Further characterization of alpha N-acetyl beta-endorphin-(1-31) regulatory activity, I: Effect on opioid- and alpha 2-mediated supraspinal antinociception in mice.
Picomol doses of the acetylated derivative of beta-endorphin-(1-31), injected intracerebroventricularly (icv) in mice, reduced the analgesic activity of morphine, etorphine and beta-endorphin-(1-31), while the efficiency of DAGO and DADLE in producing analgesia was enhanced. The effects of the delta agonists DPDPE and [D-Ala2]-Deltorphin II were not altered by this treatment. After alpha N-acetyl beta-endorphin-(1-31) injection, morphine antagonized the analgesia of DAGO. The regulatory effect of alpha N-acetyl beta-endorphin-(1-31) was exhibited when giving the peptide both before (up to 24 h) and after the opioids. Naloxone did not prevent or reverse that modulatory activity; moreover, pretreatment with the acetylated peptide did not change the pA2 value displayed by the antagonist at the mu receptor. The antinociceptive activity of the alpha 2-adrenoceptor agonist clonidine was also increased in mice treated with alpha N-acetyl beta-endorphin-(1-31). The reducing activity of alpha N-acetyl beta-endorphin-(1-31) upon morphine- and beta-endorphin-induced analgesia was not exhibited in mice undergoing treatment with pertussis toxin or N-ethylmaleimide, agents known to impair the function of Gi/Go transducer proteins. However, the enhancing activity displayed by this peptide upon DAGO- DADLE and clonidine-evoked antinociception was still manifested. These results confirm and strengthen the idea of alpha N-acetyl beta-endorphin-(1-31) acting as a non-competitive regulator of mu opioid- and alpha 2-adrenoceptor-mediated supraspinal antinociception. A neural substrate acted on by both receptors (likely Gi/Go transducer proteins) appears to be involved in the effects of that neuropeptide.
Sánchez-Blázquez
P
P
Neuropharmacology Unit, Cajal Institute, C.S.I.C., Madrid, Spain.
Garzón
J
J
D000698:Analgesia; D000700:Analgesics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D004723:Endorphins / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement; D010455:Peptides; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects; D017450:Receptors, Opioid, mu; D001615:beta-Endorphin / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000700:Analgesics; D004723:Endorphins; D004745:Enkephalins; D010455:Peptides; D011942:Receptors, Adrenergic, alpha; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D001615:beta-Endorphin; D016308:Enkephalin, Leucine-2-Alanine; C035101:N-acetyl-beta-endorphin; D019204:GTP-Binding Proteins