Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.
Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.
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DOI：
10.1124/jpet.123.001855
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发表时间：
2024-01-17
期刊：
影响因子：
--
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中科院分区：
文献类型：
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炎性疼痛是由组织过敏引起的，是风湿病的一个组成部分，经常导致慢性疼痛。目前的指南使用多模式方法来治疗疼痛，社会文化变化重新引起了人们对大麻类药物，特别是大麻二醇(CBD)治疗疼痛的兴趣。三环类抗抑郁药阿米替林(AT)被批准单独和在多模式方法中用于疼痛相关综合征。因此，我们在2.5%福尔马林炎性痛模型中研究了CBD和AT的性别和剂量依赖性的抗伤害效应。雄性和雌性C57BL/6J小鼠在福尔马林试验前分别给予溶剂、CBD(0.3-100 mg/kg)或AT(0.1-30 mg/kg)。急性期给药30~100 mg/kg，雌雄各100 mg/kg；炎症期，雄鼠2.5~100 mg/kg，雌鼠10~100 mg/kg。在急性期，AT对所有小鼠均有抗伤害作用；在炎症期，AT对雄性小鼠和雌性小鼠分别为0.3 mg/kg和3 mg/kg。结合计算的CBD和AT的半数有效剂量，对所有急性期的小鼠和只处于炎症阶段的雄性小鼠产生了相加效应。应用选择性5-羟色胺1A受体拮抗剂N-[2-[4-(2-甲氧基苯基)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide(WAY-100635)]，在联合应用CBD和AT之前，可逆转炎症阶段急性和部分逆转的抗伤害感受。给予AT仅能增强雌性小鼠大麻素受体1mRNA的表达。这些结果表明，5-羟色胺和性别在介导大麻二酚和阿米替林在炎性疼痛中诱导的抗伤害性感觉中起作用。炎性疼痛是急性疼痛和慢性疼痛的重要组成部分。我们发现，大麻二酚(CBD)和阿米替林(AT)具有剂量依赖性，而且在炎症性疼痛模型中，AT还表现出性别依赖性的抗伤害性效应。此外，CBD和AT的结合被发现增强了部分依赖于5-羟色胺1A受体的抗伤害效应，并支持在多模式疼痛治疗中使用CBD。
Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3–100 mg/kg), or AT (0.1–30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30–100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5–100 mg/kg in males and 10–100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.
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影响因子：
7.3
作者：
De Petrocellis, Luciano;Ligresti, Alessia;Di Marzo, Vincenzo
通讯作者：
Di Marzo, Vincenzo
影响因子：
5
作者：
Henderson-Redmond AN;Crawford LC;Sepulveda DE;Hale DE;Lesperance JJ;Morgan DJ
通讯作者：
Morgan DJ
DOI：
10.3390/ani10091505
发表时间：
2020-08-26
期刊：
Animals : an open access journal from MDPI
影响因子：
--
作者：
Brioschi FA;Di Cesare F;Gioeni D;Rabbogliatti V;Ferrari F;D'Urso ES;Amari M;Ravasio G
通讯作者：
Ravasio G
影响因子：
8.3
作者：
Crocq MA
通讯作者：
Crocq MA
影响因子：
11.4
作者：
Bebee, Bronwyn;Taylor, David M.;Wong, Anselm
通讯作者：
Wong, Anselm