Peripheral and spinal TRPA1 channels contribute to formalin-induced long-lasting mechanical hypersensitivity

Abstract

BackgroundTransient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed by a subset of nociceptive neurons that acts as a multimodal receptor. Its activity contributes to modulate nociceptive transmission in acute inflammatory pain. However, the role of this channel in chronic pain has been less studied. The purpose of this study was to investigate the local peripheral and spinal participation of TRPA1 channels in formalin-induced long-lasting hypersensitivity.Materials and methodsFormalin (1%)-induced chronic hypersensitivity was determined by the application of von Frey filaments to ipsilateral and contralateral paws and through pharmacological testing using a selective TRPA1 blocker (A-967079). TRPA1 expression in the dorsal root ganglion (DRG) and spinal cord was analyzed by Western blotting.ResultsFormalin (1%) injection produced acute flinching behavior (1 h) as well as secondary allodynia and hyperalgesia (12 days). Local peripheral pretreatment (10 min before) or posttreatment (6 days later) with A-967079 (1–100 µM) partially prevented and reversed, respectively, in a dose-dependent manner, long-lasting secondary mechanical allodynia and hyperalgesia evoked by 1% formalin. Likewise, intrathecal pretreatment or posttreatment with A-967079 partially prevented and reversed, respectively, formalin-induced long-lasting hypersensitivity. A-967079 (100 µM) completely abolished the pro-nociceptive effect of formalin (adjusted to pH 7.4). Finally, formalin injection increased TRPA1 protein expression in the DRG and spinal cord.ConclusionResults indicate that TRPA1 expressed in the DRG and spinal cord plays a relevant role in formalin-induced long-lasting secondary nociceptive hypersensitivity.

Androgenic TRPM8 activity drives sexual dimorphism in a murine model of chronic migraine

“…In line with our results, previous research described TRPA1-speci c neuronal responses after acute NTG 3 , and male rodents exposed to NTG were sensitive to TRPA1 antagonism 41 . Our ndings reveal an essential participation of TRPA1 for the development of chronic NTG hypersensitivity in male and female mice, in agreement with studies showing TRPA1 involvement in persistent pain sensitizations 8, [42][43][44] .…”

TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold

“…First, the neuronal expression of TRPA1 is highly sensitive to physiopathological conditions, especially inflammation. It was shown that a single subcutaneous injection of formalin or Complete Freund’s Adjuvant increased TRPA1 expression up to one-week post injection 19 , 20 . Moreover, ethanol, which we used as solvent for the retrotracer DiI, was shown to induce an inflammation associated with cyclooxygenase-2 upregulation in a model of gut inflammation 21 , 22 and therefore, could have affected TRPA1 expression in our experiments.…”

Endogenous transient receptor potential ankyrin 1 and vanilloid 1 activity potentiates glutamatergic input to spinal lamina I neurons in inflammatory pain

“…), and formalin injection increases the TRPA1 protein level in the DRG and spinal cord (Martinez‐Rojas et al . ). At the spinal cord level, exogenous stimulation of TRPA1 with allyl isothiocyanate or icilin substantially increases glutamate release to lamina II neurons (Kosugi et al .…”

“…It has been shown recently that peripheral and intrathecal injection of A‐967079, a specific TRPA1 antagonist, can reverse pain hypersensitivity caused by formalin injection (Martinez‐Rojas et al . ). These findings indicate that in addition to functioning as a transducer for tissue inflammation, TRPA1 at the spinal cord level is endogenously activated to maintain nociceptive drive to lamina I neurons in chronic inflammatory pain.…”