VIM thalamic stimulation for tremor in a patient with IgM paraproteinaemic demyelinating neuropathy.

We demonstrate the effect of deep brain stimulation of the ventral intermediate thalamic nucleus on intractable action tremor, in a 72-year-old man suffering from neuropathy associated with monoclonal gammopathy.     

Spinal Cord Stimulation in a Mouse Chronic Neuropathic Pain Model

Objective. Development of a spinal cord stimulation (SCS) system in a mouse model of chronic neuropathic pain. Materials and Methods. Male C57BL/6 mice (N = 6) underwent a partial ligation of the sciatic nerve. Development of mechanical hyperalgesia was tested using the withdrawal response to tactile stimuli with the von Frey test. An SCS system was implanted on day 14. On day 16, the mice were stimulated for 30 min (f = 50 Hz; pulse width 0.2 msec and stimulation at 2/3 of motor threshold). Repeated measure analysis of variance (anova ) and paired Student's t‐test with Bonferroni correction were used to evaluate the development of mechanical hyperalgesia and the therapeutic effect of SCS. Results. Five out of six mice developed marked mechanical hyperalgesia in the nerve‐lesioned paw that persisted for the duration of the study (16 days). No changes contralateral to the injury were observed. In four out of five mice, a successful implantation of the electrodes followed by stimulation was achieved. Then, SCS resulted in a fast and robust increase of withdrawal threshold back to pre‐injury levels. After termination of the SCS, the withdrawal threshold of the ipsilateral paw slowly decreased. No effect of SCS on the contralateral paw was noted. Conclusion. The development of a mouse SCS system is described that is practical in use, is reproducible, and shows a comparative therapeutic effect in treatment of chronic neuropathic pain as reported in rat.     

大鼠坐骨神经慢性挤压性损伤后痛阈和血清IL-6的变化及相关性研究

目的:通过大鼠坐骨神经慢性挤压伤(CCI)神经性疼痛模型的热敏变化及血清中IL-6含量的变化,探讨血清IL-6在神经性疼痛形成中的作用及可能机制.方法:36只250～300g的健康雄性Wistar大鼠,在戊巴比妥钠麻醉下于大腿中部暴露坐骨神经并作结扎,取对侧大腿坐骨神经暴露作为模拟对照(B组).术后1,3,5,7,9,11,13,15 d测定大鼠(n=12)两侧后爪对热敏阈值的变化.于术后第15 d处死大鼠,取血清,ELISA法测定IL-6浓度.结果:大鼠双侧后爪(CCI和B)的收缩潜伏期在术后第3,5,7,9,11,13,15 d有显著差异;CCI组血清IL-6与对照组比较有显著差异.结论:IL-6与大鼠坐骨神经慢性挤压性损伤后出现的神经源性疼痛过敏有关.     

Lamotrigine in the treatment of painful diabetic neuropathy

An open trial was conducted to study the potential efficacy of lamotrigine, a novel antiepileptic agent that blocks voltage-sensitive sodium channels and inhibits the release of glutamate, in relieving the pain associated with diabetic neuropathy. Subsequent to a 1 week washout period from previous analgesics, lamotrigine was administered at a dose of 25 mg/day for 1 week. The dose was doubled on a weekly basis up to 400 mg/day over 6 weeks. The McGill pain questionnaire (MPQ), spontaneous pain and a series of mechanical and thermal stimuli-induced pain were measured with the use of 0–100 visual analogue scale (VAS), on seven office visits. Pain level was also recorded by each patient twice daily, 1 week before, during, and 2 weeks after the treatment period with the use of a 0–10 numerical pain scale (NPS). Quantitative mechanical (Von Frey filaments) and thermal testing (QTT), and routine blood tests were performed at the beginning and at the end of the study. Thirteen patients completed the study. Spontaneous pain measured by VAS and NPS gradually dropped from a baseline of 49 ± 8 and 6.8 ± 0.6, to 20 ± 8.6 ( p < 0.001) and 4.3 ± 0.9 ( p < 0.001), respectively, at the end of the treatment period. Similarly, cold allodynia dropped from 38 ± 9.2 to 16 ± 15.3 ( p = 0.01), and the MPQ score from 13.6 ± 0.8 to 11.0 ± 1.5 ( p < 0.01). In contrast, no significant changes were found in the QTT, mechanical pain thresholds and laboratory results. Two patients were withdrawn from the study because of adverse effects. A long-term follow up showed that most patients were still using lamotrigine 6 months after the end of the study. The results of the study suggest that lamotrigine is potentially effective and safe in treating painful diabetic neuropathy.     

