Pharmacological assessment of thermal antinociception mediated by kappa opioid receptors in rhesus monkeys.

Abstract

The possible existence of kappa opioid receptor subtypes has been reported by several laboratories based on radioligand binding experiments. However, there are some controversial issues remaining. The purpose of this thesis was to evaluate the central and peripheral antinociceptive actions of putative kappa opioid agonists in rhesus monkeys. The warm water tail withdrawal assay was used to investigate the functional evidence of kappa receptor subtypes. The first study discussed the presence of two, distinct kappa opioid binding sites, referred to herein as kappa-1 and non-kappa-1, in the rhesus monkey brain. These kappa sites had some similarity to those previously reported in rodents and humans. Although a slight kappa-1 binding selectivity of nor-binaltorphimine (nor-BNI) was found, nor-BNI displayed a strong, selective kappa-1 antagonist profile in vivo. Further study revealed that naltrexone (NTX) exhibited approximately 3-fold higher affinity for the putative kappa-1 site than the kappa-all site. Differentiation of kappa agonists by NTX in vivo apparent $\rm pA\sb2$ analysis indicated that U69,593 and U50,488 produced antinociception by acting on kappa-1 receptors, whereas bremazocine and enadoline acted mainly via non-kappa-1 receptors. This distinctive profile among kappa agonists afforded by NTX $\rm pA\sb2$ analysis is consistent with the differentiation based on the nor-BNI antagonist study. Taken together, this is strong evidence for kappa receptor subtypes. Furthermore, a new procedure in primates was developed to study peripheral kappa receptors by utilizing capsaicin-induced local nociception. In this inflammatory pain procedure, it was found that U50,448 and bremazocine produced peripheral antinociception through different kappa receptor subtypes. These studies provide functional and biochemical evidence for kappa opioid receptor multiplicity in primates in mediating thermal antinociception. They provide a valuable pharmacological basis for characterizing new kappa opioid compounds and for exploring potentially distinct neurophysiological profiles of kappa agonists.