Cannabinoid CB2 receptors regulate central sensitization and pain responses associated with osteoarthritis of the knee joint.
Cannabinoid CB2 receptors regulate central sensitization and pain responses associated with osteoarthritis of the knee joint.
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DOI：
10.1371/journal.pone.0080440
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chapman V
中科院分区：
文献类型：
--
作者：
Burston JJ;Sagar DR;Shao P;Bai M;King E;Brailsford L;Turner JM;Hathway GJ;Bennett AJ;Walsh DA;Kendall DA;Lichtman A;Chapman V
关节骨关节炎（OA）是一种常见的疾病，伴有慢性、使人衰弱的疼痛。最近的临床证据表明，中枢致敏有助于OA疼痛。更好地了解OA关节病理学如何影响疼痛的中枢处理，对于确定新的镇痛靶点/新的治疗策略至关重要。抑制性大麻素2（CB2）受体减弱外周免疫细胞功能并调节神经变性模型中的中枢神经免疫应答。CB2受体激动剂JWH133的全身给药减弱了OA诱导的疼痛行为，以及在该模型中表现出的循环促炎和抗炎细胞因子的变化。电生理学研究表明，脊髓给药JWH133抑制OA疼痛模型中脊髓神经元的伤害性诱发反应，但在对照大鼠中没有，表明该靶点在脊髓中的新作用。我们进一步证明了在OA疼痛模型中脊髓CB2受体mRNA和蛋白表达的动态变化。在OA模型中，脊髓中神经元和小胶质细胞的CB 2受体蛋白表达显著增加。在OA疼痛模型中，中枢致敏、显著的脊髓星形胶质细胞增生和脊髓中金属蛋白酶MMP-2和MMP-9的活性增加的标志是明显的。全身施用JWH133减弱了这些中枢致敏的标志物，为CB 2受体在该OA疼痛模型中的镇痛作用提供了神经生物学基础。对人脊髓的分析显示脊髓CB2受体mRNA与肉眼可见的膝关节软骨病呈负相关。这些数据提供了新的临床相关证据，即关节损伤和脊髓CB2受体表达相关，并结合了临床前证据，即CB2受体的激活抑制中枢致敏及其对慢性OA疼痛表现的贡献。这些发现表明，靶向CB2受体可能具有治疗OA疼痛的治疗潜力。
Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies. Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy. These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.
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影响因子：
82.9
作者：
Kawasaki, Yasuhiko;Xu, Zhen-Zhong;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong
影响因子：
3.5
作者：
Huffman, JW;Liddle, J;Martin, BR
通讯作者：
Martin, BR
影响因子：
1.2
作者：
Kobayashi, K;Imaizumi, R;Komatsu, H
通讯作者：
Komatsu, H
影响因子：
7.4
作者：
Bajaj, P;Bajaj, P;Arendt-Nielsen, L
通讯作者：
Arendt-Nielsen, L
DOI：
10.1016/s0925-4439(98)00042-8
发表时间：
1998-09-30
影响因子：
6.2
作者：
Berrendero, F;Romero, J;Fernández-Ruiz, JJ
通讯作者：
Fernández-Ruiz, JJ