Substantial pain burden in frequency,intensity, interference and chronicity among children and adults with neurofibromatosis Type 1

Tumor growths, migraine headaches, and other health‐related complications reported in patients with neurofibromatosis type 1 (NF1) are often associated with pain. Thus, this study sought to describe and quantify the pain experience in children and young adults with NF1. Surveys were administered to 49 participants (28 children and 21 adults), ages 8 through 40 years. The survey included the Numeric Rating Scale 11 (NRS11) to assess pain intensity and the Patient Reported Outcomes Measurement Information System (PROMIS) to assess pain interference. A supplemental survey was created to measure pain frequency, chronicity, quality, and location. Results suggest pain is not only present in 55% of the cohort, but that it can begin at early ages. Pain was chronic in 35% of participants, with 41% reporting the use of medication to manage pain symptoms. Common sources of pain included migraine headaches and NF‐related tumors. Pain was described as having neuropathic features (i.e., burning, tingling, numbness, or itching), and was localized to the head, back, and extremities. Further, subsets of participants reported moderate‐to‐severe pain intensity, high frequency of pain, and interference of pain in daily activities. Continued investigation of the pain experience in a multisystem disorder, such as NF1, remains essential to providing guidance in the setting of complex pain management.     

神经妥乐平治疗周围神经病变的疗效观察

目的：观察神经妥乐平治疗周围神经病变的临床效果。方法：静脉滴注神经妥乐平，比较用药前后患者神经系统症状及神经传导速度的变化。结果：治疗后患者视觉模拟评分下降，患侧肢体神经传导速度改善。治疗前后比较，有显著性差异。结论：对多种疾病导致的周围神经病患者，使用神经妥乐平治疗可获得较好疗效。     

Marked enhancement of anti-allodynic effect by combined intrathecal administration of the adenosine A1-receptor agonist R-phenylisopropyladenosine and morphine in a rat model of central pain

BACKGROUND: There is often no satisfactory treatment for chronic pain after spinal cord injury. We have previously reported that intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) or the opioid morphine has anti-allodynic effects in a model of presumed chronic central pain after photochemically induced spinal cord injury in rats. In the present study, we set out to investigate the possible interaction between i.t. R-PIA and morphine in spinally injured rats. METHODS: Sprague-Dawley rats displaying allodynia-like behaviors to mechanical and cold stimuli after photochemically induced spinal cord injury with minor motor deficits were used. R-PIA and morphine, either alone or in combination, were administered i.t. through an implanted catheter to lumbar spinal cord. RESULTS: Cumulative doses of R-PIA or morphine dose-dependently reduced the mechanical allodynia-like behavior, with a threshold of 1 nmol and 1.5 nmol, respectively. When co-administrated, R-PIA and morphine produced marked suppression of mechanical allodynia at doses of 5 pmol and 7.5 pmol, respectively. The effect of i.t. co-administration of R-PIA and morphine on cold allodynia was comparable to i.t. R-PIA alone. The combination of R-PIA and morphine did not increase adverse effects such as motor deficits in comparison to either drug alone. CONCLUSION: These results demonstrate a supra-additive interaction between the adenosine A1-receptor agonist R-PIA and morphine to reduce mechanical allodynia-like behavior in rats with chronic spinal cord injury. The combination of R-PIA and morphine administered spinally may be superior to R-PIA or morphine alone for treating such pain.     

