CHRONIC OPIOID TREATMENT OF NEUROBLASTOMA X DORSAL-ROOT GANGLION NEURON HYBRID F11 CELLS RESULTS IN ELEVATED GM1 GANGLIOSIDE AND CYCLIC ADENOSINE-MONOPHOSPHATE LEVELS AND ONSET OF NALOXONE-EVOKED DECREASES IN MEMBRANE K+ CURRENTS

Prolongation of the action potential duration of dorsal root ganglion (DRG) neurons by low (nM) concentrations of opioids occurs through act ivation of excitatory opioid receptors that are positively coupled via G(s) regulatory protein to adenylate cyclase. Previous results sugges ted GM1 ganglioside to have an essential role in regulating this excit atory response, but not the inhibitory (APD-shortening) response to hi gher (mu M) opioid concentrations. Furthermore, it was proposed that s ynthesis of GM1 is upregulated by prolonged activation of excitatory o pioid receptor functions. To explore this possibility we have utilized cultures of hybrid F11 cells to carry out closely correlated electrop hysiological and biochemical analyses of the effects of chronic opioid treatment on a homogeneous population of clonal cells which express m any functions characteristic of DRG neurons. We show that chronic opio id exposure of F11 cells does, in fact, result in elevated levels of G M1 as well as cyclic adenosine monophosphate (AMP), concomitant with t he onset of opioid excitatory supersensitivity as manifested by naloxo ne-evoked decreases in voltage-dependent membrane K+ currents. Such el evation of GM1 would be expected to enhance the efficacy of excitatory opioid receptor activation of the G(s)/adenylate cyclase/cyclic AMP s ystem, thereby providing a positive feedback mechanism that may accoun t for the remarkable supersensitivity of chronic opioid-treated neuron s to the excitatory effects of opioid agonists as well as antagonists. These in vitro findings may provide novel insights into the mechanism s underlying naloxone-precipitated withdrawal syndromes and opioid-ind uced hyperalgesia after chronic opiate addiction in vivo. (C) 1995 Wil ey-Liss, Inc.