Systemic administration of (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), a highly selective delta opioid agonist, induces mu receptor-mediated analgesia in mice.
The mu opioid receptors are unquestionably implicated both in supraspinal and spinal analgesia, but there is some controversy about the role of delta receptors in the control of pain at the supraspinal level. This could be due, at least in part, to the local or i.c.v. administration of the opioid agonists. It was therefore interesting to reassess the overall contribution of mu and delta opioid receptors in modulating nociceptive thermal stimuli in the hot plate-test in mice after i.v. injections of DAMGO (Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol) and BUBU (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), two highly selective mu and delta receptor agonists, respectively, whose passage into the brain has been demonstrated recently. Both agonists induced dose-dependent, short-lasting (less than 30 min), antinociceptive responses that peaked 5 min after the administration of DAMGO and 10 min after the administration of BUBU. At these times, DAMGO [ED50: 1.26 mumols (0.65 mg)/kg] was 34 times more potent than BUBU [ED50: 42.5 mumols (34 mg)/kg] in the jump response and 13 times more potent in the paw lick. Apparent pA2 values of naloxone (0.004-0.1 mg/kg s.c.) antagonism for DAMGO and BUBU did not differ significantly, 6.95 +/- 0.054 and 7.28 +/- 0.030 for paw lick tests and 7.11 +/- 0.045 and 7.25 +/- 0.027 for jump tests, respectively. The slopes of the pA2 plots were close to the theoretical -1 value for competitive antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Baamonde
A
A
Département de Pharmacochimie Moléculaire, U 266 Institut National de Santé et de la Recherche Médicale, Paris, France.
Daugé
V
V
Gacel
G
G
Roques
B P
BP
D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009019:Morphinans / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*; D017450:Receptors, Opioid, mu
D004745:Enkephalins; D007211:Indoles; D009019:Morphinans; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C062971:tyrosyl-seryl(O-t-butyl)-glycyl-phenylalanyl-leucyl-threonine(O-t-butyl); D009271:Naltrexone; C055382:naltrindole