Dosing Time-Dependent Changes in the Analgesic Effect of Pregabalin on Diabetic Neuropathy in Mice

Abstract

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 diabetesinduced 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 daydependent 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.

Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component

“…application of 50 mg/kg pregabalin (equivalent to 314 μmol) was reported to yield a maximum analgesic effect for up to 1 hour, which was neutralized by 4 hours. 3 Here, we observed that a single dose of i.p. sivelestat at 20 mg/kg (equivalent to 46 μmol) completely reversed mechanical hypersensitivity in the STZ model for up to 6 hours.…”

The biology of ergothioneine, an antioxidant nutraceutical

“…Incubating the cells just with ERG showed that it was taken up about 100 times more quickly than was tetraethylammonium, leading to the designation of SLC22A4 as 'the' ERG transporter (130) . Subsequent work (87,(169)(170)(171)(172) has confirmed and reinforced this view of SLC22A4 and its homologues (173) as having significant specificity for ERG, and weak activity for various drugs (174)(175)(176)(177) . It is concentrative, coupled in humans to influx of 2 or 3 Na þ ions per ERG transported (130) .…”

“…It is concentrative, coupled in humans to influx of 2 or 3 Na þ ions per ERG transported (130) . Interestingly, it is up-regulated chronobiologically just before meal times (175) . The rat and human orthologues are interchangeable (178) .…”

Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line

“…It has been reported that organic cation transporter novel type 1 (OCTN1/SLC22A4) is a mediator of the intestinal absorption of pregabalin ( 31 ) and is expressed in hCMEC/D3 cells, at least at the mRNA level ( 27 ). In order to evaluate the contribution of OCTN1 to the pregabalin uptake by hCMEC/D3 cells, we utilized TEA at 1 mM, which reportedly inhibited OCTN1-mediated TEA uptake by 50–80% ( 32 , 33 ).…”