Possible mechanisms for insulin-induced attenuation of the antinociceptive effect of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin
Background: The effects of pretreatment with protein kinase C (PKC) and protein kinase A (PKA) inhibitors on the insulin-induced attenuation of the antinociceptive effect of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO) were investigated in mice.
Methods: Intracerebroventricular (i.c.v.) pretreatment with insulin was shown to dose- and time-dependently reduce the antinociceptive effect of i.c.v. DAMGO (5.6 ng) in mice. Further, i.c.v. pretreatment with herbimycin A, a highly selective tyrosine kinase inhibitor, at doses of 200 and 600 ng for 70 minutes, dose-dependently reversed the insulin-induced attenuation of DAMGO’s antinociceptive effect. Additionally, pretreatment with the serine/threonine kinase inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H7) at doses of 3-30 nmol for 60 minutes also dose-dependently reversed the attenuation of DAMGO’s antinociception caused by insulin. Moreover, i.c.v. pretreatment with the selective PKC inhibitor calphostin C at doses of 1 and 3 pmol for 60 minutes reversed the attenuation of DAMGO’s antinociceptive effect, while the PKA inhibitor (8R, 9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy-carbonyl-8-methyl-2, 3, 9, 20-tetrahydro-8, 11-epoxy-1H, 8H, 11H-2, 7b, 11a-triaqzadibenzo[a, g]cycloocta[c, d, e]-trinden-1-one (KT5720) at a dose of 10 pmol for 60 minutes had no effect.
Results: These findings suggest that the reduction of DAMGO-induced antinociception by insulin may, in part, result from the activation of PKC, which then triggers the activation of tyrosine kinase.
Conclusion: The results indicate that insulin may modulate DAMGO-induced antinociception through a mechanism involving the activation of PKC and subsequent BAY-1816032 tyrosine kinase signaling pathways.