TY - JOUR T1 - Dosing time-dependent changes in the analgesic effect of pregabalin on diabetic neuropathy in mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.115.223891 SP - jpet.115.223891 AU - Takahiro Akamine AU - Satoru Koyanagi AU - Naoki Kusunose AU - Hana Hashimoto AU - Marie Taniguichi AU - Naoya Matsunaga AU - Shigehiro Ohdo Y1 - 2015/01/01 UR - http://jpet.aspetjournals.org/content/early/2015/05/11/jpet.115.223891.abstract N2 - Patients with diabetes often develop peripheral nerve complications, including numbness and pain in the extremities. Diabetes-induced peripheral neuropathic pain is characterized by hypersensitivity to innocuous stimuli, known as "tactile allodynia". Pregabalin (PGN) is currently used to treat diabetes-induced peripheral neuropathy and alleviates allodynia. In the present study, we demonstrated that the anti-allodynic effect of PGN on diabetic mice was modulated by circadian changes in its intestinal absorption. A single intraperitoneal administration of streptozotocin (200 mg/kg) to mice induced type-I diabetic pathological changes that were accompanied by tactile allodynia. The intensity of tactile allodynia in type-I diabetic mice was alleviated by the oral administration of PGN; however, the anti-allodynic effect varied according to its dosing time. The anti-allodynic effect of PGN was enhanced by its administration at the times of day when its intestinal absorption was accelerated. Organic cation transporter novel type-1 (Octn1) mediated the uptake of PGN into intestinal epithelial cells. The expression of Octn1 in the small intestine of type-I diabetic mice oscillated in a circadian time-dependent manner. This oscillation in Octn1 appeared to cause the time of day-dependent changes in the intestinal absorption of PGN. Similar dosing time-dependencies of the anti-allodynic effect of PGN and oscillation in Octn1 expression were also detected in type-II diabetic mice. These results suggested that the dosing time-dependent differences in the anti-allodynic effect of PGN were attributable to circadian oscillations in the intestinal expression of Octn1 and also that optimizing its dosing schedule may assist in achieving rational pharmacotherapy for diabetes-induced peripheral neuropathic pain. ER -