Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Br J Pharmacol. 2020 Jun;177(12):2712-2725. doi: 10.1111/bph.14997. Epub 2020 Mar 8.
Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.
After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 μg·kg , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 μg·kg daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons.
In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.
Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.
慢性神经性疼痛（NEP）与大麻治疗的应用日益增多有关。为了在不产生精神作用的情况下提高生活质量，除了Δ9-四氢大麻酚外，大麻素如大麻二酚（CBD）及其前体大麻二酚酸（CBDA）也正在被评估。由于其不稳定性，CBDA 的研究较少，特别是作为一种抗伤害性药物。在 CBDA 上添加一个甲酯基团（CBDA-ME）可显著提高其稳定性，从而促进体内分析其镇痛效果。本研究在大鼠外周神经诱导的 NEP 模型中研究了 CBDA-ME 的早期治疗效果，并评估了性别作为生物学变量。
在手术后第 1 天通过植入坐骨神经缩窄环来诱导 NEP 后，连续 14 天每天腹膜内给予 0.01、0.1 和 1μg·kg 的 CBDA-ME，对雄性和雌性 Sprague-Dawley 大鼠进行了这种大麻素的抗伤害性效果评估，与给予载体的对照组进行比较。在雌性中，还评估了每日 2 和 4μg·kg 的 CBDA-ME 剂量。每周进行一次后爪机械和热撤回阈值的行为测试，持续 8 周。在终点，进行体内电生理记录以描述初级感觉神经元体阈值变化。
在雄性中，CBDA-ME 呈现出浓度依赖性的慢性抗痛觉过敏作用，也影响伤害性和非伤害性机械感受器，而在雌性中，在测试的任何浓度下均未观察到这种作用。
在手术后早期开始使用 CBDA-ME 治疗周围神经损伤，可为男性提供镇痛作用，值得进一步研究这种反应背后的潜在性别差异。
