Introduction

Accumulating evidence indicates that many neurons or neuronal systems adapt to chronic receptor activation by the expression of compensating mechanisms. These compensating mechanisms can take the form of a reduced sensitivity of the receptor through which the agonist acts (homologous desensitization), a reduced sensitivity of co-expressed receptors that serve similar functional roles (heterologous desensitization), and a change in the functions of effector systems to compensate for the persistent activation of one class of receptors. Each of these mechanisms has been observed in some circumstances following chronic exposure of cells or whole animals to morphine and other opiate drugs. All these processes may play a role in opiate drug tolerance, but their relative contributions will probably vary in different situations. Furthermore, the physiologic environment in which opiate drugs act may vary with time in ways that will influence the sensitivity of the system to opiates.

Altered Drug Metabolism in Opiate Tolerance

Chronic exposure to drugs like alcohol (ethanol) or barbiturates may lead to an increased metabolism of the drug and thus to a reduced pharmacologic effect, but there is little evidence of drug-induced changes in the metabolism of morphine and related drugs of sufficient magnitude to account for the level of tolerance that can be observed during chronic morphine treatment. Morphine is partially metabolized to an active metabolite, morphine-6-glucuronide, and this metabolite may contribute in part to the analgesic actions of morphine in vivo (Paul et al., 1989).