Dosing time-dependent changes in the analgesic effect of pregabalin on diabetic neuropathy in mice

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 antiallodynic effect of PGN on diabetic mice was modulated by circadian changes in its intestinal absorption. A single intraperitoneal administration of 200 mg/kg streptozotocin (STZ) to mice induced type I diabetic pathologic changes that were accompanied by tactile allodynia. The intensity of tactile allodynia in STZ-induced diabetic mice was alleviated by the oral administration of PGN; however, the antiallodynic effect varied according to its dosing time. The analgesic 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 STZ-induced 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 antiallodynic effect of PGN and oscillation in Octn1 expression were also detected in type II diabetic db/db mice. These results suggested that the dosing time-dependent differences in the analgesic 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.