Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence

Abstract

At low (< nM) concentrations, μ, δ or κ opioid peptides as well as morphine and other opioid alkaloids elicit dose-dependent excitatory prolongation of the calcium-dependent component of the action potential duration (APD) of many mouse sensory dorsal root ganglion (DRG) neurons, whereas application of the same opioids at higher (uM) concentrations results in inhibitory shortening of the APD. These bimodal opioid excitatory/inhibitory effects on DRG neurons are blocked by naloxone. In contrast to bimodally acting opioids, the opioid alkaloids, etorphine and dihydroetorphine (thebaine-oripavine derivatives) uniquely elicited only dose-dependent, naloxone-reversible inhibitory effects on sensory neurons in DRG-spinal cord explants, even at concentrations as low as 1 pM, and showed no excitatory effects at lower concentrations. These remarkably potent inhibitory opioid receptor agonists also act as antagonists at excitatory opioid receptors since pretreatment of DRG neurons with subthreshold concentrations (< pM) blocked excitatory APD prolongation by nM morphine (or other opioids) and unmasked inhibitory APD shortening which generally requires much higher concentrations. Furthermore, acute application of pM-nM etorphine to chronic μM morphine- or d-Ala 2- d-Leu 5 enkephalin (DADLE)-treated DRG neurons blocked the nM naloxone-precipitated APD prolongation that generally occurs in DRG cells sensitized by bimodally acting opioids. In the presence of pM etorphine, chronic treatment of DRG neurons with μM morphine or DADLE no longer resulted in development of tolerance/dependence effects, as previously observed after similar chronic opioid treatment in the presence of cholera toxin-B subunit. These in vitro studies may clarify the mechanisms underlying the potent analgesic effects of etorphine and dihydroetorphine in vivo and to guide the use of these and other excitatory opioid receptor antagonists in attenuating development of opiate dependence/addiction.