A型肉毒毒素对面部三叉神经痛大鼠疼痛的改善作用及对炎性介质IL-6、TNF-α表达的影响

目的 探讨A型肉毒毒素（BTA）对面部三叉神经痛（TN）大鼠疼痛的改善作用及对炎性介质IL-6、TNF-α表达的影响。方法 从50只大鼠中随机取10只为对照组,剩余大鼠用结扎眶下神经的方法建立TN模型,分为模型组、BTA低剂量组（BTA-L组）、BTA高剂量组（BTA-H组）和卡马西平组,每组各10只。BTA-L组、BTA-H组分别以9、18 μL/kg BTA溶液于手术同侧面部须垫处注射,对照组及模型组给予等量生理盐水,卡马西平组以5 mg/kg卡马西平灌胃。检测大鼠疼痛阈值,ELISA法检测血清中IL-6、TNF-α水平,HE染色观察眶下神经组织病理变化;蛋白免疫印迹法检测三叉神经节中核因子κB（NF-κB）p65、磷酸化型NF-κB p65（p-NF-κB p65）、p38丝裂原活化蛋白激酶（p38MAPK）、磷酸化型p38MAPK（p-p38MAPK）蛋白相对表达量。结果 与对照组比较,模型组注射1、2、3周时疼痛阈值降低（P均 < 0.05）;与模型组比较,BTA-L组、BTA-H组、卡马西平组注射1、2、3周时疼痛阈值升高,且BTA-L组 < BTA-H组 < 卡马西平组（P均 < 0.05）;与对照组比较,模型组血清中IL-6、TNF-α水平及p-NF-κB p65、p-p38MAPK蛋白相对表达量升高（P均< 0.05）;与模型组比较,BTA-L组、BTA-H组、卡马西平组血清中IL-6、TNF-α水平及三叉神经节中p-NF-κB p65、p-p38MAPK蛋白相对表达量降低,且卡马西平组 < BTA-H组 < BTA-L组（P均< 0.05）;HE染色显示,与模型组比较,BTA-L组、BTA-H组、卡马西平组神经纤维肿胀、排列、炎性细胞浸润等异常改变减轻,其中卡马西平组减轻更显著。结论 BTA可降低炎性介质IL-6、TNF-α水平,减轻炎症反应,改善面部疼痛,可能通过抑制NF-κB、p38MAPK信号通路发挥作用。     

Viable herpes simplex virus type 1 and varicella‐zoster virus in the trigeminal ganglia of human cadavers

Human herpes simplex virus type 1 (HSV‐1) and varicella‐zoster virus (VZV) were isolated in the bilateral trigeminal ganglia of 12 human cadavers with no history of herpes‐related symptoms within 1–5 days of death. Sixteen trigeminal ganglia were subjected to explant culture by using Vero cells, but no cytopathogenic effects (CPE) were observed. However, when another eight trigeminal ganglia were placed in a cell strainer and kept from direct contact with Vero cells during culture, CPE were clearly apparent in all cultures. The amount of DNA in the culture supernatants of 16 trigeminal ganglia decreased over time; 12 and 9 of these samples were PCR‐positive for HSV‐1 and VZV, respectively. In new Vero cells inoculated with supernatants collected 2 days after culture initiation, immunofluorescence staining revealed HSV‐1 and VZV in 6 and 5 of 8 trigeminal ganglia, respectively. HSV‐1 and VZV DNA was detected in supernatants collected 3 and 7 days after culture initiation and in Vero cells collected after culture completion, but real‐time PCR revealed the DNA amounts decreased over time. There was less VZV DNA than HSV‐1 DNA. These results demonstrate that infective HSV‐1 and VZV can be isolated in culture, and confirm that viable HSV‐1 and VZV persist in human trigeminal ganglia for some time after death. J. Med. Virol. 85:833–838, 2013. © 2013 Wiley Periodicals, Inc.     

