Enders, J. D. | bioRxiv Science

bioRxiv2025

Episodic pain in Fabry disease is mediated by a heat shock protein-TRPA1 axis.

Two-thirds of patients with Fabry disease suffer debilitating pain attacks triggered by exercise, fever, and exposure to environmental heat. These patients face an even greater risk of heat-related episodic pain in the face of global climate change. Almost nothing is known about the biological mechanisms underlying heat-induced pain crises in Fabry disease, and there is no preclinical model available to study Fabry crises. Here, we established the first model of heat-induced pain attacks in Fabry disease by exposing transgenic Fabry rats to environmental heat. Heat exposure precipitated robust mechanical hypersensitivity, closely matching temporal features reported by patients with Fabry disease. At the cellular level, heat exposure sensitized Fabry dorsal root ganglia (DRG) neurons to agonists for transient receptor potential cation channel A1 (TRPA1), but not TRPV1. The heat shock response, which normally confers heat-resilience, was impaired in Fabry disease, and we demonstrated that heat shock proteins (HSP70 and HSP90) regulate TRPA1. Strikingly, pharmacologically inhibiting HSP90 completely prevented cellular and behavioral sensitization by environmental heat in Fabry disease. Together, this work establishes the first model of episodic pain in Fabry disease, implicates the heat shock response in heat-evoked pain episodes, and identifies a novel heat shock protein-TRPA1 regulatory axis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/639340v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@14e655eorg.highwire.dtl.DTLVardef@1e13455org.highwire.dtl.DTLVardef@32c5b9org.highwire.dtl.DTLVardef@152fcfd_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

ATP-Gated Potassium Channels Contribute to Ketogenic Diet-Mediated Analgesia in Mice.

Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.

neuroscience↗