title: Decreased expression of intestinal P-glycoprotein increases the analgesic effects of oral morphine in a streptozotocin-induced diabetic mouse model.
abstract: Morphine is one of the strongest analgesics and is commonly used for the treatment of chronic pain. The pharmacokinetic properties of morphine are, in part, modulated by P-glycoprotein (P-gp). We 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 examine the analgesic effects of orally administered 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 using a HPLC-ECD system. Oral morphine analgesic effects and serum and brain morphine content were significantly increased 9 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. Our findings suggest that the analgesic effects of oral morphine are dependent on intestinal P-gp expression, and this may be one of the reasons that it is difficult to obtain stable pharmacological effects of morphine in diabetic patients.
authors: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
authors: Ayaka
authors: A
authors: Nawa
authors: Wakako
authors: W
authors: Fujita-Hamabe
authors: Shiroh
authors: S
authors: Kishioka
authors: Shogo
authors: S
authors: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000700:Analgesics / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010146:Pain / Q000188:drug therapy
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000700:Analgesics; D006146:Guanidines; D009020:Morphine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine