Figure 1. PDN: a sodium channel bound to excite. According to a study in Nature Medicine, methylglyoxal (MG) modifies sodium channel NaV1.8 (PN3; SCN10A) in nociceptive neurons to cause thermal and mechanical hypersensitivity in the extremities of patients with diabetes.

Diabetic hyperglycemia raises plasma levels of the metabolite MG [a] that accumulates in nociceptive and other peripheral neurons [b], which express only low levels of glyoxalase 1 (GLO1). The enzyme is required to convert MG to d-lactate.

In nociceptive neurons, MG binds the intracellular portion (inactivation gate) of NaV1.8 [c] and induces unknown structural modifications that inhibit the channel's ability to close in response to increases in the cell's membrane potential.

This increase allows thermal and mechanical stimuli [d] to induce excessive sodium influx [e], resulting in excessive neuronal firing [f] that causes pain [g], even in response to stimuli that are not painful in healthy individuals.

Z123212 (Z212), a small molecule that blocks NaV1.7 (SCN9A) and NaV1.8 sodium channels from Zalicus Inc., is in preclinical development to treat chronic inflammatory and neuropathic pain.