TRPA1 mediates formalin-induced pain

TLDR

The formalin model, which elicits a biphasic pain response in laboratory animals, is widely used to evaluate analgesics, with the first phase driven by direct activation of primary afferent neurons and the second phase attributed to afferent input combined with central sensitization. Our study demonstrates that formalin activates the TRPA1 channel in sensory neurons, and that pharmacologic blockade or genetic deletion of TRPA1 markedly reduces formalin‑induced calcium influx and behavioral pain responses, establishing TRPA1 as the principal mediator of formalin‑induced pain.

Abstract

The formalin model is widely used for evaluating the effects of analgesic compounds in laboratory animals. Injection of formalin into the hind paw induces a biphasic pain response; the first phase is thought to result from direct activation of primary afferent sensory neurons, whereas the second phase has been proposed to reflect the combined effects of afferent input and central sensitization in the dorsal horn. Here we show that formalin excites sensory neurons by directly activating TRPA1, a cation channel that plays an important role in inflammatory pain. Formalin induced robust calcium influx in cells expressing cloned or native TRPA1 channels, and these responses were attenuated by a previously undescribed TRPA1-selective antagonist. Moreover, sensory neurons from TRPA1-deficient mice lacked formalin sensitivity. At the behavioral level, pharmacologic blockade or genetic ablation of TRPA1 produced marked attenuation of the characteristic flinching, licking, and lifting responses resulting from intraplantar injection of formalin. Our results show that TRPA1 is the principal site of formalin's pain-producing action in vivo, and that activation of this excitatory channel underlies the physiological and behavioral responses associated with this model of pain hypersensitivity.