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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.*

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

Neurobiol. Dis. 127, 76-86 (2019)
Postprint DOI PMC
Open Access Green
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 TRPAl-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-TRPAl-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Type 2 Diabetes ; Neuropathic Pain ; Methylglyoxal ; Trpa1 ; Epac ; Ac1 ; Pka ; Glyoxalase ; Spinal ; Painful Diabetic Neuropathy; Trpa1 Ion-channel; Glyoxalase 1; Protein-kinase; Central Sensitization; Neuropathic Pain; Glycemic Control; Small Molecules; Contributes; Hyperalgesia; Activation
ISSN (print) / ISBN 0969-9961
e-ISSN 1095-953X
Zeitschrift Neurobiology of Disease
Quellenangaben Band: 127, Heft: , Seiten: 76-86 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)