Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral TRPA1 and Nav1.8 channels

Metabolism. 2016 Apr;65(4):463-74. doi: 10.1016/j.metabol.2015.12.002. Epub 2015 Dec 17.


Objective: Methylglyoxal is known to be associated with the development of nephropathy, retinopathy, and other complications in diabetes. The present study tested the hypothesis that endogenously increased levels of methylglyoxal in diabetes are causally associated with the induction of neuropathic pain.

Materials and methods: Streptozotocin- and methylglyoxal-induced pain models were established in rats, and the anti-nociceptive effects of the methylglyoxal scavenging agents, selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, and Nav1.8 antagonist were tested.

Results: Systemic injection of streptozotocin in rats induced a prolonged increase in plasma methylglyoxal by approximately 60%, which was correlated with the progressive development of mechanical allodynia and thermal hyperalgesia. Local subcutaneous injection of methylglyoxal into the hindpaw produced dose-dependent and biphasic flinching nociceptive responses, which resembled formaldehyde (formalin)-induced nociception. The local methylglyoxal nociception was significantly blocked by co-injection into the hindpaw of the selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, A967079, and the Nav1.8 antagonist, A803467. Co-incubation with the methylglyoxal scavengers, aminoguanidine, d-arginine, and metformin, reduced the level of free methylglyoxal by more than 90%, and injection of their incubation solutions into the hindpaw produced negligible (3-17%) nociception. Like the clinically effective anti-diabetic neuropathic pain drug gabapentin, systemic injection of aminoguanidine, d-arginine, and metformin at doses that effectively inhibit paw-injected methylglyoxal-induced nociception significantly blocked streptozotocin-induced mechanical allodynia.

Conclusion: Endogenously increased methylglyoxal may mediate diabetic neuropathic pain via activation of both TRPA1 and Nav1.8 expressed on primary afferent sensory neurons, and injection of methylglyoxal into the hindpaw may serve as a simple and robust model for testing the anti-diabetic pain drugs.

Keywords: Diabetic neuropathic pain; Methylglyoxal; Methylglyoxal scavengers; Nav1.8; TRPA1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology
  • Aniline Compounds / pharmacology
  • Animals
  • Blood Glucose / analysis
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetic Neuropathies / genetics*
  • Diabetic Neuropathies / metabolism*
  • Furans / pharmacology
  • Hyperalgesia / etiology
  • Hypoglycemic Agents / pharmacology
  • Male
  • NAV1.8 Voltage-Gated Sodium Channel / genetics*
  • Neuralgia / etiology*
  • Neuralgia / genetics*
  • Oximes / pharmacology
  • Pain Measurement
  • Pyruvaldehyde / blood
  • Pyruvaldehyde / metabolism*
  • Pyruvaldehyde / pharmacology
  • Rats
  • Rats, Wistar
  • TRPA1 Cation Channel
  • TRPC Cation Channels / antagonists & inhibitors
  • TRPC Cation Channels / genetics*


  • A 803467
  • A 967079
  • Analgesics
  • Aniline Compounds
  • Blood Glucose
  • Furans
  • Hypoglycemic Agents
  • NAV1.8 Voltage-Gated Sodium Channel
  • Oximes
  • Scn10a protein, rat
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Trpa1 protein, rat
  • Pyruvaldehyde