Role of cannabinoid receptor 1 and the peroxisome proliferator-activated receptor α in mediating anti-nociceptive effects of synthetic cannabinoids and a cannabinoid-like compound
Role of cannabinoid receptor 1 and the peroxisome proliferator-activated receptor α in mediating anti-nociceptive effects of synthetic cannabinoids and a cannabinoid-like compound
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DOI：
10.1007/s10787-019-00584-7
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发表时间：
2019-12-01
影响因子：
5.8
通讯作者：
El-Salem, Khalid
中科院分区：
文献类型：
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作者：
Alsalem, Mohammad;Haddad, Mansour;El-Salem, Khalid
骨关节炎(OA)的特征是软骨变性、软骨下硬化和疼痛。在慢性疼痛的动物模型中，大麻类化合物具有公认的抗伤害性特性。本研究的目的是评价人工合成的大麻素(Win-55、212和HU210)和大麻素样化合物棕榈酰乙醇胺(PEA)对大鼠骨性关节炎模型的抗伤害性作用，并探讨大麻素受体1(CB1)和过氧化物酶体增殖物激活受体α(PPARα)在介导这些作用中的作用。采用膝关节内注射碘乙酸单钠(MIA)作为骨性关节炎模型。采用von Frey细丝实验和负重差法观察Win-55、212、HU210和PEA对MIA诱导的大鼠骨性关节炎的抗伤害性作用。采用旷场自主活动系统对化合物的镇痛作用进行验证。HU210、WIN55、212和PEA以剂量依赖的方式恢复MIA所致的缩足阈值(PWT)和负重差异。CB1拮抗剂SR141716A在PWT方面显著逆转所有给药的抗伤害性作用。然而，在负重差异方面，SR141716A显著降低了HU210的抗伤害性作用，而不是PEA或WIN55,212。PPARα拮抗剂GW6471可显著逆转PEA的抗伤害性作用，但不能逆转HU210或WIN55,212的作用。HU210、WIN55、212和PEA可显著恢复MIA所致的运动活动减少。总而言之，CB1和PPARα受体都参与了骨关节炎疼痛的调节。因此，靶向这些受体可能具有重要的临床价值。
Osteoarthritis (OA) is characterized by cartilage degeneration, subchondral sclerosis, and pain. Cannabinoids have well-established anti-nociceptive properties in animal models of chronic pain. The aim of this study is to evaluate the anti-nociceptive effects of synthetic cannabinoids (WIN-55,212 and HU210) and the cannabinoid-like compound palmitoylethanolamide (PEA) in rat models of OA and to assess the role of cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor alpha (PPAR alpha) in mediating these effects. Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint was used as a model of osteoarthritis. The von Frey filament test and weight-bearing difference were used to assess the anti-nociceptive effects of WIN-55,212, HU210, and PEA on MIA-induced OA in rats. Open-field locomotor activity system was used confirm the analgesic effects of those compounds. HU210, WIN55, 212, and PEA in a dose-dependent manner restored the paw withdrawal threshold (PWT) and the weight-bearing difference induced by MIA injection. SR141716A (a CB1 antagonist) significantly reversed the anti-nociceptive effects of all the administered drugs in terms of PWT. However, in terms of weight-bearing difference, SR141716A significantly reduced the anti-nociceptive effect of HU210 but not PEA or WIN55, 212. GW6471 (a PPAR alpha antagonist) significantly reversed the anti-nociceptive effects of PEA but not those of HU210 or WIN55, 212. HU210, WIN55, 212 and PEA significantly restored the MIA-induced reduction in locomotor activity. In conclusions, both CB1 and PPAR alpha receptors are involved in mediating pain in osteoarthritis. Therefore, targeting these receptors may be of great clinical value.