Decreased expression of intestinal P-glycoprotein increase the analgesic effects of oral morphine in a streptozotocin-induced diabetic mouse model

抄録

  Morphine is one of the strongest analgesics and commonly used for the treatment of chronic pain. The pharmacokinetic properties of morphine are, in part, modulated by P-glycoprotein (P-gp). We have previously reported that intestinal P-gp expression levels are influenced via the activation of inducible nitric oxide synthase (iNOS) in streptozotocin (STZ)-induced diabetic mice. Herein, we examined the analgesic effects of orally administrated morphine and its pharmacokinetic properties under diabetic conditions, specifically we focusing on the involvement of intestinal P-gp in a type 1 diabetic mouse model. We assessed the analgesic effect of morphine using the tail-flick test. Serum and brain morphine levels were determined on a HPLC-ECD system. Oral morphine analgesic effects, and serum and brain morphine content were significantly increased nine days after STZ administration. The increase in the analgesic effects of morphine, as well as serum and brain morphine content, was suppressed by aminoguanidine, a specific iNOS inhibitor. Conversely, there were no changes in the analgesic effects obtained with subcutaneous morphine in STZ-treated mice. In conclusions, our findings suggest that the analgesic effects of oral morphine are dependent on intestinal P-gp expression, and that may be one of the problems against obtaining stable pharmacological effects of morphine in diabetic patients.