Research ArticlePain

Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice

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Science Translational Medicine  26 May 2021:
Vol. 13, Issue 595, eabd7702
DOI: 10.1126/scitranslmed.abd7702

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A channel for mechanical hypersensitivity

Inflammation and nerve injury can cause chronic pain hypersensitivity, which is an increased sensitivity to evoked mechanical stimuli. Unfortunately, the mechanisms mediating pain hypersensitivity are not fully elucidated. Here, Sadler et al. used multiple rodent models and identified the transient receptor potential canonical 5 (TRPC5) channels as critical molecular player for the development of pain hypersensitivity of multiple causes. Activation of TRPC5 increased mechanical sensitivity to pain in rodents. The authors also found that TRPC5 channels are expressed in human sensory neurons, suggesting that TRPC5 inhibition could be effective in reducing pain hypersensitivity in patients.


Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express TRPC5, the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.

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