TRPA1 Modulates Mechanotransduction in Cutaneous Sensory Neurons

Abstract

Transient receptor potential ankyrin 1 (TRPA1) is expressed by nociceptive neurons of the dorsal root ganglia (DRGs) and trigeminal ganglia, but its roles in cold and mechanotransduction are controversial. To determine the contribution of TRPA1 to cold and mechanotransduction in cutaneous primary afferent terminals, we used the ex vivo skin-nerve preparation from Trpa1 ϩ/ϩ , Trpa1 ϩ/Ϫ , and Trpa1Ϫ/Ϫ adult mouse littermates. Cutaneous fibers from TRPA1-deficient mice showed no deficits in acute cold sensitivity, but they displayed striking deficits in mechanical response properties. C-fiber nociceptors from Trpa1 Ϫ/Ϫ mice exhibited action potential firing rates 50% lower than those in wild-type C-fibers across a wide range of force intensities. A␦-fiber mechanonociceptors also had reduced firing, but only at high intensity forces (Ͼ100 mN). Surprisingly, the firing rates of low-threshold A␤ and D-hair mechanoreceptive fibers were also altered. TRPA1 protein and mRNA expression was assessed in DRG neurons and cutaneous innervation by using Trpa1 in situ hybridization, an antibody for TRPA1, and an antibody for placental alkaline phosphatase (PLAP) in mice in which PLAP was substituted for Trpa1. DRG neurons of all sizes expressed Trpa1 mRNA or PLAP immunoreactivity. TRPA1 or PLAP immunolabeling was detected not only on many thin-caliber axons and intraepidermal endings but also on many large-caliber axons as well as lanceolate and Meissner endings. Epidermal and hair follicle keratinocytes also express TRPA1 message and protein. We propose that TRPA1 modulates mechanotransduction via a cell-autonomous mechanism in nociceptor terminals and possibly through a modulatory role in keratinocytes, which may interact with sensory terminals to modify their mechanical firing properties.

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1)

“…Cold sensitivity mediated by TRPA1 receptors has been shown in different models, and its contribution to cold hypersensitivity under neuropathic and inflammatory conditions has become a consensus (77,78). Other cold-sensitive transduction channels like TRPM8 may contribute to painful cold sensations because naïve cold responsiveness was normal in C-fibers recorded from TRPA1 knock-out mice in an experimental approach similar to ours (79). Painful diabetic neuropathy is accompanied by deteriorated cold perception (80), and these patients suffer from impaired thermoregulation (81).…”

“…A␦-fibers with low mechanical thresholds are not considered to express functional TRPA1 receptors (42,79,84). Consequently, most of the recorded A␦-fibers (11 of 15) did not respond to MG application.…”

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

“…Thus since mechanosensitive channels are calcium permeable it is possible that ion fluxes generated by transducing currents could be rapidly amplified by activating TRPA1 channels (Brierley et al, 2011). Similarly to ASIC proteins there is some evidence that TRPA1 channels are regulated by NGF availability (Malin et al, 2011), and deletion of the TRPA1 gene leads to complex changes in the mechanosensitivity of identified C-fiber afferents innervating the hairy skin (Kwan et al, 2009). There is solid pharmacological evidence that TRPA1 blockade can prevent the moderate sensitization of C-fibers to supra-threshold mechanical stimulation following complete Freund's adjuvant inflammation (Lennertz et al, 2012).…”

Transient receptor potential A1 channel contributes to activation of the muscle reflex

“…The RSNA response to intermittent contraction is considered to be predominantly mediated by mechanosensitive afferents (23)(24)(25)58). The role played by TRPA1 in mechanical sensation has been previously suggested (9,22,30,31). Thus we had expected that the muscle mechanoreceptor-mediated RSNA responses would be reduced by blockade of TRPA1.…”

“…The TRP A1 channel (TRPA1), a member of the TRP family of ion channels, is found preferentially on nociceptive sensory neurons in mice, rats, and humans (1,27,36). Pharmacological experiments in vitro and in vivo, as well as studies using TRPA1 knockout mice, have revealed that TRPA1 is the sensory neuronal receptor for pungent painful stimuli, such as mustard oil (3,5,17), arachidonic acid metabolites (3,55), bradykinin (3,60), oxidative stress (2,7,46), and noxious cold (18,54), as well as the mechanosensitive channel (9,22,30,31). Evidence demonstrates that activation of TRPA1 stimulates afferent C fibers, causing cold and mechanical hyperalgesia and neurogenic inflammation (4,35,39,56).…”