McGaraughty Steve, Chu Katharine L, Xu Jun, Leys Laura, Radek Richard J, Dart Michael J, Gomtsyan Arthur, Schmidt Robert G, Kym Philip R, Brederson Jill-Desiree
Neuroscience Research, AbbVie, North Chicago, Illinois
Neuroscience Research, AbbVie, North Chicago, Illinois.
J Neurophysiol. 2017 Aug 1;118(2):904-916. doi: 10.1152/jn.00104.2017. Epub 2017 May 3.
TRPV3 is a nonselective cation channel activated by temperatures above 33°C and is reported to be localized in keratinocytes and nervous tissue. To investigate a role for TRPV3 in pain modulation, we conducted a series of in vivo electrophysiological studies on spinal and brain nociceptive neurons. Structurally diverse TRPV3 receptor antagonists reduced responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in neuropathic rats, but only CNS-penetrant antagonists decreased elevated spontaneous firing. Injections of an antagonist into the neuronal receptive field, into the L dorsal root ganglion, or intracerebroventricularly (ICV) attenuated the evoked firing, but only ICV injections reduced spontaneous activity. Intraspinal injections did not affect either. Spinal transection blocked the effect on spontaneous but not evoked firing after systemic delivery of a TRPV3 antagonist. Systemic administration of an antagonist to neuropathic rats also impacted the firing of On- and Off-cells in the rostral ventromedial medulla in a manner consistent with dampening nociceptive signaling. An assessment of nonevoked "pain," an EEG-measured pain-induced sleep disturbance induced by hind paw injections of CFA, was also improved with CNS-penetrant TRPV3 antagonists but not by an antagonist with poor CNS penetration. Antagonism of TRPV3 receptors modulates activity of key classes of neurons in the pain pathway in a manner consistent with limiting pathological nociceptive signaling and was mediated by receptors in the periphery and brain. Blockade of TRPV3 receptors is likely an effective means to alleviate mechanical allodynia and nonevoked pain. However, the latter will only be obtained by blocking supraspinal TRPV3 receptors. Recent studies have linked TRPV3 to pain modulation, and much of this work has focused on its role in the skin-primary afferent interface. In this electrophysiological study, we demonstrate that receptor antagonists modulate evoked signals through peripheral mechanisms but blockade of supraspinal TRPV3 receptors contributes to dampening both evoked and nonevoked "pain" through descending modulation. Thus, the full therapeutic potential of TRPV3 antagonists may only be realized with the ability to access receptors in the brain.
瞬时受体电位香草酸亚型3（TRPV3）是一种非选择性阳离子通道，在温度高于33°C时被激活，据报道定位于角质形成细胞和神经组织中。为了研究TRPV3在疼痛调节中的作用，我们对脊髓和脑伤害性神经元进行了一系列体内电生理研究。结构多样的TRPV3受体拮抗剂可降低神经性大鼠脊髓广动力范围（WDR）神经元对低强度机械刺激的反应，但只有可穿透中枢神经系统的拮抗剂能降低升高的自发放电。将拮抗剂注射到神经元感受野、L背根神经节或脑室内（ICV）可减弱诱发放电，但只有ICV注射能降低自发放电。脊髓内注射对两者均无影响。脊髓横断阻断了全身给予TRPV3拮抗剂后对自发放电的影响，但未阻断对诱发放电的影响。对神经性大鼠全身给予拮抗剂也以与抑制伤害性信号传导一致的方式影响延髓头端腹内侧核中开-关细胞的放电。对非诱发“疼痛”的评估，即通过后爪注射弗氏完全佐剂（CFA）诱导的脑电图测量的疼痛诱导睡眠障碍，也可被可穿透中枢神经系统的TRPV3拮抗剂改善，但不能被中枢神经系统穿透性差的拮抗剂改善。TRPV3受体的拮抗作用以与限制病理性伤害性信号传导一致的方式调节疼痛通路中关键神经元类别的活性，并且由外周和脑中的受体介导。阻断TRPV3受体可能是减轻机械性异常性疼痛和非诱发疼痛的有效手段。然而，后者只有通过阻断脊髓上的TRPV3受体才能实现。最近的研究将TRPV3与疼痛调节联系起来，并且这项工作大部分集中在其在皮肤-初级传入界面中的作用。在这项电生理研究中，我们证明受体拮抗剂通过外周机制调节诱发信号，但阻断脊髓上的TRPV3受体通过下行调节有助于抑制诱发和非诱发“疼痛”。因此，TRPV3拮抗剂的全部治疗潜力可能只有在能够作用于脑中的受体时才能实现。
