Nociceptin is a potent inhibitor of N-type Ca(2+) channels in rat sympathetic ganglion neurons.
Nociceptin, an endogenous agonist of the opioid receptor-like(1) (ORL(1)) receptor, is implicated in a wide range of physiological functions including cardiovascular control. However, the effect of nociceptin on peripheral sympathetic ganglion neurons has not been studied. Whole-cell voltage clamp was used to study Ca(2+) currents on freshly dissociated sympathetic superior cervical ganglion neurons from juvenile rats. Nociceptin (1 microM) caused a fast inhibition of the peak currents by 69+/-3% in all neurons. Strong positive prepulses counteracted the inhibition of the peak current by 64% and no effect of nociceptin was observed when the cells were pre-incubated with Pertussis toxin. The inhibition was reversible and dose-dependent with an EC(50) of 508+/-50 pM. Blockade of N-type channels by 1 microM omega-conotoxin GVIA reduced the peak currents by 83+/-1% and abolished the action of nociceptin. Naloxone could not prevent the inhibition by nociceptin and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol] enkephalin (DAMGO) only depressed a small proportion of the current in 1/7 neurons. These data suggests that nociceptin inhibits transmitter release from sympathetic neurons by a selective blockade of N-type channels, which may be of importance for its depressive effect on the cardiovascular system.
Larsson
K P
KP
Department of General Pharmacology, Novo Nordisk A/S, DK-2760, Maaloev, Denmark.
Olsen
U B
UB
Hansen
A J
AJ
D000818:Animals; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018847:Opioid Peptides / Q000378:metabolism / Q000494:pharmacology*; D037342:Pertussis Toxin; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D020864:Calcium Channels, N-Type; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019204:GTP-Binding Proteins; D018847:Opioid Peptides; D037342:Pertussis Toxin; D011957:Receptors, Opioid; D010566:Virulence Factors, Bordetella; D020960:omega-Conotoxins; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722285:Oprl1 protein, rat