Experimental Models of Opiate Tolerance and Dependence

Abstract: Since observations in whole animals provide only limited information on the mechanisms underlying tolerance and dependence, less complex isolated tissue, cell culture and single neurone models have been developed, the most widely exploited of which is the guinea pig ileum. Prolonged exposure to morphine leads to tolerance to its acute inhibitory effects. Dependence is indicated by neuronal hyperexcitability when morphine is withdrawn or abruptly displaced from its receptor by naloxone. The mechanism of withdrawal hyperexcitability may be relatively non‐selective since responses of both central and peripheral neurones to a variety of excitants are enhanced. Behavioural and biochemical experiments implicate elevated neuronal calcium and adenylate cyclase in the expression of dependence. However the relationship between these observations and the hyperexcitability of single neurones has not been rigorously examined. Moreover the relevance of an analysis of tolerance and physical dependence in experimental models to opioid reward mechanisms is uncertain. Although recent evidence suggests the importance of the ventral tegmental area in the rewarding actions of opiates, the biochemical and electrophysiological effects of exogenous opiates and of endogenous opioids on these neurones remain largely unexplored.