Newborn with Giant Non-Involuting Congenital Hemangioma: Mechanisms of Allodynia, Hyperalgesia and Treatment

In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale which rates pain intensity. The baby presented signs of these pathological events over long periods of the disease. They may be attributed to the high amount of the nociceptive ligands in the hemangioma microenviroment and to the elevated concentration of TNF-alpha and IL-6 in the blood. For a long time, the pain was relieved by a combination of opioids, adjuvants and paracetamol, but also by thalidomide and unexpectedly by interferon alpha. A mechanism-based pain treatment needs to take into account the processes underlying pain and also the ongoing pathology.

Puerarin ameliorates allodynia and hyperalgesia in rats with peripheral nerve injury

Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.

Dynamic mechanical allodynia following finger amputation:Unexpected skin hyperinnervation

The development of chronic pain after amputations is not an uncommon event. In some cases the most disabling problem is represented by the symptom called dynamic mechanical allodynia, characterized by the painful sensation evoked by gently stroking the skin. Despite the growing interest in understanding pain mechanisms, little is known about the mechanism sustaining this peculiar type of pain. We present here the case of a 53-year-old female patient who complained of severe tactile allodynia in the hand after amputation of her left second finger, resistant to several medical and surgical treatments. In order to gain information about the pain mechanism, two neurodiagnostic skin biopsies were obtained from the area of tactile allodynia and from the contralateral, normal skin area. Skin biopsies showed an unexpected increased innervation of the allodynic skin compared to the contralateral, normal skin area(+ 80.1%). Hyperinnervation has been proposed as a mechanism of pain following nerve lesions, but the increased innervation described here could be also attributed to neuronal plasticity occurring in chronic inflammatory conditions. Independently from the uncertain cause of the epidermal hyperinnervation, in this patient we tried to reduce the elevated number of epidermal nerve fibres by treating the skin with topical capsaicin(0.075%) three times a day, and obtained a persistent pain relief. In conclusion, neurodiagnostic skin biopsy might represent an useful tool for detecting derangements of epidermal innervation in patients with dynamic mechanical allodynia and can help to select an individually tailored therapeutic strategy in such difficult clinical conditions. Further studies are needed to clarify this issue and try to gain better understanding of chronic pain mechanisms in patients who underwent finger amputation.

The Primary Motor Cortex Stimulation Attenuates Cold Allodynia in a Chronic Peripheral Neuropathic Pain Condition in <i>Rattus norvegicus</i>

Background: The primary motor cortex (M1) stimulation (MCS) is a useful tool for attenuation of the peripheral neuropathic pain in patients with pharmacologically refractory pain. Furthermore, that neurological procedure may also cause antinociception in rodents with neuropathic pain. Cold allodynia is a frequent clinical finding in patients with neuropathic pain, then, we evaluated if an adapted model of neuropathy induced by chronic constriction injury (CCI) of the ischiadicus nervus (sciatic nerve) produces cold allodynia in an animal model of chronic pain. In addition, we also investigated the effect of the electrical stimulation of the M1 on chronic neuropathic pain condition in laboratory animals. Methods: Male Wistar rats were used. An adapted model of peripheral mononeuropathy induced by CCI was carried out by placing a single loose ligature around the right sciatic nerve. The acetone test was used to evaluate the cold allodynia in CCI or Sham (without ligature) rats. The MCS (M1) was performed at low-frequency (20 μA, 100 Hz) during 15 s by deep brain stimulation (DBS-Thomas Recording device) 21 days after CCI or Sham procedures. The cold allodynia was measured before and immediately after the neurostimulation of M1 in the following time-window: 0, 15 and 30 min after MCS. Results: Cold allodynia threshold increased in animals with chronic neuropathic pain submitted to the acetone test 21 days after the CCI surgery. The M1-stimulation by DBS procedure decreased the cold allodynia immediately and until 30 min after M1-stimulation in rats with chronic neuropathic pain. Conclusion: The current proposal for a CCI model by a single loose ligature of the sciatic nerve can be employed as an experimental model of chronic neuropathic pain in rats submitted to peripheral nervous system injury. The M1-stimulation produced antinociception in rats with chronic neuropathic pain. Thus, we reinforced that the MCS decreases cold allodynia in laboratory animals submitted to persistent sciatic nerve constriction and can be a more reasonable procedure for the treatment of chronic intractable neuropathic pain.

