Effect of opioid receptor ligands on the mu-S196A knock-in and mu knockout mouse vas deferens.
We have determined the effect of naltrexone, naloxone, [D-Ala2,D-Leu5]enkephalin (DADLE), and morphine on the mu-S196A opioid receptor knock-in and mu-opioid receptor knockout mouse vas deferens preparations. The antagonists, naltrexone and naloxone, exhibited agonist activity and possessed IC50 values that were 14- and 37-fold greater than morphine on the S196A preparation. Morphine was found to be threefold more potent at S196A relative to wild-type mu-opioid receptor. The mouse vas deferens data suggest that S196 in transmembrane helix 4 of the mu-opioid receptor modulates efficacy. It is proposed that this may be due to decreased dimerization of the receptor. Identical IC50 values of DADLE obtained on the wild-type, S196A knock-in, and mu-opioid receptor knockout preparations support the absence of mu-delta heterodimers in the mouse vas deferens.
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA. porto001@umn.edu
Philip S
PS
Portoghese
Ping-Yee
PY
Law
Horace H
HH
Loh
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000235:genetics*; D014649:Vas Deferens / Q000187:drug effects*
D000701:Analgesics, Opioid; D008024:Ligands; D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D009270:Naloxone; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine