Micro-opioid receptor preferentially inhibits oxytocin release from neurohypophysial terminals by blocking R-type Ca2+ channels.
Oxytocin release from neurophypophysial terminals is particularly sensitive to inhibition by the micro-opioid receptor agonist, DAMGO. Because the R-type component of the neurophypophysial terminal Ca2+ current (ICa) mediates exclusively oxytocin release, we hypothesised that micro-opioids could preferentially inhibit oxytocin release by blocking this channel subtype. Whole-terminal recordings showed that DAMGO and the R-type selective blocker SNX-482 inhibit a similar ICa component. Measurements of [Ca2+]i levels and oxytocin release confirmed that the effects of DAMGO and SNX-482 are not additive. Finally, isolation of the R-type component and its associated rise in [Ca2+]i and oxytocin release allowed us to demonstrate the selective inhibition by DAMGO of this channel subtype. Thus, micro-opioid agonists modulate specifically oxytocin release in neurophypophysial terminals by selectively targeting R-type Ca2+ channels. Modulation of Ca2+ channel subtypes could be a general mechanism for drugs of abuse to regulate the release of specific neurotransmitters at central nervous system synapses.
Ortiz-Miranda
S
S
Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Dayanithi
G
G
Custer
E
E
Treistman
S N
SN
Lemos
J R
JR
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020908:Calcium Channels, R-Type / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology; D010121:Oxytocin / Q000378:metabolism*; D010904:Pituitary Gland, Posterior / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013111:Spider Venoms / Q000494:pharmacology
D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020908:Calcium Channels, R-Type; D009479:Neuropeptides; D017450:Receptors, Opioid, mu; C115521:SNX 482; D013111:Spider Venoms; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D001127:Arginine Vasopressin; D010121:Oxytocin; D002118:Calcium