SPECIFIC N-TERMINUS OR C-TERMINUS MODIFIED DYNORPHIN AND BETA-ENDORPHIN PEPTIDES CAN SELECTIVELY BLOCK EXCITATORY OPIOID RECEPTOR FUNCTIONSIN SENSORY NEURONS AND UNMASK POTENT INHIBITORY EFFECTS OF OPIOID AGONISTS

We recently showed that the opioid alkaloids, etorphine, dihydroetorph ine and diprenorphine, have remarkably potent antagonist actions on ex citatory opioid receptor functions in mouse sensory dorsal root gangli on (DRG) neurons. Pretreatment of naive nociceptive types of neurons w ith pM concentrations of these antagonists blocks excitatory prolongat ion of the calcium-dependent component of the action potential duratio n (APD) elicited by pM-nM morphine or other bimodally acting mu, delta and kappa opioid agonists and unmasks inhibitory APD shortening which usually requires much higher (ca. mu M) concentrations. The present s tudy demonstrates that pM concentrations of [des-Tyr(1)] fragments of dynorphin and beta-endorphin, as well as beta-endorphin-(1-27), can al so selectively block excitatory opioid receptor functions in DRG neuro ns and unmask potent inhibitory effects of low concentrations of bimod ally acting mu, delta and kappa opioid peptides and alkaloid agonists. These N- or C-terminus modified dynorphin or beta-endorphin peptides can be readily formed in neurons by specific peptidase activities. Sin ce sustained activation of excitatory opioid receptor functions is ess ential for the development of tolerance/dependence in chronic morphine -treated DRG neurons in culture, the present in vitro study may help t o account for the unexplained efficacy of [des-Tyr(1)] dynorphin fragm ents, as well as the endogenous opioids dynorphin A and beta-endorphin , in suppressing development and expression of naloxone-precipitated w ithdrawal and morphine tolerance in vivo.