MODULATORY EFFECTS OF GS-COUPLED EXCITATORY OPIOID RECEPTOR FUNCTIONSON OPIOID ANALGESIA, TOLERANCE, AND DEPENDENCE

Electrophysiologic studies of opioid effects on nociceptive types of d orsal root ganglion (DRG) neurons in organotypic cultures have shown t hat morphine and most mu, delta, and kappa opioid agonists can elicit bimodal excitatory as well as inhibitory modulation of the action pote ntial duration (APD) of these cells. Excitatory opioid effects have be en shown to be mediated by opioid receptors that are coupled via Gs to cyclic AMP-dependent ionic conductances that prolong the APD, whereas inhibitory opioid effects are mediated by opioid receptors coupled vi a Gi/Go to ionic conductances that shorten the APD. Selective blockade of excitatory opioid receptor functions by low (ca. pM) concentration s of naloxone, naltrexone, etorphine and other specific agents markedl y increases the inhibitory potency of morphine or other bimodally acti ng agonists and attenuates development of tolerance/dependence. These in vitro studies have been confirmed by tail-flick assays showing that acute co-treatment of mice with morphine plus ultra-low-dose naltrexo ne or etorphine remarkably enhances the antinociceptive potency of mor phine whereas chronic co-treatment attenuates development of tolerance and naloxone-precipitated withdrawal-jumping symptoms.