Intraperitoneally Administered Lidocaine Attenuates Thermal Allodynia in a Murine “Two-Hit” Chronic Constriction Injury Model

Background: Mechanical ventilation (hit one) during surgery (hit two) is often needed and both induce an inflammatory response. Dysregulation of the inflammatory response can cause chronic postoperative pain. Methods: Healthy C57BL6 mice (n = 56) were mechanically ventilated (MV) and allocated to receive sham (MV-sham) or mechanically ventilation with chronic constriction injury (MV-CCI) surgery in the left hind paw. Plasma interleukin (IL)-1β, IL-6, IL-10, keratinocyte derived chemokine (KC) and tumor necrosis factor (TNF)-α were determined on day 0 and 16. Sensory testing was performed on day 0, 3, 7 and 16 by cold plate test (number of lifts (NOL) and cumulative reaction time (CRT)) and von Frey test. The effect of lidocaine on cytokines and sensory testing was analyzed. Results: MV-Sham showed an increase in IL-1β and TNF-α, and MV- CCI-lido increased levels of KC compared with MV on day 0. No difference in cytokine levels was observed on day 16. NOL of the left paw versus the right was increased in MV-CCI on day 7, and in MV-CCI-lido on day 7 and 16. The NOL of the left paw was decreased in MV-sham and MV-CCI-lido compared with MV-CCI on day 16. The CRT of the left paw was increased for MV-CCI on day 3 and 7, and for MV-CCI-lido on day 7. On day 16, MV-sham and MV-CCI-lido showed a decreased CRT of the left paw compared with MV-CCI. Conclusion: Nerve injury and not systemic inflammatory response seems mandatory for development of neuropathic pain in this “two-hit” model. Lidocaine attenuates cold allodynia in mice.

Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity(OIH)and analgesic tolerance.Among the different forms of OIH and tolerance,the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved.Here we demonstrated that the loss of peripheralμ-opioid receptors(MORs)or MOR-expressing neurons attenuated thermal tolerance,but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance.To confirm this result,we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons.Consistent with the behavioral results,peripheral MOR loss did not prevent the opening of Aβmechanical allodynia pathways in the spinal dorsal horn.Therefore,the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance.Future studies should focus more on central mechanisms.

Microglial Depletion does not Afect the Laterality of Mechanical Allodynia in Mice

Mechanical allodynia(MA),including punctate and dynamic forms,is a common and debilitating symptom suffered by millions of chronic pain patients.Some peripheral injuries result in the development of bilateral MA,while most injuries usually led to unilateral MA.To date,the control of such laterality remains poorly understood.Here,to study the role of microglia in the control of MA laterality,we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice.Surprisingly,the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA.Moreover,in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons.Consistent with behavioral results,microglial depletion did not prevent the opening of bilateral gates for Aβpathways in the superficial dorsal horn.This study challenges the role of microglia in the control of MA laterality in mice.Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.

Involvement of NF-κB and the CX3CR1 Signaling Network in Mechanical Allodynia Induced by Tetanic Sciatic Stimulation

Tetanic stimulation of the sciatic nerve （TSS） triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1- CX3CR1 signaling is an important pathway in neuronal- microglial activation. Nuclear factor nB （NF-KB） is a key signal transduction molecule that regulates neuroinflamma- tion and neuropathic pain. Here, we set out to determine whether and how NF-~B and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-nB （pNF-nB） and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammo- nium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down- regulated the expression of CX3CL1-CX3CR1 signaling,and conversely the CX3CRl-neutralizing antibody also down-regulated pNF-rd3. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR 1-neutralizing antibodies in treating pathological pain.

