Electrophysiologic studies of dorsal‐root ganglion (DRG) neurons in culture have demonstrated both excitatory (Gs‐coupled) as well as inhibitory (Gi/Go‐coupled) opioid receptor‐mediated actions. Brief treatment of DRG neurons with cholera toxin‐B which binds specifically to GM1 sites on neuronal membranes, selectively blocks opioid excitatory but not inhibitory effects. Conversely, after brief treatment of DRG neurons with GM1, but not with GM2, GM3, or other related gangliosides, the threshold concentration of opioid agonists for eliciting excitatory effects is markedly decreased from nM to pM‐fM levels and opioid antagonists, for example, naloxone (NLX), at low nM concentrations paradoxically elicit excitatory effects. These studies suggest that the excitatory opioid supersensitivity of GM1‐treated DRG neurons is due primarily to increased efficacy of excitatory opioid‐receptor activation of Gs. Recent studies of cloned δ opioid receptors transfected into CHO cells suggest that this supersensitivity of GM1‐treated DRG neurons may be further augmented by rapid conversion of many opioid receptors from a Gi/Go‐coupled inhibitory mode to a Gs‐coupled excitatory mode. The opioid excitatory supersensitivity elicited in DRG neurons by acute elevation of exogenous GM1 provides novel insights into mechanisms underlying opioid tolerance and dependence, since remarkably similar supersensitivity occurs in DRG and other neurons after chronic treatment with morphine or other opioid agonists that upregulate endogenous GM1.