Specific N- or C-terminus modified dynorphin and beta-endorphin peptides can selectively block excitatory opioid receptor functions in sensory neurons and unmask potent inhibitory effects of opioid agonists.

We recently showed that the opioid alkaloids, etorphine, dihydroetorphine and diprenorphine, have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse sensory dorsal root ganglion (DRG) neurons. Pretreatment of naive nociceptive types of neurons with pM concentrations of these antagonists blocks excitatory prolongation of the calcium-dependent component of the action potential duration (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. microM) concentrations. The present study demonstrates that pM concentrations of [des-Tyr1] fragments of dynorphin and beta-endorphin, as well as beta-endorphin-(1-27), can also selectively block excitatory opioid receptor functions in DRG neurons and unmask potent inhibitory effects of low concentrations of bimodally 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. Since sustained activation of excitatory opioid receptor functions is essential for the development of tolerance/dependence in chronic morphine-treated DRG neurons in culture, the present in vitro study may help to account for the unexplained efficacy of [des-Tyr1] dynorphin fragments, as well as the endogenous opioids dynorphin A and beta-endorphin, in suppressing development and expression of naloxone-precipitated withdrawal and morphine tolerance in vivo.