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

Ryan B. Griggs, Diogo F. Santos, Don E. Laird, Suzanne Doolen, Renee R. Donahue, Caitlin R. Wessel, Weisi Fu, Ghanshyam P. Sinha, Pingyuan Wang, Jia Zhou, Sebastian Brings, Thomas Fleming, Peter P. Nawroth, Keiichiro Susuki, Bradley K. Taylor

Research output: Contribution to journalArticle

2 Scopus citations

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 Ca 2+ 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. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPA1-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)76-86
Number of pages11
JournalNeurobiology of Disease
Volume127
DOIs
StatePublished - Jul 2019

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Keywords

  • AC1
  • Epac
  • Glyoxalase
  • Methylglyoxal
  • Neuropathic pain
  • PKA
  • Painful diabetic neuropathy
  • Spinal
  • TRPA1
  • Type 2 diabetes

ASJC Scopus subject areas

  • Neurology

Cite this

Griggs, R. B., Santos, D. F., Laird, D. E., Doolen, S., Donahue, R. R., Wessel, C. R., Fu, W., Sinha, G. P., Wang, P., Zhou, J., Brings, S., Fleming, T., Nawroth, P. P., Susuki, K., & Taylor, B. K. (2019). Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes. Neurobiology of Disease, 127, 76-86. https://doi.org/10.1016/j.nbd.2019.02.019