Possible involvement of dynorphin A-(1-17) release via mu1-opioid receptors in spinal antinociception by endomorphin-2.
The antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated via mu-opioid receptors. However, although endomorphins do not have an appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist norbinaltorphimine markedly reduces the antinociceptive response to i.c.v. or i.t. administered endomorphin-2 but not endomorphin-1. These results suggest that endomorphin-2 initially stimulates mu-opioid receptors, which subsequently induce the release of dynorphins that act on kappa-opioid receptors to produce antinociception. The present study was performed in mice to determine whether the release of dynorphins by i.t. administered endomorphin-2 is mediated through mu-opioid receptors to produce antinociception. Intrathecal pretreatment with an antiserum against dynorphin A-(1-17), but not against dynorphin B-(1-13) or alpha-neoendorphin, dose-dependently prevented the paw-withdrawal inhibition by endomorphin-2. The pretreatments with these antisera did not affect the endomorphin-1- or [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin-induced paw-withdrawal inhibition. The attenuation of endomorphin-2-induced antinociception by i.t. pretreatment with an antiserum against dynorphin A-(1-17) or s.c. pretreatment with norbinaltorphimine was blocked dose-dependently by s.c. pretreatment with the mu-opioid receptor antagonist beta-funaltrexamine or the mu(1)-opioid receptor antagonist naloxonazine at ultra-low doses that are ineffective against mu-opioid receptor agonists. These results suggest that the spinal antinociception induced by endomorphin-2 is mediated through the stimulation of a distinct subtype of mu(1)-opioid receptor that induces the release of the endogenous kappa-opioid peptide dynorphin A-(1-17) in the spinal cord.
Mizoguchi
Hirokazu
H
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan.
Watanabe
Hiroyuki
H
Hayashi
Takafumi
T
Sakurada
Wataru
W
Sawai
Toshiki
T
Fujimura
Tsutomu
T
Sakurada
Tsukasa
T
Sakurada
Shinobu
S
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000276:immunology / Q000378:metabolism*; D006358:Hot Temperature / Q000009:adverse effects; D007106:Immune Sera / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D010812:Physical Stimulation; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013997:Time Factors
D000701:Analgesics, Opioid; D007106:Immune Sera; D009842:Oligopeptides; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D004399:Dynorphins