脊髓胶质细胞活化与病理性疼痛调节

背景 研究表明脊髓胶质细胞(星形胶质细胞和小胶质细胞)在各种病理性疼痛模型中活化,并且活化的胶质细胞在各种病理性疼痛的发生和发展中具有重要作用.目的 探讨脊髓胶质细胞在病理性疼痛调节中的作用.内容 从脊髓胶质细胞活化参与病理性疼痛调节的生理基础,脊髓胶质细胞活化及其检测,脊髓胶质细胞活化与病理性疼痛和脊髓胶质细胞参与病...     

抑制病理性疼痛相关胶质细胞活化药物的研究进展

背景 病理性疼痛的产生和持续机制十分复杂.近些年越来越多的研究者关注到脊髓胶质细胞在病理性疼痛中所发挥的作用,其中胶质细胞活化和增殖的抑制剂成为了研究的重点.目的 系统阐述胶质细胞在病理性疼痛中的作用和部分胶质细胞抑制剂的作用机制及研究进展.内容 胶质细胞不仅具有营养和支持作用,还参与了病理性疼痛,已有许多实验证实了应用胶质细胞抑制剂可以减弱胶质细胞的激活从而削弱疼痛反应.趋向 期望能为进一步的药物实验研究提供有价值的思路和借鉴.     

神经病理性疼痛中脊髓小胶质细胞活化的分子机制

背景 研究表明脊髓小胶质细胞活化对神经元功能调控起重要作用,并可影响脊髓背角伤害性信号的传递进而参与调控神经病理性疼痛(neuropathic pain,NP)的中枢敏化过程. 目的 探讨NP状态下脊髓小胶质细胞活化的分子机制. 内容 分别从脊髓小胶质细胞活化的胞外分子机制和胞内分子机制两方面就与此相关的研究进展作一综述. 趋向 小胶质细胞在NP中的作用将继续成为疼痛研究的热点,对小胶质细胞的深入研究可能使NP得到更为有效的治疗.     

丝裂原活化蛋白激酶家族与病理性疼痛

病理性疼痛包括炎性痛和神经病理性痛。炎性痛是由创伤、细菌或病毒感染及外科手术等引起的外周组织损伤导致的炎症而引起的疼痛;神经病理性疼痛是由于外周或中枢神经系统的直接损伤或功能紊乱引起的疼痛,其共同的临床表现有自发性疼痛、痛觉过敏、触诱发痛等。许多脊髓或高级中枢神经病理生理的改变都可引起或参与病理性神经痛的形成。目前的研究认为,脊髓背角神经元及脊髓胶质细胞丝裂原活化蛋白激酶家族活化与病理性疼痛有关[1,2]。现就MAPKs在病理性疼痛的发生、发展过程中所起的作用作一综述。1 MAPKsMAPKs在所有真核细胞中均有表…     

脊髓小胶质细胞内信号p38丝裂原活化蛋白激酶在神经病理性疼痛的作用

证据表明小胶质细胞在神经病理性疼痛中扮演着重要的角色.神经损伤后,小胶质细胞内p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)激活,致小胶质细胞产生各种生物活性物质,引发痛觉超敏.小胶质细胞内p38MAPK在神经病理性疼痛的发生和发展中起重要作用,p38MAPK及其亚型有望成为治疗神经病理性疼痛的新靶点.     

脊髓小胶质细胞内信号p38丝裂原活化蛋白激酶在神经病理性疼痛的作用

证据表明小胶质细胞在神经病理性疼痛中扮演着重要的角色.神经损伤后,小胶质细胞内p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)激活,致小胶质细胞产生各种生物活性物质,引发痛觉超敏.小胶质细胞内p38MAPK在神经病理性疼痛的发生和发展中起重要作用,p38MAPK及其亚型有望成为治疗神经病理性疼痛的新靶点.     

脊髓小胶质细胞内信号p38丝裂原活化蛋白激酶在神经病理性疼痛的作用

证据表明小胶质细胞在神经病理性疼痛中扮演着重要的角色.神经损伤后,小胶质细胞内p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)激活,致小胶质细胞产生各种生物活性物质,引发痛觉超敏.小胶质细胞内p38MAPK在神经病理性疼痛的发生和发展中起重要作用,p38MAPK及其亚型有望成为治疗神经病理性疼痛的新靶点.     

