Nociceptin inhibits T-type Ca2+ channel current in rat sensory neurons by a G-protein-independent mechanism.
Nociceptin (orphanin FQ) is a novel, opioid-like, heptadecapeptide that is an endogenous ligand for the opioid receptor-like (ORL1) receptor. Unlike classical opioids, nociceptin can produce hyperalgesia when injected intracerebroventricularly into mice. Despite this, nociceptin has been reported to decrease transmitter release, activate an inwardly rectifying K+ conductance, and suppress high-voltage-activated Ca2+ channel conductances (HVA gCa) in much the same way as micro-, delta-, and kappa-opioids. We report an action of nociceptin that is not shared by morphine: the suppression of low-voltage-activated, transient calcium (barium) current (IBa,T) in acutely dissociated rat dorsal root ganglion (DRG) neurons (EC50 = 100 nM). This effect was reflected as inhibition of bursts of action potentials that can be evoked in "medium-sized" DRG neurons. Experiments with GTP-gamma-S (100 microM), GDP-beta-S (2 mM), or aluminum fluoride (AlF3) (100 microM) in the patch pipette failed to provide evidence for G-protein involvement in nociceptin-induced IBa,T suppression. By contrast, both morphine and nociceptin suppressed HVA gCa, and the latter response was affected by intracellular GTP-gamma-S, GDP-beta-S, and AlF3 in ways that confirmed G-protein involvement. The selective effect of nociceptin on IBa,T may therefore be relevant to understanding why its behavioral actions differ from those of other opioids. This G-protein-independent effect of the action of nociceptin may reflect a new general mechanism of action for opioid peptides within the nervous system.
Abdulla
F A
FA
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
Smith
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PA
D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009475:Neurons, Afferent / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018847:Opioid Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists; D000097629:Nociceptin
D000701:Analgesics, Opioid; D002118:Calcium; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019204:GTP-Binding Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000097629:Nociceptin