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Molecular determinants of opioid analgesia: Modulation of presynaptic calcium channels
Author(s) -
Beedle Aaron M.,
Zamponi Gerald W.
Publication year - 2001
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10026
Subject(s) - opioid , opioid receptor , chemistry , pharmacology , calcium channel , voltage dependent calcium channel , neurotransmitter receptor , desensitization (medicine) , receptor , g protein , neurotransmitter , neuroscience , n type calcium channel , calcium , t type calcium channel , biology , biochemistry , organic chemistry
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 (δ, κ, and μ), most opioid analgesics act at the μ receptor subtype to decrease cAMP formation, activate hyperpolarizing K + channels, and inhibit Ca 2+ 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 βγ complex to specific structural elements of the presynaptic calcium channel. The modulated calcium channel displays characteristic inhibition and kinetic slowing resulting in reduced Ca 2+ 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 β‐arrestins. Further advances in our understanding of these subcellular events mediating opioid pain relief offer new prospects in the development of improved analgesic agents. Drug Dev. Res. 54:118–128, 2002. © 2002 Wiley‐Liss, Inc.