Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada.
Osteoarthritis Cartilage. 2010 Nov;18(11):1536-43. doi: 10.1016/j.joca.2010.09.005. Epub 2010 Sep 21.
The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA).
OA was induced in male Wistar rats by intra-articular injection of sodium monoiodo-acetate with a recovery period of 14 days. Immunohistochemistry was used to evaluate the expression of CB(2) and transient receptor potential vanilloid channel-1 (TRPV1) receptors in the dorsal root ganglion (DRG) and synovial membrane of sham- and sodium mono-iodoacetate (MIA)-treated animals. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint both before and following close intra-arterial injection of different doses of GW405833. The effect of intra-articular GW405833 on joint pain perception was determined by hindlimb incapacitance. An in vitro neuronal release assay was used to see if GW405833 caused release of an inflammatory neuropeptide (calcitonin gene-related peptide - CGRP).
CB(2) and TRPV1 receptors were co-localized in DRG neurons and synoviocytes in both sham- and MIA-treated animals. Local application of the GW405833 significantly reduced joint afferent firing rate by up to 31% in control knees. In OA knee joints, however, GW405833 had a pronounced sensitising effect on joint mechanoreceptors. Co-administration of GW405833 with the CB(2) receptor antagonist AM630 or pre-administration of the TRPV1 ion channel antagonist SB366791 attenuated the sensitising effect of GW405833. In the pain studies, intra-articular injection of GW405833 into OA knees augmented hindlimb incapacitance, but had no effect on pain behaviour in saline-injected control joints. GW405833 evoked increased CGRP release via a TRPV1 channel-dependent mechanism.
These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.
本研究旨在探讨局部给予大麻素-2（CB（2））受体激动剂 GW405833 是否可以调节正常大鼠膝关节的关节痛觉和骨关节炎（OA）动物模型中的关节痛觉。
通过关节内注射单碘乙酸钠在雄性 Wistar 大鼠中诱导 OA，并在 14 天的恢复期后进行评估。免疫组织化学用于评估 Sham 和单碘乙酸钠（MIA）处理动物的背根神经节（DRG）和滑膜中 CB（2）和瞬时受体电位香草醛通道-1（TRPV1）受体的表达。在膝关节初级传入神经对关节旋转的反应进行电生理记录，然后在膝关节内注射不同剂量的 GW405833 前后进行记录。通过后肢失能来确定关节内 GW405833 对关节疼痛感知的影响。使用体外神经元释放测定法来确定 GW405833 是否引起炎症神经肽（降钙素基因相关肽 - CGRP）的释放。
在 Sham 和 MIA 处理的动物中，DRG 神经元和滑膜细胞中均存在 CB（2）和 TRPV1 受体的共定位。GW405833 的局部应用可使正常膝关节的关节传入神经放电率降低高达 31％。然而，在 OA 膝关节中，GW405833 对关节机械感受器具有明显的致敏作用。GW405833 与 CB（2）受体拮抗剂 AM630 联合给药或 TRPV1 离子通道拮抗剂 SB366791 预先给药可减弱 GW405833 的致敏作用。在疼痛研究中，将 GW405833 关节内注射到 OA 膝关节中会增加后肢失能，但对盐水注射的对照关节中的疼痛行为没有影响。GW405833 通过 TRPV1 通道依赖性机制引起 CGRP 释放增加。
这些数据表明，GW405833 降低了正常关节传入神经纤维的机械敏感性，但在 OA 关节中引起伤害性反应。观察到的 GW405833 的促伤害作用似乎涉及 TRPV1 受体。