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

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⁺ currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K⁺ 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.SIGNIFICANCE STATEMENT Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K⁺ channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.     

显微血管减压术中单纯应用涤纶垫棉治疗基底动脉压迫所致三叉神经痛的临床疗效

目的初步探讨显微血管减压术中单纯应用涤纶垫棉治疗基底动脉压迫所致三叉神经痛的临床疗效。方法回顾性分析2012年1月至2019年12月陆军军医大学大坪医院神经外科收治的31例基底动脉压迫引发三叉神经痛患者的临床资料。31例患者在显微血管减压术中均单纯使用涤纶垫棉作为减压材料,且未使用其他减压方式。手术采用经乙状窦后入路,于脑干和责任动脉之间放置涤纶垫棉实现减压。采用巴罗神经学研究所(BNI)提出的疼痛分级评估手术效果。结果31例三叉神经痛患者中,27例(87.1%)术后疼痛即刻完全缓解(BNI分级Ⅰ级),3例在术后3个月内完全缓解(BNI分级Ⅰ级),1例疼痛部分缓解(BNI分级Ⅲ级)。5例(16.1%)患者术后出现面部感觉减退,其中3例自愈;1例患者出现渐进性听力下降。31例患者的随访时间为6~85个月(中位时间为40个月),随访期间有4例(12.9%)复发(BNI分级Ⅳ~Ⅴ级),其中2例再次接受手术治疗,另外2例采用立体定向放射治疗配合药物治疗可部分控制面部疼痛。结论显微血管减压术中单纯应用涤纶垫棉治疗基底动脉所致三叉神经痛的术后即刻效果显著,但其复发率及并发症的发生率较高。     

Implantable Peripheral Nerve Stimulation for Trigeminal Neuropathic Pain: A Systematic Review and Meta-Analysis

ObjectivesImplantable peripheral nerve stimulation has been increasingly used to treat neuropathic pain. This neuromodulation strategy may be an alternative option for intractable trigeminal neuropathic pain; however, evidence for this treatment approach remains limited. A systematic review was conducted to identify studies of patients that underwent peripheral nerve stimulation implantation for trigeminal neuropathic pain.Materials and MethodsDatabases including, PubMed, EMBASE, and Cochrane Library were searched up to October 5, 2020. The primary outcomes were changes in pain scores and response rates of neuromodulation therapy. A random effects model was used for meta-analysis. Subgroup analysis was performed to examine the source of heterogeneity.ResultsThirteen studies including 221 participants were evaluated. The estimated response rate of neuromodulation treatment was 61.3% (95% CI: 44.4–75.9%, I² = 70.733%, p < 0.0001) at the last follow-up. The overall reduction in pain scores was 2.363 (95% CI: 1.408–3.319, I² = 85.723%, p < 0.0001). Subgroup analysis further confirmed that stimulation target (peripheral branch vs. trigeminal ganglion vs. trigeminal nerve root) contributed the heterogeneity across enrolled studies. Better clinical outcome was associated with stimulation of the trigeminal peripheral branch (p < 0.0001).ConclusionPeripheral nerve stimulation may be a promising approach in the management of trigeminal neuropathic pain, especially for patients intractable to conventional therapy.     

The claustrum of the sheep and its connections to the visual cortex

The present study analyses the organization and selected neurochemical features of the claustrum and visual cortex of the sheep, based on the patterns of calcium-binding proteins expression. Connections of the claustrum with the visual cortex have been studied by tractography. Parvalbumin-immunoreactive (PV-ir) and Calbindin-immunoreactive (CB-ir) cell bodies increased along the rostro-caudal axis of the nucleus. Calretinin (CR)-labeled somata were few and evenly distributed along the rostro-caudal axis. PV and CB distribution in the visual cortex was characterized by larger round and multipolar cells for PV, and more bitufted neurons for CB. The staining pattern for PV was the opposite of that of CR, which showed densely stained but rare cell bodies. Tractography shows the existence of connections with the caudal visual cortex. However, we detected no contralateral projection in the visuo-claustral interconnections. Since sheep and goats have laterally placed eyes and a limited binocular vision, the absence of contralateral projections could be of prime importance if confirmed by other studies, to rule out the role of the claustrum in stereopsis.     

