TRESK is a modality‐specific brake on nociceptor excitability

Sharif‐Naeini, Reza

doi:10.1113/jp279548

Cited by 1 publication

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“…Membrane excitability of nociceptive afferent nerves are controlled by multiple types of ion channels including voltage-gated K 1 channels (Waxman and Zamponi, 2014) and two pore-domain K 1 channels (K2P; Gada and Plant, 2019). Previous studies have found that, in addition to TRPM8 channels, cold sensitivity in somatosensory neurons is also controlled by Kv1 type of voltage-gated K 1 channels (Madrid et al, 2009;González et al, 2017) and TASK-3 as well as TRESK types of K2P channels (Morenilla-Palao et al, 2014;Castellanos et al, 2020;Sharif-Naeini, 2020). Dysregulated ion channel expression in response to nerve injury and inflammation can result in enhanced neuronal excitability that underlies inflammatory and neuropathic pain (Waxman and Zamponi, 2014).…”

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confidence: 99%

Kv4.3 Channel Dysfunction Contributes to Trigeminal Neuropathic Pain Manifested with Orofacial Cold Hypersensitivity in Rats

et al. 2021

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Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K 1 currents (IA currents) in these TG neurons. We further showed that these smallsized TG neurons expressed Kv4.3 voltage-gated K 1 channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain.

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