脊髓小胶质细胞内信号p38丝裂原活化蛋白激酶在神经病理性疼痛的作用

证据表明小胶质细胞在神经病理性疼痛中扮演着重要的角色.神经损伤后,小胶质细胞内p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)激活,致小胶质细胞产生各种生物活性物质,引发痛觉超敏.小胶质细胞内p38MAPK在神经病理性疼痛的发生和发展中起重要作用,p38MAPK及其亚型有望成为治疗神经病理性疼痛的新靶点.     

脊髓小胶质细胞内信号p38丝裂原活化蛋白激酶在神经病理性疼痛的作用

证据表明小胶质细胞在神经病理性疼痛中扮演着重要的角色.神经损伤后,小胶质细胞内p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)激活,致小胶质细胞产生各种生物活性物质,引发痛觉超敏.小胶质细胞内p38MAPK在神经病理性疼痛的发生和发展中起重要作用,p38MAPK及其亚型有望成为治疗神经病理性疼痛的新靶点.     

脊髓小胶质细胞内信号p38丝裂原活化蛋白激酶在神经病理性疼痛的作用

证据表明小胶质细胞在神经病理性疼痛中扮演着重要的角色.神经损伤后,小胶质细胞内p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,p38MAPK)激活,致小胶质细胞产生各种生物活性物质,引发痛觉超敏.小胶质细胞内p38MAPK在神经病理性疼痛的发生和发展中起重要作用,p38MAPK及其亚型有望成为治疗神经病理性疼痛的新靶点.     

Activation of glial cells in the spinal cord of a model of lumbar radiculopathy

Purpose  

Glial cells in the spinal cord of a lumbar radiculopathy model were investigated using immunohistochemical methods. Neuropathic pain is a consequence of neural plasticity. In models of neuropathic pain models, roles for glial cells in the development of pain behaviors have been reported. Accumulating evidence suggests that activation of p38 mitogen-activated protein kinase (p38) in glial cells contributes to the pathogenesis of neuropathic pain. We examined whether activation of glial cells is involved in the development of neuropathic pain-like behavior observed in a model of lumbar radicular pain that we developed. However, the pathogenesis of lumbar radiculopathy and in particular the effect of spinal glial activation on pain transmission in the dorsal horn of the spinal cord are still not fully known.     

Role for cyclooxygenase 2 in the development and maintenance of neuropathic pain and spinal glial activation

BACKGROUND: Lines of evidence have indicated that cyclooxygenase 2 plays a role in the pathophysiology of neuropathic pain. However, the site and mechanism of its action are still unclear. Spinal glia has also been reported to mediate pathologic pain states. The authors evaluated the effect of continuous intrathecal or systemic cyclooxygenase-2 inhibitor on the development and maintenance of neuropathic pain and glial activation in a spinal nerve ligation model of rats. METHODS: Continuous intrathecal infusion of meloxicam (32 or 320 mug . kg . day) or saline was started immediately after L5-L6 spinal nerve ligation. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively. Spinal astrocytic activation was evaluated with glial fibrially acidic protein immunoreactivity on day 7. In other groups of rats, continuous intrathecal meloxicam was started 7 days after spinal nerve ligation, and effects on established neuropathic pain and glial activation were evaluated. Last, effects of continuous systemic meloxicam (16 mg . kg . day) on existing neuropathic pain and glial activation were examined. RESULTS: Intrathecal meloxicam prevented the development of mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation. It also inhibited spinal glial activation responses. In contrast, when started 7 days after the nerve ligation, intrathecal meloxicam did not reverse established neuropathic pain and glial activation. Systemic meloxicam started 7 days after ligation partially reversed neuropathic behaviors but not glial activation. CONCLUSIONS: Spinal cyclooxygenase 2 mediates the development but not the maintenance of neuropathic pain and glial activation in rats. Peripheral cyclooxygenase 2 plays a part in the maintenance of neuropathic pain.     

Spinal Microglial and Perivascular Cell Cannabinoid Receptor Type 2 Activation Reduces Behavioral Hypersensitivity without Tolerance after Peripheral Nerve Injury

Background: Cannabinoids induce analgesia by acting on cannabinoid receptor (CBR) types 1 and/or 2. However, central nervous system side effects and antinociceptive tolerance from CBR1 limit their clinical use. CBR2 exist on spinal glia and perivascular cells, suggesting an immunoregulatory role of these receptors in the central nervous system. Previously, the authors showed that spinal CBR2 activation reduces paw incision hypersensitivity and glial activation. This study tested whether CBR2 are expressed in glia and whether their activation would induce antinociception, glial inhibition, central side effects, and antinociceptive tolerance in a neuropathic rodent pain model.

