Possible involvement of dynorphin A release via mu1-opioid receptor on supraspinal antinociception of endomorphin-2.
It has been demonstrated that the antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated through mu-opioid receptors. Moreover, though endomorphins do not have appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist nor-binaltorphimine markedly blocks the antinociception induced by i.c.v.- or i.t.-injected endomorphin-2, but not endomorphin-1. These evidences propose the hypothesis that endomorphin-2 may initially stimulate the mu-opioid receptors, which subsequently induces the release of dynorphins acting on kappa-opioid receptors to produce antinociception. The present study was performed to determine whether the release of dynorphins by i.c.v.-administered endomorphin-2 is mediated through mu-opioid receptors for producing antinociception. Intracerebroventricular pretreatment with an antiserum against dynorphin A, but not dynorphin B or alpha-neo-endorphin, and s.c. pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine dose-dependently attenuated the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1 and DAMGO. The attenuation of endomorphin-2-induced antinociception by pretreatment with antiserum against dynorphin A or nor-binaltorphimine was dose-dependently eliminated by additional s.c. pretreatment with a selective mu-opioid receptor antagonist beta-funaltrexamine or a selective mu1-opioid receptor antagonist naloxonazine at ultra low doses, which are inactive against micro-opioid receptor agonists in antinociception, suggesting that endomorphin-2 stimulates distinct subclass of micro1-opioid receptor that induces the release of dynorphin A acting on kappa-opioid receptors in the brain. It concludes that the antinociception induced by supraspinally administered endomorphin-2 is in part mediated through the release of endogenous kappa-opioid peptide dynorphin A, which is caused by the stimulation of distinct subclass of micro1-opioid receptor.
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Sendai 981-8558, Japan. s-sakura@tohoku-pharm.ac.jp
Shinobu
S
Sakurada
Toshiki
T
Sawai
Hirokazu
H
Mizoguchi
Hiroyuki
H
Watanabe
Chizuko
C
Watanabe
Akihiko
A
Yonezawa
Masaya
M
Morimoto
Takumi
T
Sato
Takaaki
T
Komatsu
Tsukasa
T
Sakurada
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004399:Dynorphins / Q000276:immunology / Q000378:metabolism*; D004723:Endorphins / Q000276:immunology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology / Q000502:physiology; D011498:Protein Precursors / Q000276:immunology; D017473:Receptors, Opioid, kappa / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology*
D000700:Analgesics; D004723:Endorphins; D007106:Immune Sera; D009842:Oligopeptides; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; C051844:norbinaltorphimine; C105294:endomorphin 2; D009271:Naltrexone; C025681:alpha-neoendorphin; C024524:beta-funaltrexamine; D004399:Dynorphins; C034643:naloxonazine; C036200:rimorphin