Kir2.1 Channel Regulation of Glycinergic Transmission Selectively Contributes to Dynamic Mechanical Allodynia in a Mouse Model of Spared Nerve Injury

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brushevoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1(Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury(SNI).Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in na¨?ve but also in ML133-pretreated mice. In contrast, bicuculline, a GABAAreceptor antagonist, induced only punctate, but not dynamic,allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents(gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration oracute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively.In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.

Exercise combined with administration of adipose-derived stem cells ameliorates neuropathic pain after spinal cord injury

Experimental studies have shown that exercise and human adipose-derived stem cells(ADSCs)play positive roles in spinal cord injury(SCI).However,whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear.Thus,there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI.In this study,a thoracic 11(T11)SCI contusion model was established in adult C57BL/6 mice.Exercise was initiated from 7 days post-injury and continued to 28 days post-injury,and approximately 1×105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI.Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale,von Frey filament test,Hargreaves method,and cold plate test.Histological studies(Eriochrome cyanine staining and immunohistochemistry)were performed at the end of the experiment(28 days post-injury).Exercise combined with administration of ADSCs partially improved early motor function(7,14,and 21 days postinjury),mechanical allodynia,mechanical hypoalgesia,thermal hyperalgesia,and thermal hypoalgesia.Administration of ADSCs reduced white and gray matter loss at the lesion site.In addition,fewer microglia and astrocytes(as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein,respectively)were present in the lumbar dorsal horn in the SCI+ADSCs and SCI+exercise+ADSCs groups compared with the sham group.Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCIinduced neuropathic pain.

Ⅲ型代谢型谷氨酸受体在痛觉调控中的作用

代谢型谷氨酸受体(mGluR)是G蛋白偶联受体,通过与谷氨酸这一主要中枢神经递质结合后而激活。目前已有8种不同的mGluR亚型被鉴定出来,并根据其分子结构、药理学特性和信号转导机制分为Ⅰ、Ⅱ及Ⅲ型。mGluR介导了多种生理功能,如神经元兴奋性和突触可塑性,但它们同时也参与了如疼痛等多种病理条件下的调控。mGluR广泛表达于外周及中枢痛觉调控通路中,近些年来,随着Ⅲ型mGluR新的选择性配体及正性变构调节剂的开发,使得Ⅲ型mGluR在痛觉中的生理及病理性调控作用及机制逐渐明确,提示Ⅲ型mGluR可能是治疗病理性疼痛的潜在靶点。本文就Ⅲ型mGluR在痛觉调控中的作用进行综述。

神经病理性疼痛动物模型的选择与建立

神经病理性疼痛(neuropathic pain,NP)是临床上最常见的难治性慢性疼痛,已成为最具挑战性的公共健康问题之一。由于NP发病率高,致病机制复杂且尚未完全阐明,目前尚无有效的治疗和预防策略,严重影响病人的生活质量和身心健康。因此,有必要进一步深入研究NP的致病机制,为NP的治疗提供更多证据。选择与建立合适的疼痛动物模型是NP机制研究中需要解决的关键问题。目前动物模型多根据NP病因进行分类,不利于研究者对动物模型的筛选比较与建模。本文基于神经受损的方式,如单次损伤、持续损伤、全身疾病或药物诱导损伤等,对常见NP模型的动物选择和分类进行总结,以期为NP研究中动物模型的选择与建立提供有益的参考。

不同频率的电针对大鼠神经源性痛的治疗作用

目的 :探讨不同频率的电针能否减轻大鼠神经源性痛。方法 :将大鼠右侧L5 /L6脊神经结扎 ,用引起 5 0 %抬足的机械刺激阈值评价机械性痛觉超敏 ,用大鼠 5min内从 5℃冷板上的抬足次数反映冷诱发的持续性疼痛。用韩氏穴位神经刺激仪给与 2Hz或 10 0Hz电刺激。结果 :① 2Hz和 10 0Hz电针均能减轻痛觉超敏 ,2Hz起效较早。②两种频率电针均能减轻冷诱发的持续性疼痛 ,但 2Hz持续的时间长 ,多次电针后 2Hz的镇痛效果可持续长达 4 8h。③针刺而不通电也能显著减轻冷诱发的持续性痛。结论 :电针能减轻神经源性痛 ,且低频 (2Hz)电针的镇痛效果优于高频 (10 0Hz)电针。

