Mulpuri Yatendra, Yamamoto Toru, Nishimura Ichiro, Spigelman Igor
Section of Oral Biology, School of Dentistry, University of California, Los Angeles, CA, USA.
Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, CA, USA.
Neurobiol Pain. 2022 Jan 21;11:100084. doi: 10.1016/j.ynpai.2022.100084. eCollection 2022 Jan-Jul.
Chronic pain arising from peripheral nerve injuries represents a significant clinical challenge because even the most efficacious anticonvulsant drug treatments are limited by their side effects profile. We investigated pain behavior, changes in axonal signal conduction and excitability of trigeminal neurons, and expression of voltage-gated sodium channels (NaVs) in the infraorbital nerve and trigeminal ganglion (TG) after infraorbital nerve entrapment (IoNE). Compared to Sham, IoNE rats had increased A- and C-fiber compound action potentials (CAPs) and Aδ component of A-CAP area from fibers innervating the vibrissal pad. After IoNE, A- and C-fiber CAPs were more sensitive to blockade by tetrodotoxin (TTX), and those fibers that were TTX-resistant were more sensitive to blockade by the NaV1.8 selective blocker, A-803467. Although NaV1.7 blocker, ICA-121431 alone, did not affect Aδ-fiber signal propagation, cumulative application with A-803467 and 4,9-anhydro-TTX significantly reduced the Aδ-fiber CAP in IoNE rats. In patch clamp recordings from small- and medium-sized TG neurons, IoNE resulted in reduced action potential (AP) depolarizing current threshold, hyperpolarized AP voltage threshold, increased AP duration, and a more depolarized membrane potential. While the transcripts of most NaVs were reduced in the ipsilateral TG after IoNE, NaV1.3, NaV1.7, and NaV1.8 mRNAs, and NaV1.8 protein, were significantly increased in the nerve. Altogether, our data suggest that axonal redistribution of NaV1.8, and to a lesser extent NaV1.3, and NaV1.7 contributes to enhanced nociceptive signal propagation in peripheral nerve after IoNE.
周围神经损伤引起的慢性疼痛是一项重大的临床挑战，因为即使是最有效的抗惊厥药物治疗也受到其副作用的限制。我们研究了眶下神经卡压（IoNE）后疼痛行为、三叉神经元轴突信号传导和兴奋性的变化，以及眶下神经和三叉神经节（TG）中电压门控钠通道（NaVs）的表达。与假手术组相比，IoNE大鼠支配触须垫的纤维的A纤维和C纤维复合动作电位（CAPs）以及A-CAP面积的Aδ成分增加。IoNE后，A纤维和C纤维CAPs对河豚毒素（TTX）阻断更敏感，而那些对TTX耐药的纤维对NaV1.8选择性阻断剂A-803467阻断更敏感。虽然单独使用NaV1.7阻断剂ICA-121431不影响Aδ纤维信号传导，但与A-803467和4,9-脱水-TTX联合应用可显著降低IoNE大鼠的Aδ纤维CAP。在中小尺寸TG神经元的膜片钳记录中，IoNE导致动作电位（AP）去极化电流阈值降低、AP电压阈值超极化、AP持续时间增加以及膜电位更去极化。虽然IoNE后同侧TG中大多数NaVs的转录本减少，但神经中NaV1.3、NaV1.7和NaV1.8 mRNA以及NaV1.8蛋白显著增加。总之，我们的数据表明，NaV1.8以及在较小程度上NaV1.3和NaV1.7的轴突重新分布有助于IoNE后外周神经中伤害性信号传播的增强。
