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首页> 外文期刊>Pain research & management: the journal of the Canadian Pain Society = journal de la socie?te? canadienne pour le traitement de la douleur >Antiallodynic Effects of Cannabinoid Receptor 2 (CB2R) Agonists on Retrovirus Infection-Induced Neuropathic Pain
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Antiallodynic Effects of Cannabinoid Receptor 2 (CB2R) Agonists on Retrovirus Infection-Induced Neuropathic Pain

机译：大麻受体2（CB2R）激动剂对逆转录病毒感染引起的神经性疼痛的镇痛作用

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The most common neurological complication in patients receiving successful combination antiretroviral therapy (cART) is peripheral neuropathic pain. Data show that distal symmetric polyneuropathy (DSP) also develops along with murine acquired immunodeficiency syndrome (MAIDS) after infection with the LP-BM5 murine retrovirus mixture. Links between cannabinoid receptor 2 (CB2R) and peripheral neuropathy have been established in animal models using nerve transection, chemotherapy-induced pain, and various other stimuli. Diverse types of neuropathic pain respond differently to standard drug intervention, and little is currently known regarding the effects of modulation through CB2Rs. In this study, we evaluated whether treatment with the exogenous synthetic CB2R agonists JWH015, JWH133, Gp1a, and HU308 controls neuropathic pain and neuroinflammation in animals with chronic retroviral infection. Hind-paw mechanical hypersensitivity in CB2R agonist-treated versus untreated animals was assessed using the MouseMet electronic von Frey system. Multicolor flow cytometry was used to determine the effects of CB2R agonists on macrophage activation and T-lymphocyte infiltration into dorsal root ganglia (DRG) and lumbar spinal cord (LSC). Results demonstrated that, following weekly intraperitoneal injections starting at 5?wk p.i., JWH015, JWH133, and Gp1a, but not HU308 (5?mg/kg), significantly ameliorated allodynia when assessed 2?h after ligand injection. However, these same agonists (2x/wk) did not display antiallodynic effects when mechanical sensitivity was assessed 24?h after ligand injection. Infection-induced macrophage activation and T-cell infiltration into the DRG and LSC were observed at 12?wk p.i., but this neuroinflammation was not affected by treatment with any CB2R agonist. Activation of JAK/STAT3 has been shown to contribute to development of neuropathic pain in the LSC and pretreatment of primary murine microglia (2?h) with JWH015-, JWH133-, or Gp1a-blocked IFN-gamma-induced phosphorylation of STAT1 and STAT3. Taken together, these data show that CB2R agonists demonstrate acute, but not long-term, antiallodynic effects on retrovirus infection-induced neuropathic pain.
机译：成功接受抗逆转录病毒治疗（cART）的患者中最常见的神经系统并发症是周围神经性疼痛。数据显示，用LP-BM5鼠逆转录病毒混合物感染后，远端对称性多发性神经病（DSP）也会与鼠获得性免疫缺陷综合症（MAIDS）一起发展。大麻素受体2（CB2R）与周围神经病变之间的联系已在动物模型中使用神经横切，化学疗法诱发的疼痛和各种其他刺激进行了建立。多种类型的神经性疼痛对标准药物干预的反应不同，目前对于通过CB2R进行调节的作用知之甚少。在这项研究中，我们评估了外源性合成CB2R激动剂JWH015，JWH133，Gp1a和HU308的治疗是否能控制慢性逆转录病毒感染动物的神经性疼痛和神经炎症。使用MouseMet电子von Frey系统评估了CB2R激动剂治疗动物与未治疗动物的后爪机械性超敏反应。多色流式细胞仪用于确定CB2R激动剂对巨噬细胞激活和T淋巴细胞浸入背根神经节（DRG）和腰脊髓（LSC）的影响。结果表明，在配体注射后2 h评估为每周5周w.p.i，JWH015，JWH133和Gp1a，但不是HU308（5 mg / kg）腹膜内注射后，异常疼痛明显改善。但是，当在配体注射后24小时评估机械敏感性时，这些相同的激动剂（2x / wk）没有显示出抗痛觉过敏作用。感染诱导巨噬细胞活化和T细胞浸入DRG和LSC的p.i. 12点，但这种神经炎症不受任何CB2R激动剂治疗的影响。已经证明，JAK / STAT3的激活可促进LSC的神经性疼痛的发展，并用JWH015-，JWH133-或Gp1a阻断的IFN-γ诱导的STAT1和STAT3磷酸化来预处理原发性小鼠小胶质细胞（2？h）。 。总而言之，这些数据表明CB2R激动剂对逆转录病毒感染引起的神经性疼痛表现出急性但非长期的抗痛觉过敏作用。

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