2 Hz电针减轻神经源性痛大鼠的痛觉超敏和冷诱发的持续性疼痛

目的 :已知电针能减轻大鼠辐射热引起的疼痛和急、慢性炎症痛 ,本文探讨电针能否减轻大鼠神经源性痛。方法 :将大鼠右侧L5/L6 脊神经结扎 ,用引起 5 0 %缩足的机械刺激阈值评价机械性痛觉超敏 ,用大鼠 5min内在 5± 1℃冷板上的缩足次数反映冷诱发的持续性疼痛。用韩氏穴位神经刺激仪给予电刺激 ,波宽 0 .6ms ,频率 2Hz ,电流强度为 0 .5 ,1和 2mA ,各 10min ,共刺激 30min。结果 :2Hz电针能减轻痛觉超敏 (持续 1h)和冷诱发的持续性疼痛 (持续 12小时 )。电针前15min皮下注射纳洛酮 (1mg/kg)能阻断电针对冷诱发的持续性疼痛的作用 ,但不能阻断对痛觉超敏的作用。结论 :低频 (2Hz)电针可能通过阿片机制减轻持续性的神经源性疼痛 ,低频电针也能减轻机械性痛觉超敏 ,该作用可能不是通过阿片机制完成的。

TRPV4在介导大鼠背根神经节持续受压后机械和热痛敏中的作用

目的:观察持续机械压迫(CCD)对瞬时感受器电位离子通道4(TRPV4)基因、蛋白表达及功能的影响,明确TRPV4是否参与CCD导致的机械和热痛敏。方法:建立CCD模型后,分别于手术前及手术后第7天、第14天及第28天取材前测量运动功能、机械刺激缩爪反应阈值和热辐射刺激缩爪反应潜伏期。为了测量TRPV4反义核苷酸干扰对机械和热痛阈值的影响,在蛛网膜下腔内注入TRPV4寡脱氧核苷酸(ODN)40μg/d,每天1次,第7天后测量大鼠行为学变化。使用实时定量RT-PCR检测TRPV4基因表达的变化,Western blot检测TRPV4蛋白质表达量的变化,激光共聚焦检测低渗溶液和佛波醇(4α-PDD)刺激背根神经节(DRG)神经元后细胞内钙离子浓度的变化。结果:所有动物在损伤前后步态均正常,持续压迫明显降低大鼠的机械和热痛阈,TRPV4干扰可部分逆转该痛敏。持续机械压迫可以明显增加TRPV4基因和蛋白的表达,手术后第7天,第14天和第28天,TRPV4mRNA的表达分别为假手术组大鼠的4.29倍、2.95倍和2.48倍,蛋白表达量分别为假手术组大鼠的4.34倍,3.88倍和2.47倍。持续机械压迫后,对低渗溶液和4α-PDD产生反应的DRG神经元的比例数增加,细胞内钙的峰值增高。这种反应被TRPV4反义ODN所抑制。结论:CCD可以上调TRPV4的基因、蛋白表达,敏化通道的功能;TRPV4参与介导CCD导致的机械和热痛敏。