Wnt3a信号通路通过JMJD6的表观遗传修饰参与神经病理性疼痛

目的：探讨Wnt3a通过Jumonji C结构域6( Jumonji C domain 6,JMJD6)的表观遗传修饰在神经病理性疼痛 中发挥作用的机制。方法：将SD大鼠分为4组：Sham组,慢性缩窄性损伤(chronic constriction injury,CCI)组,CCI+阴性慢病毒表达载体(LV-NC)组;CCI+慢病毒过表达载体(LV-JMJD6)组。构建SD大鼠坐骨神经CCI模型和JMJD6慢病毒 表达载体。CCI术后第3天通过鞘内导管给药,按照分组分别给予生理盐水和含慢病毒的试剂(病毒滴度1×108 TU/mL) 各20 μL。监测大鼠的机械缩足阈值(paw withdrawal mechanical threshold,PWMT)和热缩足潜伏期(paw withdrawal thermal latency,PWTL),并运用蛋白质印迹法检测脊髓水平Wnt3a及NR2B蛋白的表达变化,免疫共沉淀检测JMJD6与Wnt3a之间是否存在直接相互作用。结果：与Sham组相比,CCI术后各组大鼠的PWMT明显降低和PWTL明显缩短(P<0.05)。与CCI组和CCI+LV-NC组相比,CCI+LV-JMJD6组的PWMT在术后第10和14天明显升高,PWTL在术后第14 天明显延长(P<0.05)。CCI术后第14天,CCI组及CCI+LV-NC组Wnt3a和NR2B蛋白表达水平较Sham组明显升高,鞘内注 射慢病毒载体后, CCI+LV-JMJD6组的Wnt3a和NR2B蛋白表达水平较CCI+LV-NC组降低(P<0.05)。免疫共沉淀结果显示Wnt3a与JMJD6之间无直接相互作用。结论：Wnt3a参与调节神经病理性疼痛,其作用可能与JMJD6的表观遗传修饰相关,两者可能通过间接相互作用进行调节。     

中药调控一氧化氮合酶-一氧化氮系统的研究

一氧化氮(NO)是生物体细胞内及细胞间的重要信号分子,由不同类型一氧化氮合酶(NOS)催化生成,即内皮型一氧化氮合酶(eNOS)、神经元型一氧化氮合成酶(nNOS)和诱导型一氧化氮合酶(iNOS)。生理情况下,组织中eNOS和nNOS持续低水平表达维持正常生理功能。病理情况下,eNOS活性下降,NO生成减少,中药可以通过蛋白质磷酸化调节eNOS活性增加NO浓度以及通过抗氧化作用提高NO的生物利用度。而iNOS在生理情况下不表达,炎症状态下,iNOS被激活产生大量NO,导致组织损伤,加剧炎症进程。中药通过NF-κB和p38MAPK下调iNOS减少NO生成治疗炎症。不少活血化瘀药可以下调iNOS起到抗炎作用,为活血化瘀药治疗炎症提供了试验依据。     

SUMOylation of Kir7.1 participates in neuropathic pain through regulating its membrane expression in spinal cord neurons

AimsPotassium (K⁺) channels have been demonstrated to play a prominent involvement in nociceptive processing. Kir7.1, the newest members of the Kir channel family, has not been extensively studied in the CNS, and its function remains largely unknown. The present study investigated the role of spinal Kir7.1 in the development of pathological pain.Methods and ResultsNeuropathic pain was induced by spared nerve injury (SNI). The mechanical sensitivity was assessed by von Frey test. Immunofluorescence staining assay revealed that Kir7.1 was predominantly expressed in spinal neurons but not astrocytes or microglia in normal rats. Western blot results showed that SNI markedly decreased the total and membrane expression of Kir7.1 in the spinal dorsal horn accompanied by mechanical hypersensitivity. Blocking Kir7.1 with the specific antagonist ML418 or knockdown kir7.1 by siRNA led to mechanical allodynia. Co‐IP results showed that the spinal kir7.1 channels were decorated by SUMO‐1 but not SUMO‐2/3, and Kir7.1 SUMOylation was upregulated following SNI. Moreover, inhibited SUMOylation by GA (E1 inhibitor) or 2‐D08 (UBC9 inhibitor) can increase the spinal surface Kir7.1 expression.ConclusionSUMOylation of the Kir7.1 in the spinal cord might contribute to the development of SNI‐induced mechanical allodynia by decreasing the Kir7.1 surface expression in rats.