N-acetyl beta-endorphin-(1-31) and substance P regulate the supraspinal antinociception mediated by mu opioid and alpha-2 adrenoceptors but not by delta opioid receptors in the mouse.
A desensitizing protocol to i.c.v. substance P (SP) (from 0.1-10 nmol x 2 at 25-min interval) diminished the supraspinal mu-mediated antinociceptive activity of morphine, D-Ala2-N-MePhe4-Gly-ol5-enkephalin (DAMGO), beta-endorphin-(1-31), D-Ala2-D-Leu5-enkephalin and of the alpha-2 agonist clonidine, whereas the activity of the highly selective delta ligands [D-Pen2,5]-enkephalin and [D-Ala2]-Deltorphin II remained unchanged. This effect was noncompetitive as the slopes for the antinociceptive dose-response curves diminished after SP pretreatment. The antagonism was evident within a few hours after SP and lasted longer than 15 days. The N-acetyl derivative of beta-endorphin-(1-31) (1 pmol) increased the antinociceptive response of DAMGO, D-Ala2-D-Leu5-enkephalin and clonidine, but not of morphine, in SP-pretreated mice. ED80 values of opioid agonists or naltrexone did not prevent SP from reducing the antinociceptive activity of opioids and clonidine. The effect of N-acetyl beta-endorphin-(1-31) was transitory and disappeared within 48 hr, after this period the long-lasting antagonism of SP was revealed. Clonidine (150 nmol) also enhanced opioid antinociception in SP-treated mice. This effect was reversed by the alpha-2 antagonist yohimbine (50 nmol) when given 10 min before clonidine. In mice undergoing treatment with pertussis toxin (0.5 micrograms i.c.v.), an agent that impairs the function of GTP-binding regulatory proteins (Gi/Go), the SP desensitizing protocol did not reduce further the antinociception of DAMGO or morphine. These results suggest a modulatory role for the SP system and the neuropeptide N-acetyl beta-endorphin-(1-31) upon mu and alpha-2 but not delta-mediated supraspinal antinociception in mice.
Sánchez-Blázquez
P
P
Neuropharmacology Unit, Cajal Institute, CSIC, Madrid, Spain.
Garzón
J
J
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D001615:beta-Endorphin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000700:Analgesics; D010446:Peptide Fragments; D011942:Receptors, Adrenergic, alpha; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013373:Substance P; D001615:beta-Endorphin; C035101:N-acetyl-beta-endorphin; D003000:Clonidine