Multiple opioid receptor systems in brain and spinal cord: Part I.

The biological activity of opioid agents reflects their interaction with specific membrane sites. The fact that the drug interaction resulting in physiological responses shows distinguishing characteristics with regard to rank order of agonist potency, affinity of the antagonist for the site acted upon by the agent to produce the effect, tolerance and cross-tolerance, may be interpreted as indicating that different opioids produce their effects by an action on distinctive receptors. Examination of the literature provides support for the hypothesis proposed by different investigators that the physiological effects of the several opioid ligands may be parsimoniously explained in terms of several possibly overlapping receptor classes including mu, delta, kappa, sigma and epsilon. Binding studies examining the affinity of the ligand for a tissue site have in general provided confirming support for these receptor profiles. It is stressed that the majority of the documentation for receptor classes derives from in vitro work. However, a growing number of quantitative studies of the receptors in brain which regulate central nervous system processing are also showing evidence of definable differences in drug action which are comparable to those reported for in vitro bioassays and binding studies. Examination of the pharmacology of the analgesic effects of opioids indicates that the differences in the activity of opioid drugs (such as between mu and kappa agonists) probably reflect the role of different pain processing systems. Though not reviewed, it is likely that a similar complexity underlies the interaction of opioids with neural substrates mediating other functions. Thus different opioid receptors may modulate the same physiological phenomenon because they are on different systems which have a similar output (e.g. spinal reflex inhibition) or they may co-exist on the same neurone. In short, it appears likely that there are discriminable populations of opioid receptors and that no single receptor can be said to modulate a given physiological effect.