Page 100 - Pagetit

4. PSYCHOPHARMACOLOGY OF DEPENDENCE FOR DIFFERENT DRUG CLASSES

Opioids

Introduction
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, Leu-
enkephalin 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.

79

Chapter_4 79 19.1.2004, 11:42