Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes

Neurobiology of Disease
Ryan B GriggsBradley K Taylor

Abstract

Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca2+ mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Sim...Continue Reading

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Citations

Aug 14, 2020·Molecular Pain·Muhammad Saad YousufBradley J Kerr
Sep 17, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Xu-Hui LiMin Zhuo
Dec 19, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Valéria TékusZsuzsanna Helyes
Oct 27, 2021·Physiological Reviews·Katrina F OstromRennolds S Ostrom

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