Neurophysiological investigations of opiate tolerance and dependence in the central nervous system

In this essay I have presented several examples of cellular neurophysiological approaches used to investigate opiate tolerance and dependence. In many ways, these central nervous system studies parallel earlier investigations carried out in in vitro preparations and cell culture systems reviewed by others in this volume. The examples presented here have demonstrated that opiate/opioid tolerance and dependence are observed at all levels of electrophysiological analysis. Moreover, recent studies utilizing the locus coeruleus slice preparation have shown the feasibility of separating the processes underlying opiate tolerance and those of dependence (Andrade et al. 1983). Several important issues remain unresolved: (1) Can acute tolerance to opiates/opioids be demonstrated in all preparations (and in all brain areas studied) or is this phenomenon, in part, due to technical shortcomings of iontophoresis? (2) What are the characteristics of the subpopulations of opioid receptor agonists and their differential ability to alter, in naive or tolerant preparations, synaptic and nonsynaptic processes in neurons? and (3) What are the intracellular events associated with dependence on other brain areas known to contain neurons that are post-synaptic to endogenous opioid peptides? In addition, what is the relationship, at the synaptic level, of opioid-induced synaptic activity and the cascade of intracellular events coupled to "second messenger" processes? Are these intracellular processes ubiquitous for all opioid agonist subtypes or are regional as well as intracellular coupling mechanisms heterogeneous? Many of these questions currently remain unanswered. However, taking our lead from investigators using molecular approaches to study receptor function (see Sigworth 1982; Walker et al. 1982; Taylor et al. 1983; Dunn et al. 1983 and others vis-a-vis muscarinic ACh receptor), "opioid" physiologists are likely to play a major role in elucidating and characterizing endogenous ligand/receptor interactions in the coming years.