吸入大麻通过分离中缝核来抑制化疗诱导的神经病理性痛觉：在大鼠中的功能成像研究。

Inhaled Cannabis Suppresses Chemotherapy-Induced Neuropathic Nociception by Decoupling the Raphe Nucleus: A Functional Imaging Study in Rats.

机构信息

Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts.

Psychological and Brain Sciences, Program in Neuroscience, and Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana.

出版信息

Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Apr;6(4):479-489. doi: 10.1016/j.bpsc.2020.11.015. Epub 2020 Dec 13.

DOI:10.1016/j.bpsc.2020.11.015

PMID:33622657

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8351528/

Abstract

BACKGROUND

Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei.

METHODS

We assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level-dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas.

RESULTS

Prior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization.

CONCLUSIONS

Inhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.

摘要

背景

吸入大麻治疗疼痛的疗效存在争议。有效的化疗引起的周围神经病变的治疗方法尚未满足医疗需求。我们假设大麻通过降低中缝核的功能耦合来减轻神经性疼痛。

方法

我们评估了吸入雾化大麻植物（含 10.3% Δ-四氢大麻酚/0.05%大麻二酚）或安慰剂大麻对紫杉醇诱导的大鼠疼痛行为和脑静息状态血氧水平依赖功能连接的影响。大鼠接受紫杉醇以产生化疗引起的周围神经病变或其载体。在神经病变建立且稳定后进行行为和成像实验。图像通过 3D 磁共振成像大鼠图谱进行配准和分析，该图谱提供了超过 168 个不同脑区的特定部位数据。

结果

在雾化之前，紫杉醇会引起冷感觉过敏。与雾化前或安慰剂大麻相比，吸入雾化大麻增加了冷退缩潜伏期，这与 Δ-四氢大麻酚的镇痛作用一致。在紫杉醇治疗的大鼠中，中脑 5-羟色胺能系统（包括背侧和中缝核）与皮质、脑干和海马区显示出超连接性，这与伤害性处理一致。吸入雾化大麻使紫杉醇诱导的超连接模式脱耦。在吸入安慰剂大麻后，没有观察到连接性或冷反应性的这种变化。