Dependence potential and receptor subtype of opioids

Dependence potential of μ-agonists such as morphine and codeine is known to be very high both physically and psychologically. The reinforcing effect of these drugs is markedly intensified at withdrawal when subjects developed physical dependence. For example, final ratios obtained by the ingressive ratio method in intravenous self-administration of codeine inrhesus monkeys were 4,540 under a physical dependence-free state and 5,080 under a physically dependent state in average of 3 or 4 monkeys. Contrary to this, the dependence potentials of agonist/antagonist analgesics such as pentazocine, cyclazocine, buprenorphine, and propiram are infinitely lower than the opiates, with no significant intensification of the reinforcing effect at withdrawal. Especially the physical dependence potential of buprenorphine and psychological dependence potential of cyclazocine are extremely low in both animals and humans. In morphine dependent and withdrawn monkeys, these drugs did not suppress the withdrawal signs, but precipitated the signs in non-withdrawn monkeys. However, when physical dependence was maintained by low doses of morphine, pentazocine suppressed the morphine withdrawal signs, and buprenorphine and propiram were also reported to have suppressed the signs. These results may be attributable to the fact that these drugs are either μ-antagonists or partial μ-agonists. It has been reported that the dependence potential of highly selective κ-agonists such as ketocyclazocine is very low,and that of a σ-agonist, SKF-10047,is negligible. Thus, the strong dependence on opioids, particularly strong physical dependence, appears to be developed by a mechanism which involves the μ-receptors.