N-ALPHA-ACETYL-BETA-ENDORPHIN-(1-31) DISRUPTS THE DIMINISHING EFFECT OF MASTOPARAN ON OPIOID-EVOKED AND CLONIDINE-EVOKED SUPRASPINAL ANTINOCICEPTION IN MICE

Intracerebroventricular (i.c.v.) administration to mice of the venom t etradecapeptide mastoparan (MP), which binds certain G transducer prot eins, resulted in a long-lasting reduction of the supraspinal antinoci ception induced by opioids and clonidine, the alpha-2 adrenoceptor ago nist. The N-alpha-acetyl derivative of beta-endorphin-(1-31) (NAC-beta -END; 1 pmol, i.c.v. per mouse) injected 1 hr before an equimolar dose of MP lessened the antagonist activity of the venom peptide on the an tinociception induced by D-pen(2,5)-enkephalin, [D-Ala(2)]deltorphin I I, D-Ala(2)-N-MePhe(4)-Gly-ol(5)-enkephalin and clonidine when evaluat ed 24 hr later with the tail-flick test. The impairment exerted by MP on these analgesic substances was not altered when NAC-beta-END was ad ministered after the venom peptide. Therefore, the antinociceptive eff ect depends on which peptide was injected first. The protective activi ty of NAC-beta-END against MP antagonism of opioid/clonidine antinocic eption was dose related and exerted at attomolar and femtomolar doses. This finding strengthens the idea of a neural substrate (possibly G p roteins) distinct from the opioid receptor enacted by NAC-beta-END to modulate opioid/clonidine antinociception. This research shows that a series of substances, neuropeptides and venoms dissimilarly influence the functional state of G proteins, thus altering the agonist-activate d transduction cascade.