Differential antinociceptive effects induced by intrathecally administeredendomorphin-1 and endomorphin-2 in the mouse

Two highly selective p-opioid receptor agonists, endomorphin-1 and endomorp hin-2, have been identified and postulated to be endogenous ligands for VL- opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and en domorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinoc iception with the paw-withdrawal test. The paw-withdrawal inhibition rapidl y reached its peak at I min, rapidly declined and returned to the pre-injec tion levels in 20 min. The inhibition of the paw-withdrawal responses to en domorphin-1 and endomorphin-2 at a dose of 5 nmol observed at I and 5 min a fter injection was blocked by pretreatment with a non-selective opioid rece ptor antagonist naloxone (I mg/kg, s.c.). The antinociceptive effect of end omorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, nal oxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdra wal inhibition at both 1 and 5 min after injection was blocked by pretreatm ent with K-opioid receptor antagonist nor-binaltorphimine (10 mg/ka, s.c.) or the delta (2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta (1)-opioid receptor antagonist 7-benzylidine naltrexone (BNT X) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both I and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), nal triben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induce d paw-withdrawal inhibition was blocked by the pretreatment with an antiser um against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum a gainst dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate t hat endomorphin-2 given i.t. produces its antinociceptive effects via the s timulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additiona l components, which are mediated by the release of dynorphin A-(1-17) and [ Met(5)]enkephalin which subsequently act on kappa -opioid receptors and del ta (2)-opioid receptors to produce antinociception. (C) 2001 Elsevier Scien ce B.V. All rights reserved.