Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain

Sadler, K. E.; Moehring, F.; Shiers, S. I.; Laskowski, L. J.; Mikesell, A. R.; Plautz, Z. R.; Mecca, C. M.; Dussor, G.; Price, T. J.; McCorvy, J. D.; Stucky, C. L.

doi:10.1101/2020.07.13.201186

bioRxiv · 10.1101/2020.07.13.201186

Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain

Sadler, K. E.·Moehring, F.·Shiers, S. I.·Laskowski, L. J.·Mikesell, A. R.·Plautz, Z. R.·Mecca, C. M.·Dussor, G.·Price, T. J.·McCorvy, J. D.·Stucky, C. L.

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Abstract

Persistent tactile pain is a poorly managed symptom of inflammatory and neuropathic injury. To develop therapies for this maladaptive sensation, the underlying molecular mediators must be identified. Using knockout mice and pharmacological inhibitors, we identified transient receptor canonical 5 (TRPC5) as a key contributor to the persistent tactile pain that occurs in many inflammatory and neuropathic preclinical rodent models. TRPC5 inhibition was effective in injuries associated with elevated levels of the bioactive phospholipid lysophosphatidylcholine (LPC). Exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain. In vitro, LPC activated both homomeric mouse and human TRPC5 channels, which upon examination of human dorsal root ganglia tissue, were expressed in 75% of human sensory neurons. Based on these results, TRPC5 inhibitors should be pursued as personalized therapy for spontaneous and tactile pain in conditions where elevated LPC is a biomarker.

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Sadler, K. E., Moehring, F., Shiers, S. I., Laskowski, L. J., Mikesell, A. R., Plautz, Z. R., Mecca, C. M., Dussor, G., Price, T. J., McCorvy, J. D., Stucky, C. L.. 2020-07-14. Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain. https://doi.org/10.1101/2020.07.13.201186

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