Changes in the gene expression of specific G-protein subunits correlate with morphine insensitivity in streptozotocin-induced diabetic rats.

Several animal and human studies have shown a decreased analgesic potency of morphine in diabetic subjects. Since G-protein subunits have an important role in morphine effects at the cellular level and the exact mechanism(s) of diabetes-induced morphine insensitivity has not been fully clarified yet, the present study was designed to determine the changes in the levels of G(alphai), G(alphas), G(beta) mRNAs and proteins involved in this phenomenon. All experiments were carried out on male Wistar rats. The tail-flick test was used to assess the nociceptive threshold. Diabetes was induced by injection of 50 mg/kg (i.p.) streptozotocin. Four weeks after diabetes induction, the dorsal half of the lumbar spinal cord was assayed for the expression of G-protein subunits using semiquantitative RT-PCR and immunoblotting. The antinociceptive effect of intrathecal morphine (5, 10 and 15 microg i.t.) was significantly reduced in diabetic rats and these effects were reversed with insulin replacement. In diabetic animals, a significant increase in the mRNA levels of G(alphai) (23.5%) was observed in the dorsal portion of the lumbar spinal cord. The mRNA level of G(alphas) and G(beta) did not change. Following diabetes a significant decrease in the protein levels of G(alphai) was induced. In contrast, no significant changes were observed in the protein level of G(alphas) and G(beta). In diabetic animals that received insulin, levels of G(alphai) mRNA and protein were close to those in control rats. In conclusion, our results demonstrate that the expression pattern of the cellular components involved in morphine analgesia changes in diabetic animals. This may be, at least partly, responsible for diabetes-induced morphine insensitivity.