Evidence for differential modulation of μ-opioid receptor-mediated antinociceptive and antitussive activities by spleen-derived factor(s) from diabetic mice

Abstract

The effects of spleen-derived factor(s) from diabetic mice on the antinociceptive and antitussive effects of μ-opioid receptor agonists were examined in mice. The antinociceptive effects were examined 1 week after adoptive transfer of the supernatant of spleen cell homogenate (SSCH) from diabetic mice (SSCH-D). Naive mice which had been injected with SSCH-D were less sensitive to the antinociceptive effects of μ-opioid receptor agonists, such as morphine and [ d-Ala 2, N-MePhe 4, Gly-ol 5]enkephalin (DAMGO), than mice which had been injected with SSCH from non-diabetic mice. The antinociceptive effects of DAMGO was also significantly lower in naive mice injected with SSCH-D than in SSCH from non-diabetic mice (SSCH-ND)-treated naive mice, when assessed 2 weeks after adoptive transfer of SSCH. The sensitivity to the antinociceptive effect of [ d]-Pen 2,5]enkephalin (DPDPE), a δ-opioid receptor agonist, was significantly enhanced 2 weeks, but not 1 week, after adoptive transfer of SSCH-D. On the other hand, adoptive transfer of SSCH-D to naive mice had no significant effect on the recipients' antitussive sensitivities to morphine and DAMGO when assessed 1 week after transfer of SSCH-D. However, when the antitussive effect was assessed 2 weeks after adoptive transfer of SSCH, the antitussive effect of DAMGO was significantly lower in naive mice injected with SSCH-D than in SSCH-ND-treated naive mice. The reduction in the antitussive effect of DAMGO in naive mice had been injected with SSCH-D 2 weeks before testing was abolished when they were pretreated with naltrindole, a selective δ-opioid receptor antagonist. These findings suggest that some factor(s) derived from spleen cells may primarily contribute to the reduction in the antinociceptive effects, but not the antitussive effects, of supraspinal μ-opioid receptors. Furthermore, the dysfunction of μ-opioid receptors may up-regulate δ-opioid receptors, which would reduce μ-opioid receptor-mediated antitussive effects.