小鼠骨癌痛模型的建立及痛行为学和骨损害的观察

目的:在小鼠骨癌痛模型的基础上观察小鼠行为学和骨质损害的程度。方法:将2×105个NCTC2472小鼠纤维肉瘤细胞注射到C3H/HeJ小鼠右侧股骨远端骨髓腔内制作骨癌痛动物模型。分别于注射后1、3、5、7、10、14、21、28天观察小鼠的体重和痛行为学表现:vonFrey细丝刺激足底测量机械缩足阈值和行走后足使用评分评价行走诱发患肢痛;分别于注射后7、14、21、28天进行X线检查评估股骨破坏程度;取股骨进行组织切片,HE染色光镜下观察肿瘤组织和骨结构破坏情况。结果:模型组小鼠体重在注射后第28天显著低于对照组和基础体重(P<0.05),注射后第7天模型组小鼠出现机械性痛觉超敏,第14天出现行走诱发患肢痛。第14天X线摄片显示有明显的骨破坏,第28天出现病理性骨折。组织学研究显示骨髓腔内肿瘤生长,向外侵蚀破坏骨皮质。结论:从疼痛行为学、放射学、组织学多方面的研究表明小鼠骨癌痛模型复制成功。

己酮可可碱能减轻神经病理性疼痛大鼠痛觉过敏的发展

目的：观察预防性腹腔给予己酮可可碱对大鼠腰5脊神经切断后机械痛觉过敏的作用，以及相应脊髓节段胶质细胞活化、炎症及细胞因子表达的影响。方法：雄性SD大鼠48只，随机均分为6组，每组8只。Ⅰ组为假手术组；Ⅱ组为等渗盐水对照组；Ⅲ组为12．5mg／kg己酮可可碱治疗组；Ⅳ组为25mg／kg己酮可可碱治疗组；Ⅴ组为50mg／kg己酮可可碱治疗组；Ⅵ组为100mg／kg己酮可可碱治疗组。采用大鼠腰5脊神经切断神经病理性疼痛模型，术前1h，Ⅰ和Ⅱ组腹腔注射等渗盐水，Ⅲ-Ⅵ组腹腔注射相应剂量的己酮可可碱。术后第1—6d每天16时，各组大鼠腹腔注射相应剂量药物。计数手术前、术后第1、4、7d各组大鼠2g和12g范氟雷丝刺激手术同侧后爪后跟撤腿次数。术后第7d行为学检测完毕，处死大鼠，取腰5脊髓，测定肿瘤坏死因子α（TNFα）、白细胞介素18（IL-1β）以及白细胞介素6（IL-6）浓度，胶质细胞表面标记物Toll样受体4（TLR4）、白细胞分化抗原11b（CD11b），胶质纤维酸性蛋白（GFAP）mRNA的表达水平。结果：腰5神经切断后，与Ⅰ组相比各手术组对2g和12g刺激均有明显增多的撤腿反应，但与Ⅱ组相比，Ⅴ组和Ⅵ组对2g和12g刺激的撤腿次数明显减少，Ⅲ组和Ⅳ组则差异无统计学意义（P〉0．05）。术后第7d，与Ⅰ组相比各手术组腰5脊髓TNFα、IL-1β、IL-6及胶质细胞表面标记物TLR-4、CD11b、GFAP的mRNA表达水平明显增高（P〈0．05）。但与Ⅱ组相比，Ⅴ组和Ⅵ组TNFα、IL-1β、IL-6及TLR-4、CD11b、GFAP的mRNA表达水平明显低（P〈0．05），Ⅲ组和Ⅳ组差异则无统计学意义（P〉0．05）。结论：己酮可可碱能够剂量依赖的缓解神经病理性疼痛大鼠痛觉过敏的发展，这与它能减轻脊髓胶质细胞活化、炎症因子表达的效应相关。

