ETORPHINE ELICITS ANOMALOUS EXCITATORY OPIOID EFFECTS ON SENSORY NEURONS TREATED WITH GM1 GANGLIOSIDE OR PERTUSSIS TOXIN IN CONTRAST TO ITSPOTENT INHIBITORY EFFECTS ON NAIVE OR CHRONIC MORPHINE-TREATED CELLS

The ultra-potent opioid analgesic, etorphine, elicits naloxone-reversi ble, dose-dependent inhibitory effects, i.e., shortening of the action potential duration (APD) of naive and chronic morphine-treated sensor y dorsal root ganglion (DRG) neurons, even at low (pM-nM) concentratio ns. In contrast, morphine and most other opioid agonists elicit excita tory effects, i.e., APD prolongation, at these low opioid concentratio ns, require much higher (ca. 0.1-1 mu M) concentrations to shorten the APD of naive neurons, and evoke only excitatory effects on chronic mo rphine-treated cells even at high >1-10 mu M concentrations. In additi on to the potent agonist action of etorphine at mu, delta- and kappa-i nhibitory opioid receptors in vivo and on DRG neurons in culture, this opioid has also been shown to be a potent antagonist of excitatory mu -, delta- and kappa-receptor functions in naive and chronic morphine-t reated DRG neurons. The present study demonstrates that the potent inh ibitory APD-shortening effects of etorphine still occur in DRG neurons tested in the presence of a mixture of selective antagonists that blo cks all mu-, delta- and kappa-opioid receptor-mediated functions, wher eas addition of the epsilon (epsilon)-opioid-receptor antagonist, beta -endorphin(1-27) prevents these effects of etorphine. Furthermore, aft er markedly enhancing excitatory opioid receptor functions in DRG neur ons by treatment with GM1 ganglioside or pertussis toxin, etorphine sh ows excitatory agonist action on non-mu/delta/kappa-opioid receptor fu nctions in these sensory neurons, in contrast to its usual potent anta gonist action on mu-, delta- and kappa-excitatory receptor functions i n naive and even in chronic morphine-treated cells which become supers ensitive to the excitatory effects of mu-, delta- and kappa-opioid ago nists. This weak excitatory agonist action of etorphine on non-mu-/del ta-/kappa-opioid receptor functions may account for the tolerance and dependence observed after chronic treatment with extremely high doses of etorphine in vivo.