Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: Evidence for delta opioid receptor subtypes

In this study naltrindole (NTI) and its benzofuran derivative (NTB) were studied for their antagonist activity against various delta opioid receptor agonists in the tail-flick antinociceptive assay in mice. The antinociceptive ED₅₀ of i.c.v. administered DSLET [(D-Ser², Leu⁵,Thr⁶)enkephalin] was shifted about 4-fold by either s.c. NTB or i.c.v. NTI injection. On the other hand, the antinociceptive ED₅₀ of i.c.v. administered DPDPE [(D-Pen²,D-Pen⁵)enkephalin] was shifted 1.4- and 1.8-fold, with s.c. NTB and i.c.v. NTI administration, respectively, which were significantly lower than the shifts observed with DSLET. NTB did not alter the antinociceptive action of i.c.v. administered [(D-Ala²,D-Leu⁵)enkephalin], morphine sulfate, [(D-Ala²,MePhe⁴,Gly-ol⁵)enkephalin] or U-50,488H {trans(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide}. At spinal sites, the antinociceptive ED₅₀ of intrathecal (i.t.) administered DSLET was increased by 12.5-fold by s.c NTB injection, whereas that of DPDPE was unaffected. NTB injection at this site also did not alter the antinociceptive action of i.t. administered [D-Ala², D-Leu⁵]enkephalin, [(D-Ala²,MePhe⁴,Gly-ol⁵)enkephalin] or morphine sulfate. Pretreatment of animals with β-funaltrexamine caused a large increase in the capacity of NTB to antagonize the antinociceptive activity of i.t. administered DSLET with little change in that of i.t. administered DPDPE. When cross-tolerance between DSLET and DPDPE was studied by i.c.v. injection of a single large dose of either DSLET or DPDPE 24 hr before the antinociceptive assay, there was no development of cross-tolerance between the two peptides. Based on these results, it was concluded that the antinociceptive action of DSLET and DPDPE may be mediated by different receptors, possibly delta opioid subtypes.