Methylglyoxal (MG) is a metabolite of
glucose that may contribute to
peripheral neuropathy and
pain in diabetic patients. MG increases intracellular
calcium in sensory neurons and produces behavioral nociception via the
cation channel transient receptor potential
ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of
methylglyoxal-evoked
pain is needed, including testing whether
methylglyoxal promotes negative
pain affect. Furthermore, it remains unknown whether
methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the
calcium-sensitive
adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked
pain. We administered intraplantar
methylglyoxal and then evaluated immunohistochemical phosphorylation of
extracellular signal-regulated kinase (p-ERK) and multiple
pain-like behaviors in wild-type rats and mice and after disruption of either TRPA1 or AC1.
Methylglyoxal produced conditioned place avoidance (CPA) (a measure of affective
pain), dose-dependent licking and lifting nociceptive behaviors,
hyperalgesia to heat and mechanical stimulation, and p-ERK in the spinal cord dorsal horn. TRPA1 knockout or intrathecal administration of a TRPA1 antagonist (
HC030031) attenuated
methylglyoxal-evoked p-ERK, nociception, and
hyperalgesia. AC1 knockout abolished
hyperalgesia but not nociceptive behaviors. These results indicate that intraplantar administration of
methylglyoxal recapitulates multiple signs of
painful diabetic neuropathy found in animal models of or patients with diabetes, including the activation of spinal nociresponsive neurons and the potential involvement of a TRPA1-AC1 sensitization mechanism. We conclude that administration of MG is a valuable model for investigating both peripheral and central components of a MG-TRPA1-AC1 pathway that contribute to
painful diabetic neuropathy.