N-ACETYL BETA-ENDORPHIN-(1-31) AND SUBSTANCE-P REGULATE THE SUPRASPINAL ANTINOCICEPTION MEDIATED BY MU-OPIOID AND ALPHA-2-ADRENOCEPTORS BUTNOT 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 antinoci ceptive activity of morphine, D-Ala2-N-Me-Phe4-Gly-ol5-enkephalin (DAM GO), beta-endorphin-(1-31), D-Ala2-D-Leu5-enkephalin and of the alpha- 2 agonist clonidine, whereas the activity of the highly selective delt a ligands [D-Pen2,5]-enkephalin and [D-Ala2]-Deltorphin II remained un changed. This effect was noncompetitive as the slopes for the antinoci ceptive dose-response curves diminished after SP pretreatment. The ant agonism 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) in creased the antinociceptive response of DAMGO, D,Ala2-D-Leu5-enkephali n and clonidine, but not of morphine, in SP-pretreated mice. ED80 valu es of opioid agonists or naltrexone did not prevent SP from reducing t he antinociceptive activity of opioids and clonidine. The effect of N- acetyl-endorphin-(1-31) was transitory and disappeared within 48 hr, a fter this period the long-lasting antagonism of SP was revealed. Cloni dine (150 nmol) also enhanced opioid antinociception in SP-treated mic e. This effect was reversed by the alpha-2 antagonist yohimbine (50 nm ol) when given 1 0 min before clonidine. In mice undergoing treatment with pertussis toxin (0.5 mug i.c.v.), an agent that impairs the funct ion of GTP-binding regulatory proteins (G(i)/G0), the SP desensitizing protocol did not reduce further the antinociception of DAMGO or morph ine. 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 n ot delta-mediated supraspinal antinociception in mice.