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

• Published in: Neurobiology of disease Vol. 127; pp. 76 - 86
• Main Authors: Griggs, Ryan B., Santos, Diogo F., Laird, Don E., Doolen, Suzanne, Donahue, Renee R., Wessel, Caitlin R., Fu, Weisi, Sinha, Ghanshyam P., Wang, Pingyuan, Zhou, Jia, Brings, Sebastian, Fleming, Thomas, Nawroth, Peter P., Susuki, Keiichiro, Taylor, Bradley K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2019; Elsevier
• Subjects: AC1; Adenylyl Cyclases - metabolism; Animals; Avoidance Learning - drug effects; Avoidance Learning - physiology; Behavior, Animal - drug effects; Behavior, Animal - physiology; Cyclic AMP-Dependent Protein Kinases - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetic Neuropathies - metabolism; Epac; Glyoxalase; Guanine Nucleotide Exchange Factors - metabolism; Male; Methylglyoxal; Mice; Neuropathic pain; Pain Measurement; Painful diabetic neuropathy; PKA; Posterior Horn Cells - drug effects; Posterior Horn Cells - metabolism; Pyruvaldehyde - metabolism; Pyruvaldehyde - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Spinal; TRPA1; TRPA1 Cation Channel - metabolism; Type 2 diabetes; Type 2 diabetes; Spinal; Methylglyoxal; TRPA1; Glyoxalase; PKA; Epac; Painful diabetic neuropathy; Neuropathic pain; AC1
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2019.02.019

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. 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.
Schematic illustrating our experimental approach and working hypothesis. We tested whether a spinal MG➔TRPA1➔AC1➔PKA/Epac cascade contributes to type 2 painful diabetic neuropathy (PDN) by using pharmacological and genetic approaches (as shown by ▪) and measuring pain-like behavior and calcium imaging in the db/db and intrathecal MG models. The dashed line leading from PKA represents the possibility that PKA contributes to the initiation but not maintenance of PDN (see discussion). Our results support the conclusion that MG in type 2 diabetes leads to activation of a TRPA1-AC1-Epac signaling cascade to produce PDN. [Display omitted]
•Methylglyoxal activates spinal nociresponsive neurons and produces affective pain.•Methylglyoxal contributes to spinal sensitization and pain in db/db mice.•MG scavenger GERP10 reduces painful diabetic neuropathy in db/db.•Glyoxalase 1 overexpression vector reduces painful diabetic neuropathy in db/db.•A spinal TRPA1-AC1-Epac signaling pathway facilitates pain in db/db.