Antinociceptive effects of the selective non-peptidic δ-opioid receptor agonist TAN-67 in diabetic mice

The antinociceptive potencies of 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), a non-peptidic δ-opioid receptor agonist, were examined using the acetic acid abdominal constriction test and the tail-flick test in diabetic mice. TAN-67, at doses of 3-100 mg/kg, i.p., produced a marked and dose-dependent inhibition of the number of acetic acid-induced abdominal constrictions in both non-diabetic and diabetic mice. The antinociceptive effect of TAN-67 in the acetic acid abdominal constriction test in diabetic mice was greater than that in non-diabetic mice. Indeed, the ED₅₀ (95% confidence limits) value of TAN-67 for the inhibition of acetic acid-induced abdominal constrictions in diabetic mice (6.0 (3.5-10.5) mg/kg) was significantly lower than that in non-diabetic mice (31.4 (14.2-69.4) mg/kg). The antinociceptive effect of TAN-67 was not antagonized by pretreatment with either β-funaltrexamine, a selective μ-opioid receptor antagonist, or nor-binaltorphimine, a selective κ-opioid receptor antagonist. When 7-benzylidenenaltrexone (0.3 mg/kg, s.c.), a selective δ₁-opioid receptor antagonist, was administered 10 min before treatment with TAN-67, the antinociceptive effect of TAN-67 was significantly antagonized. However, naltriben, a selective δ₂-opioid receptor antagonist, had no significant effect on the antinociceptive effect of TAN-67. Furthermore, in the tail-flick test, TAN-67 at doses of 3-30 mg/kg, i.p., also produced a marked and dose-dependent antinociceptive effect in diabetic mice, but not in non-diabetic mice. In conclusion, TAN-67 produced an antinociceptive effect through the activation of δ₁-opioid receptors. Furthermore, the results of this study support our hypothesis that mice with diabetes are selectively hyperresponsive to δ₁-opioid receptor-mediated antinociception.