Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation

Pain. 2019 Nov;160(11):2497-2507. doi: 10.1097/j.pain.0000000000001644.


The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. Methylglyoxal could be a mediator of diabetes-induced neuropathic pain through TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C fibers was assessed through selective A-fiber nerve block, axon-reflex-erythema, and through single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema, and long-lasting hyperalgesia through the activation of C nociceptors. Predominantly, the subclass of mechano-insensitive C fibers is activated by MG. A fibers contribute only negligibly to the burning pain sensation. Selective pharmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the actions of MG through TRPA1 activation on predominantly mechano-insensitive C fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Calcium Channels / metabolism
  • Diabetic Neuropathies / physiopathology
  • Female
  • Humans
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology*
  • Male
  • Nerve Fibers, Unmyelinated / physiology*
  • Neuralgia / physiopathology*
  • Nociceptors / metabolism*
  • Skin / innervation
  • Young Adult


  • Calcium Channels