Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, 14040-904, Brazil; Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, 14049-900, Brazil.
Department of Neuroscience, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, 14049-900, Brazil.
Neuropharmacology. 2020 Feb;163:107808. doi: 10.1016/j.neuropharm.2019.107808. Epub 2019 Nov 7.
Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.
能提高痛阈的药物在帕金森病（PD）的药物治疗中可能有用。疼痛是 PD 的一种常见非运动症状，患者开具的镇痛药处方比例更高。然而，针对 PD 相关疼痛的特定治疗方法并不存在。由于内源性大麻素系统在不同水平的疼痛通路中广泛表达，因此针对该系统的药物在调节疼痛方面具有很大的治疗潜力。因此，我们研究了 6-羟多巴胺诱导的 PD 对小鼠伤害性反应的影响，以及大麻二酚（CBD）对 6-羟多巴胺诱导的伤害性感受的影响。此外，我们通过联合使用脂肪酸酰胺水解酶（FAAH）抑制剂来研究 CBD 的镇痛作用所涉及的途径，从而增加内源性大麻素的水平，以及可能的大麻素受体亚型 1 和 2（CB1 和 CB2）和香草素瞬时受体 1（TRPV1）等靶点。我们报告，6-羟多巴胺诱导的帕金森病降低了热和机械性伤害感受阈值，而 CBD（急性和慢性治疗）减轻了 6-羟多巴胺引起的这种痛觉过敏和痛觉过敏。此外，无效剂量的 FAAH 抑制剂或 TRPV1 受体拮抗剂增强了 CBD 引起的镇痛作用，而 CB1 和 CB2 受体的反向激动剂则阻止了 CBD 的镇痛作用。总之，这些结果表明，CBD 可能是一种有用的药物，可以预防帕金森病引起的伤害感受阈值降低。它们还表明，CB1 和 TRPV1 受体对 CBD 诱导的镇痛作用很重要，并且 CBD 可能通过增加内源性大麻素水平来产生这些镇痛作用。