脊髓小胶质细胞激活对SNI模型大鼠神经病理性疼痛的影响

目的观察小胶质细胞对大鼠坐骨神经分支选择性损伤(SNI)所致神经病理性疼痛的影响。方法选择雄性SD大鼠64只,随机分为4组(n=16):假手术组(Sh组);模型组(SNI组);模型+米诺环素40mg/kg组(Mb组);模型+米诺环素10mg/kg组(Ms组)。其中Mb和Ms组从造模前1d起连续7d每日2次腹腔注射相应剂量的米诺环素。分别记录全组动物在术前1d及术后1,3,5,7,14d的机械缩足反射阈值(MWT)和热缩足反射持续时间(TWD)作为大鼠疼痛行为学指标;各组大鼠分别在术后1,3,5,7,14d随机选取4只处死,取脊髓,用免疫荧光的方法检测脊髓小胶质细胞标志物OX-42的表达。结果SNI组从术后1d起即出现明显MWT降低和TWD延长,与术前及Sh组术后各时点比较均有统计学差异(P<0.05);Mb组和Ms组与SNI组相应时点比较MWT降低和TWD延长程度有显著性差异(P<0.05);Mb与Ms组比较MWT降低和TWD延长程度有统计学差异(P<0.05);Mb、Ms组与SNI组比较脊髓OX-42的表达减少,并呈剂量依赖性。结论米诺环素腹腔注射可剂量依赖性的减少OX-42的表达,抑制脊髓小胶质细胞的激活,减轻痛觉超敏和痛觉过敏,提示小胶质细胞的活化参与SNI神经病理痛的形成。

脊髓蛋白激酶Cα和γ亚型在吗啡依赖和戒断反应中的不同作用

在大鼠吗啡依赖和戒断模型上,采用行为学、免疫组织化学和Western blot方法观察鞘内应用蛋白激酶C(protien kinase C.PKC)抑制剂chelerythrine chloride(CHE)对吗啡依赖大鼠纳洛酮催促戒断反应、脊髓Fos蛋白表达和脊髓神经元胞膜和胞浆PKC α、γ表达的影响,以探讨不同亚型PKC在吗啡依赖和戒断反应中的作用。结果表明,鞘内注射CHE能明显减轻吗啡成断痱状的评分和吗啡成断引起的痛觉异常,抑制吗啡戒断期间脊髓Fos蛋白表达的增加;吗啡依赖可引起脊髓神经元PKCα和γ表达的上调和转位;吗啡戒断期间存在明显的且可被鞘内注射CHE抑制的PKC α转位,但未观察到明显的PKC γ转位。上述结果提示,脊髓PKC表达上调和转位可能参与吗啡依赖的形成和戒断反应的表达,且PKC α和γ亚型在吗啡依赖和戒断反应中的作用存在差异。

大鼠硬膜外间隙应用辣椒素镇痛的实验研究

目的 :通过行为学、免疫组织化学和神经电生理学方法观察正常大鼠硬膜外间隙注射辣椒素的镇痛效果 ,并探讨利多卡因消除辣椒素不良反应的可行性。方法 :将正常大鼠 71只 ,随机分为 5组 ,分别于硬膜外间隙置管注射 (0 .1%、0 .2 %、0 .4 % )辣椒素、0 .2 %辣椒素 +利多卡因 ,和生理盐水 +溶媒 (简称NC0 .1组、NC0 .2组、NC0 .4组、LC0 .2组和NT组 ) ,实验采用热辐射仪测定大鼠的热痛阈 ,并观察其不良反应的发生率和痛阈恢复情况。另取硬膜外间隙置管大鼠 6 0只 ,平均分为NC0 .1组、NC0 .2组和LC0 .2组 ,并用正常大鼠 2 0只作为对照组 ,分别于硬膜外间隙注药后 30min和第 5天观察脊髓背角CGRP LI的分布变化 ,并计算其阳性面积。结果 :随着辣椒素浓度的增大 ,其镇痛强度和作用时间逐渐延长 ,不良反应的发生率也随之增高 ;利多卡因可完全消除辣椒素引起的呼吸麻痹和神经刺激性疼痛 ,对痛觉超敏亦具有一定的抑制作用。在硬膜外间隙注射辣椒素后30min和第 5天 ,NC0 .1组脊髓背角的CGRP LI的分布和呈色无明显改变 ;NC0 .2组的CGRP LI呈色浅 ,阳性面积下降 (P〈0 .0 5 ) ;LC0 .2组于 30min时CGRP LI的分布与正常并无明显差别 ,但第 5天时的阳性面积明显下降 ;第 5天时NC0 .2组和LC0 .2组背角CRGP阳性面积间无显?