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

Abstract

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.

Electrophysiological properties of maxillary trigeminal Aβ-afferent neurons of rats

“…The maxillary nerves or V2 branches of the trigeminal nerves are somatosensory nerves that innervate orofacial regions ( Figure 1(a) ). The somas of these trigeminal afferent nerves are located in the V2 part in the trigeminal ganglion 12 ( Figure 1(b) ). Under an IR-DIC microscope, individual TG neurons in our ex vivo TG preparations could be visualized in the V2 TG regions, and these V2 TG neurons showed different cell sizes ( Figure 1(b) and (c) ).…”

“…Previous electrophysiological studies have mainly focused on small-sized nociceptive-like TG neurons including V2 trigeminal afferent neurons that innervate orofacial regions. 12 , 14 , 15 Yet electrophysiological properties of Aβ-afferent neurons in TGs have not been well characterized so far. In the present study we characterized electrophysiological properties of V2 trigeminal Aβ-afferent neurons by using ex vivo rat trigeminal nerve preparations and patch-clamp recording technique, and found these neurons can be classified into at least 4 subtypes.…”

Effects of GABAB receptor activation on excitability of IB4-positive maxillary trigeminal ganglion neurons: Possible involvement of TREK2 activation

“…These neurons give rise to afferent fibers primarily innervating orofacial regions. 23 Under an IR-DIC microscope, individual neurons in V2 region could be visualized in our ex vivo TG preparations. Many maxillary TG neurons were small-sized cells with mean diameters smaller than 35 µm ( Figure 1(a) , left panel).…”

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

“…Improved knowledge into the intercommunication of TRPM8 channels with other protein receptors, as well as with related and unrelated ion channels, is another crucial aspect to identify cellular pathways interconnected in TRPM8-linked diseases. Lately, numerous articles are being published on this respect [54,[190][191][192]; thus, providing crucial information on physiological and pathological cellular pathways related to these TRP channels.…”