不同部位电刺激治疗带状疱疹神经痛的疗效分析

目的:对治疗带状疱疹神经痛(zoster-related neuralgia,ZRN)的短时程背根神经电刺激与脊髓电刺激两种方法的手术时间、放射暴露剂量、疗效及花费进行比较。方法:本文采用回顾性分析方法,对202例在DSA(digital subtraction angiography)引导下使用短时程电刺激治疗的带状疱疹神经痛病人(其中64例采用背根神经电刺激,138例采用脊髓电刺激),记录手术操作时间及每一例手术的辐射剂量,术后病人的程控次数,术前及术后1、2、3月等各时间段病人的疼痛程度,生活质量以及医疗耗材费等信息,并进行分析比较。结果:在3个月的随访期间,所有病人在两种方法治疗后疼痛视觉模拟评分法(visual analogue scale,VAS)评分和匹兹堡睡眠质量指数(Pittsburgh sleep quality index,PQSI)显著下降,而生活质量(SF-36健康调查简表)评分显著上升(P<0.01),且两种方法之间无统计学差异,然而背根神经电刺激病人的手术时间和术中辐射量明显少于脊髓电刺激组(P<0.05);且术后平均程控次数以及医疗耗材费用也明显少于脊髓电刺激组(P<0.05)。结论:短时程背根神经电刺激和脊髓电刺激都能有效治疗带状疱疹神经痛,但背根神经电刺激具有程控次数少、覆盖好、花费少等优点。     

Unilateral facial injection of Botulinum neurotoxin A attenuates bilateral trigeminal neuropathic pain and anxiety-like behaviors through inhibition of TLR2-mediated neuroinflammation in mice

ObjectivesIn this study, we investigated the possible analgesic effects of Botulinum toxin type A (BoNT/A) on trigeminal neuralgia (TN). A modified TN mouse model was established by chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) in mice, and the possible roles of microglia toll-like receptor 2 (TLR2) and neuroinflammation was investigated.MethodsMale C57BL/6 mice were divided into 3 groups, including sham group, vehicle-treated TN group and BoNT/A-treated TN group. Bilateral mechanical pain hypersensitivity, anxiety-like and depressive-like behaviors were evaluated by using von Frey test, open field, elevated plus-maze testing, and forced swimming test in mice, respectively. The mRNA or protein expression levels of toll-like receptors (TLRs), glia activation markers and proinflammatory factors in the trigeminal nucleus caudalis (TNC) were tested by RT-qPCR, immunofluorescence and Western blotting. We also tested the pain behaviors of TN in Tlr2^−/− mice.ResultsWe found that unilateral subcutaneous injection of BoNT/A into the whisker pad on the ipsilateral side of dIoN-CCI mice significantly attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors induced by dIoN-CCI surgery in mice. The dIoN-CCI surgery significantly up-regulated the expression of TLR2, MyD88, CD11b (a microglia marker), IL-1β, TNF-α and IL-6 in the ipsilateral TNC in mice, and BoNT/A injection significantly inhibited the expression of these factors. Immunostaining results confirmed that BoNT/A injection significantly inhibited the microglia activation in the ipsilateral TNC in dIoN-CCI mice. TLR2 deficiency also alleviated bilateral mechanical pain hypersensitivity and the up-regulation of MyD88 expression in the TNC of dIoN-CCI mice.ConclusionThese results indicate that unilateral injection of BoNT/A attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors in dIoN-CCI mice, and the analgesic effects of BoNT/A may be associated with the inhibition of TLR2-mediated neuroinflammation in the TNC.