Molecular determinants of opioid analgesia: Modulation of presynaptic calcium channels

Opioid receptor agonists remain one of the most efficacious classes of analgesic drugs available for clinical use. Although multiple subclasses of opioid receptors have been identified (5, K, and la), most opioid analgesics act at the mu receptor subtype to decrease cAMP fort-nation, activate hyperpolarizing K+ channels, and inhibit Ca2+ channels. Here, we discuss the molecular interactions underlying opioid receptor-mediated modulation of voltage-dependent calcium channels. Opioid receptor activation results in binding of the G protein betagamma complex to specific structural elements of the presynaptic calcium channel. The modulated calcium channel displays characteristic inhibition and kinetic slowing resulting in reduced Ca2+ influx and diminished release of neurotransmitter. Mounting evidence suggests that desensitization of this opioid response involves regulators of G-protein signaling (RGS), G-protein coupled receptor kinases (GRK), and beta-arrestins. Further advances in our understanding of these subcellular events mediating opioid pain relief offer new prospects in the development of improved analgesic agents. (C) 2002 Wilcy-Liss, Inc.