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Understanding pain sensitization
Inflammation or nerve injury can alter tactile sensation, making a gentle touch perceived as painful. The molecular mechanisms mediating this alteration in sensation, called mechanical allodynia, are not completely understood. Murthy et al. and Szczot et al. discovered that PIEZO2 ion channels expressed in sensory neurons are required for the development of mechanical allodynia in mice and humans. The authors independently reached this conclusion using different animal models. Szczot et al. extended the discovery to humans, showing that PIEZO2 loss of function resulted in failure to develop mechanical allodynia. These two studies suggest that local inhibition of PIEZO2 ion channels might be effective for treating mechanical allodynia.
Abstract
The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury can disrupt this sensory coding and result in maladaptive pain states, including mechanical allodynia, the development of pain in response to innocuous touch. However, the molecular mechanisms underlying the alteration of mechanical sensitization are poorly understood. In mice and humans, loss of mechanically activated PIEZO2 channels results in the inability to sense discriminative touch. However, the role of Piezo2 in acute and sensitized mechanical pain is not well defined. Here, we showed that optogenetic activation of Piezo2-expressing sensory neurons induced nociception in mice. Mice lacking Piezo2 in caudal sensory neurons had impaired nocifensive responses to mechanical stimuli. Consistently, ex vivo recordings in skin-nerve preparations from these mice showed diminished Aδ-nociceptor and C-fiber firing in response to mechanical stimulation. Punctate and dynamic allodynia in response to capsaicin-induced inflammation and spared nerve injury was absent in Piezo2-deficient mice. These results indicate that Piezo2 mediates inflammation- and nerve injury–induced sensitized mechanical pain, and suggest that targeting PIEZO2 might be an effective strategy for treating mechanical allodynia.
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