Pronociceptive effects of a TRPA1 channel agonist methylglyoxal in healthy control and diabetic animals

Abstract

Abstract Aims Methylglyoxal (MG), a reactive carbonyl compound generated in diabetes mellitus (DM), activates the TRPA1 ion channel. Here we studied whether MG induces mechanical hypersensitivity or ongoing pain and whether the pronociceptive effect of MG is changed following its sustained endogenous release in DM. Methods DM was induced by streptozotocin (50-60 mg/kg i.p.) in the rat. MG and Chembridge-5861528 (CHEM), a selective TRPA1 channel antagonist, were administered intraplantarly (i.pl.) in control and diabetic animals. Limb withdrawal to monofilaments was used as an index of hypersensitivity, and observation of sustained pain-like behavior and conditioned place-avoidance test were used to assess ongoing pain. In vitro calcium imaging was used to study whether MG induces sustained activation of dorsal root ganglion (DRG) neurons of diabetic as well as control animals. Results MG produced mechanical hypersensitivity and ongoing pain behavior in control animals, which effects were reduced in diabetic animals. CHEM treatment at a dose suppressing the MG-induced mechanical hypersensitivity failed to suppress the MG-induced ongoing pain behavior. MG was able to produce sustained calcium inflow in DRG neurons of DM as well as control animals. Conclusions The results suggest that MG induces hypersensitivity and ongoing pain that are reduced in diabetes mellitus, possibly due to changes caused by the DM-induced sustained endogenous release of MG. Moreover, the MG-induced mechanical hypersensitivity can be more effectively reversed by a TRPA1 antagonist than the MG-induced ongoing pain behavior.