| Abstract: | The ultra-potent opioid analgesic, etorphine, elicits naloxone-reversible, dose-dependent inhibitory effects, i.e. shortening of the action potential duration (APD) of naive and chronic morphine-treated sensory dorsal root ganglion (DRG) neurons, even at low (pM-nM) concentrations. In contrast, morphine and most other opioid agonists elicit excitatory effects, i.e. APD prolongation, at these low opioid concentrations, require much higher (ca. 0.1–1 μM) concentrations to shorten the APD of naive neurons, and evoke only excitatory effects on chronic morphine-treated cells even at high > 1–10 wM concentrations. In addition to the potent agonist action of etorphine at μ-, δ- and κ-inhibitory opioid receptors in vivo and on DRG neurons in culture, this opioid has also been shown to be a potentantagonist of excitatory μ-, δ- and κ-receptor functions in naive and chronic morphine-treated DRG neurons. The present study demonstrates that the potent inhibitory APD-shortening effects of etorphine still occur in DRG neurons tested in the presence of a mixture of selective antagonists that blocks all μ-, δ- and κ-opioid receptor-mediated functions, whereas addition of the epsilon (ε)-opioid-receptor antagonist, β-endorphin(1–27) prevents these effects of etorphine. Furthermore, after markedly enhancing excitatory opioid receptor functions in DRG neurons by treatment with GM1 ganglioside or pertussis toxin, etorphine showsexcitatory agonist action onnon-μ-/δ-/κ-opioid receptor functions in these sensory neurons, in contrast to its usual potent antagonist action on μ-, δ- and κ-excitatory receptor functions in naive and even in chronic morphine-treated cells which become supersensitive to the excitatory effects of μ-, δ- and -opioid agonists. This weak excitatory agonist action of etorphine on non-μ-/δ-/κ-opioid receptor functions may account for the tolerance and dependence observed after chronic treatment with extremely high doses of etorphine in vivo. |