Methods: Rats underwent L5 spinal nerve transection or sham surgery, and CBR2 expression and cell localization were assessed by immunohistochemistry. Animals received intrathecal injections of CBR agonists and antagonists, and mechanical withdrawal thresholds and behavioral side effects were assessed.

Results: Peripheral nerve transection induced hypersensitivity, increased expression of CR3/CD11b and CBR2, and reduced ED2/CD163 expression in the spinal cord. The CBR2 were localized to microglia and perivascular cells. Intrathecal JWH015 reduced peripheral nerve injury hypersensitivity and CR3/CD11b expression and increased ED2/CD163 expression in a dose-dependent fashion. These effects were prevented by intrathecal administration of the CBR2 antagonist (AM630) but not the CBR1 antagonist (AM281). JWH015 did not cause behavioral side effects. Chronic intrathecal JWH015 treatment did not induce antinociceptive tolerance.     

Role for Cyclooxygenase 2 in the Development and Maintenance of Neuropathic Pain and Spinal Glial Activation

Background: Lines of evidence have indicated that cyclooxygenase 2 plays a role in the pathophysiology of neuropathic pain. However, the site and mechanism of its action are still unclear. Spinal glia has also been reported to mediate pathologic pain states. The authors evaluated the effect of continuous intrathecal or systemic cyclooxygenase-2 inhibitor on the development and maintenance of neuropathic pain and glial activation in a spinal nerve ligation model of rats.

Methods: Continuous intrathecal infusion of meloxicam (32 or 320 [mu]g [middle dot] kg-1 [middle dot] day-1) or saline was started immediately after L5-L6 spinal nerve ligation. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively. Spinal astrocytic activation was evaluated with glial fibrially acidic protein immunoreactivity on day 7. In other groups of rats, continuous intrathecal meloxicam was started 7 days after spinal nerve ligation, and effects on established neuropathic pain and glial activation were evaluated. Last, effects of continuous systemic meloxicam (16 mg [middle dot] kg-1 [middle dot] day-1) on existing neuropathic pain and glial activation were examined.

Results: Intrathecal meloxicam prevented the development of mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation. It also inhibited spinal glial activation responses. In contrast, when started 7 days after the nerve ligation, intrathecal meloxicam did not reverse established neuropathic pain and glial activation. Systemic meloxicam started 7 days after ligation partially reversed neuropathic behaviors but not glial activation.     

胶质细胞活化对慢性前列腺炎/慢性盆腔疼痛综合征(CP/CPPS)大鼠脊髓背角P物质的影响

目的探讨胶质细胞活化对慢性前列腺炎/慢性盆腔疼痛综合征（chronic prostatitis/chronic pelvic pain syndromes,CP/CPPS）大鼠脊髓背角P物质的影响。方法完全福氏佐剂和3%角叉菜胶前列腺内注射造成CP/CPPS模型,脊髓插管给药胶质细胞活化抑制剂Propentofylline干扰CP/CPPS模型大鼠,免疫组织化学方法观察正常组、疼痛模型组、药物干扰组脊髓节段（L6和S1）背角的胶质细胞的活化和P物质的定性定位,并用放射免疫的方法观察三组脊髓背角P物质的变化。结果脊髓背角胶质细胞活化阳性细胞数疼痛组明显增加,药物干扰组明显减少;P物质主要表达于脊髓背角且疼痛模型组明显增多,药物干扰组明显减少。结论胶质细胞活化是CP/CPPS大鼠脊髓背角P物质变化的重要原因,胶质细胞活化抑制剂的应用将是治疗CP/CPPS的新亮点。     

Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision

BACKGROUND: Cannabinoids bind to cannabinoid receptors type 1 and 2 and produce analgesia in several pain models, but central side effects from cannabinoid 1 receptors limit their clinical use. Cannabinoid 2 receptors reduce inflammatory responses in the periphery by acting on immune cells, and they are present on glia in the central nervous system. This study tested whether spinal cannabinoid activation would induce analgesia, glial inhibition, and central side effects in a postoperative model or incisional pain. METHODS: Rats underwent paw incision surgery, with intrathecal injections of cannabinoid agonists and antagonists and assessment of withdrawal thresholds and behavioral side effects. Spinal glial activation was determined by immunohistochemistry. RESULTS: Intrathecal administration CP55940 reduced postoperative hypersensitivity (91 +/- 9% maximum possible effect; P < 0.05), and this was prevented by intrathecal administration of both cannabinoid 1 receptor (AM281) and cannabinoid 2 receptor (AM630) antagonists. CP55940 also caused several behavioral side effects, and these were prevented by the cannabinoid 1 receptor but not by the cannabinoid 2 receptor antagonist. Intrathecal injection of the cannabinoid 2 receptor agonist JWH015 reversed postoperative hypersensitivity (89 +/- 5% maximum possible effect; P < 0.05), and this was reversed by the cannabinoid 2 but not by the cannabinoid 1 receptor antagonist. JWH015, which did not induce behavioral side effects, reduced paw incision induced microglial and astrocytic activation in spinal cord (P < 0.05). CONCLUSIONS: These data indicate that intrathecal administration of cannabinoid receptor agonists may provide postoperative analgesia while reducing spinal glial activation, and that selective cannabinoid 2 receptor agonists may do so without central side effects.     

Repeated injury to the lumbar nerve roots produces enhanced mechanical allodynia and persistent spinal neuroinflammation.

STUDY DESIGN: A lumbar radiculopathy model investigated pain behavioral responses after nerve root reinjury. OBJECTIVES: To gain a further understanding of central sensitization and neuroinflammation associated with chronic lumbar radiculopathy after repeated nerve root injury. SUMMARY OF BACKGROUND DATA: The pathophysiologic mechanisms associated with chronic radicular pain remain obscure. It has been hypothesized that lumbar root injury produces neuroimmunologic and neurochemical changes, sensitizing the spinal cord and causing pain responses to manifest with greater intensity and longer duration after reinjury. However, this remains untested experimentally. METHODS: Male Holtzman rats were divided into two groups: a sham group having only nerve root exposure, and a chromic group in which the nerve root was ligated loosely with chromic gut suture. Animals underwent a second procedure at 42 days. The chromic group was further divided into a reinjury group and a chromic-sham group, in which the lumbar roots were only re-exposed. Bilateral mechanical allodynia was continuously assessed throughout the study. Qualitative assessment of spinal cord glial activation and IL-beta expression was performed. RESULTS: Mechanical allodynia was significantly greater on both the ipsilateral and contralateral sides after reinjury (P < 0.001), and the response did not return to baseline after reinjury, as it did with the initial injury. There were also persistent spinal astrocytic and microglial activation and interleukin-1beta expression. CONCLUSIONS: The bilateral responses support central modulation of radicular pain after nerve root injury. An exaggerated and more prolonged response bilaterally after reinjury suggests central sensitization after initial injury. Neuroinflammatory activation in the spinal cord further supports the hypothesis that central neuroinflammation plays an important role in chronic radicular pain.     

Spinal Cannabinoid Receptor Type 2 Activation Reduces Hypersensitivity and Spinal Cord Glial Activation after Paw Incision

Background: Cannabinoids bind to cannabinoid receptors type 1 and 2 and produce analgesia in several pain models, but central side effects from cannabinoid 1 receptors limit their clinical use. Cannabinoid 2 receptors reduce inflammatory responses in the periphery by acting on immune cells, and they are present on glia in the central nervous system. This study tested whether spinal cannabinoid activation would induce analgesia, glial inhibition, and central side effects in a postoperative model or incisional pain.

Methods: Rats underwent paw incision surgery, with intrathecal injections of cannabinoid agonists and antagonists and assessment of withdrawal thresholds and behavioral side effects. Spinal glial activation was determined by immunohistochemistry.

Results: Intrathecal administration CP55940 reduced postoperative hypersensitivity (91 +/- 9% maximum possible effect; P < 0.05), and this was prevented by intrathecal administration of both cannabinoid 1 receptor (AM281) and cannabinoid 2 receptor (AM630) antagonists. CP55940 also caused several behavioral side effects, and these were prevented by the cannabinoid 1 receptor but not by the cannabinoid 2 receptor antagonist. Intrathecal injection of the cannabinoid 2 receptor agonist JWH015 reversed postoperative hypersensitivity (89 +/- 5% maximum possible effect; P < 0.05), and this was reversed by the cannabinoid 2 but not by the cannabinoid 1 receptor antagonist. JWH015, which did not induce behavioral side effects, reduced paw incision induced microglial and astrocytic activation in spinal cord (P < 0.05).