7-Benzylidenenaltrexone (BNTX): A selective δ₁ opioid receptor antagonist in the mouse spinal cord

Recent reports provided evidence that at least two δ opioid receptors may mediate antinociception in mice. In this study, we studied further the involvement of δ opioid receptor subtypes in mediating antinociception at spinal sites in mice using subtype selective agonists and antagonists. The antinociceptive ED₅₀ values (95 % C.I.) of i.t. administered DPDPE [(D-Pen², D-Pen⁵)enkephalin] (δ₁ receptor agonist) and DELT II [(D-Ala²)deltorphin II] (δ₂ receptor agonist) were 6.3 (5.2-7.6) and 6.4 (5.4-7.7) nmol/mouse, respectively. Administration of BNTX, s.c. increased the antinociceptive ED₅₀ value of DPDPE 5.9-fold whereas that of DELT II was not changed significantly. On the other hand administration of maltriben (NTB, the benzofuran derivative of naltrindole), s.c. increased the antinociceptive ED₅₀ value of DELT II 12.5-fold but did not alter that of DPDPE. Similarly administration of BNTX, i.t. increased the antinociceptive ED₅₀ value of DPDPE 4-fold without altering significantly that of DELT II. NTB given i.t. enlarged the antinociceptive ED₅₀ of DELT II 11-fold without affecting significantly that of DPDPE. BNTX, s.c. did not alter the antinociceptive ED₅₀ values of the μ-agonists, DAMGO [(D-Ala², MePhe⁴, Gly-ol⁵) enkephalin] and morphine or that of the κ-agonist, U50,488H [trans(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinylcyclohexyl]benzeneacetamide] These results demonstrate that BNTX is highly selective for δ₁ opioid receptors at spinal sites. Also, the present data provide for the involvement of both δ₁ and δ₂ opioid receptors in mediating antinociception at spinal sites in mice.