons and neural networks. Tolerance develops, and higher doses of the drugs are required to gain the desired effect.

Humans and experimental animals develop profound tolerance to opioids over periods of several weeks of escalating chronic administration. Tolerance involves distinct cellular and neural processes. Acute desensitization or tolerance of the opioid receptor develops in minutes during opioid use and  abates in minutes to hours after exposure. There is also a long-term desensitization of the receptor that slowly develops and persists for hours to days after removal of opioid agonists. There are also counteradaptations to opioid effects of intracellular signalling mechanisms and in neuronal circuitry that contribute to tolerance. These processes have been recently reviewed (Williams, Christie & Manzoni, 2001).

Cessation of chronic opioid use is associated with an intensely dysphoric withdrawal syndrome, which may be a negative drive to reinstate substance use. The withdrawal is characterized by watering eyes, runny nose, yawning,sweating, restlessness, irritability, tremor, nausea, vomiting, diarrhea, increased blood pressure and heart rate, chills, cramps and muscle aches, which can last 7–10 days (Jaffe, 1990).

This was once thought to be sufficient to explain the persistence of opioid dependence (Collier, 1980).There is no doubt that the intensely dysphoric withdrawal syndrome plays an important role in maintaining episodes of opioid use, but opioid dependence,and relapse that occurs long after withdrawal cannot be explained solely on this basis (Koob & Bloom, 1988). Currently, long-term adaptations in neural systems are also thought to play an important role independence and relapse.

In conclusion, the data show complex and broad changes ofthe endogenous opioid system following repeated stimulation of mu receptors by opioids. The precise consequences of those changes remain unclear, but it is likely that the long-term dysregulation of the opioid system influences stress responses and drug-taking behaviour.

Neurobiological Adaptations To Prolonged Use

Adaptations following chronic drug exposure extend well beyond reward circuits to other brain areas, notably those involved in learning and stress responses. Important regions are the amygdala, hippocampus and cerebral cortex, which are all connected to the nucleus accumbens. All these areas express opioid receptors and peptides, and the overall distribution of opioid peptide-expressing cells in neural circuits of dependence has been reviewed (Nestler, 2001; Koob & Nestler, 1997).

Repeated exposure to opioids induces drastic and perhaps irreversible modifications in the brain. Hallmarks of adaptations to chronic opioid use are tolerance, defined as a reduced sensitivity to the drug effects and generally referring to attenuation of analgesic efficacy.

 Drug craving and the physiological manifestations of drug withdrawal are also indications of longterm neuroadaptations. These phenomena are a consequence of sustained  mu receptor stimulation by opiate  drugs inducing neurochemical adaptations  in  opioid receptor -bearing neurons.  (Kieffer &   Evans).                                                                                                                                                                                                                                               

Pharmacological Treatment of Opioid Dependence


Treatment of heroin dependence has been quite successful because of substitution therapy and methadone maintenance treatment in particular (see Box 4.1). Methadone is a synthetic opioid agonist that acts on the same receptors as opiate drugs, and therefore blocks the effects of heroin, eliminates withdrawal symptoms, and reduces craving. When properly used, methadone is non-sedating, non-intoxicating and does not interfere with regular activities. The medication is taken orally, and it suppresses opioid withdrawal for 24 hours. There is no cognitive blunting. Its most important feature is to relieve the craving associated with heroin dependence, thereby reducing relapse. Methadone maintenance treatment is safe, and very effective in helping people to stop taking heroin, especially when combined with behavioural therapies or counselling and other supportive services. Methadone maintenance treatment can also reduce the risk of contracting and transmitting HIV, tuberculosis and hepatitis (Krambeer et al., 2001).

References: (1) Neuroscience of Psychoactive Substance Use and Dependence (Chapter 4) Psychopharmacology of
                            Dependence For Different Drug Classes 79-84

Compiled & Edited By: D. Shrira   Upated: 11 February 2007