Methylglyoxal, A Noxious Metabolite, Drives Nociceptive Axon Loss in The Skin

Intraepidermal nerve fiber loss (IENF) is present in many human diseases and is strongly associated with chronic pain. Understanding the mechanisms underlying IENF loss will provide insight into better therapeutic options and improved peripheral nerve health with patients experiencing chronic pain. The reactive dicarbonyl methylglyoxal (MGO) is elevated in chronic pain conditions associated with metabolic dysfunction. We tested how MGO impacts pain and epidermal axon health in various rodent models. A single intraperitoneal injection of MGO (750ng) into C57Bl/6 mice induced acute pain behaviors and long-term mechanical allodynia. Surprisingly, MGO injection significantly decreased IENF density (Control: 55 + 3.5, MGO: 40+ 2.6) in the hind paw. We know consuming a ketogenic diet for one week before an MGO injection prevents MGO-induced pain. Here, we show that seven days of a ketogenic diet prevents IENF loss and can stimulate the regeneration of MGO-damaged axons. Next, we utilized a genetic mouse model (BALB/cByJ) overexpressing glyoxylase 1, an enzyme that breaks down MGO. BALB/cByJ mice injected with MGO had no changes in IENF density. SARM1 is an enzyme involved in axon degeneration. MGO injection in SARM1 null mutant mice did not lead to decreased IENF density. We show a ketogenic diet, overexpression of Glo1, or knockdown of SARM1 in mice combats these effects. We know MGO is a noxious metabolite leading to pain, and we add new evidence that MGO contributes to IENF loss. These findings identify an important link between pain and IENF loss, providing a new tool to investigate this relationship. Grants to be cited: R01NS043314-17 and 5P20GM103418.