Sex Differences in Tolerance to Delta-9-Tetrahydrocannabinol in Mice With Cisplatin-Evoked Chronic Neuropathic Pain.
Sex Differences in Tolerance to Delta-9-Tetrahydrocannabinol in Mice With Cisplatin-Evoked Chronic Neuropathic Pain.
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DOI：
10.3389/fmolb.2021.684115
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发表时间：
2021
影响因子：
5
通讯作者：
Morgan DJ
中科院分区：
文献类型：
--
作者：
Henderson-Redmond AN;Crawford LC;Sepulveda DE;Hale DE;Lesperance JJ;Morgan DJ
对大麻素止痛作用的耐受性限制了这些药物在慢性疼痛患者中的治疗潜力。最近对啮齿动物的临床前研究和对人类的临床研究表明，男性和女性在对大麻素的耐受性发展方面存在重要差异。我们以前的工作发现，表达1型大麻素受体（CB 1 R）的脱敏抗性形式（S426 A/S430 A）的雄性小鼠对δ-9-四氢大麻酚（δ-9-THC）的抗伤害作用表现出延迟的耐受性和增加的敏感性。在啮齿类动物模型中报告了耐受性的性别差异，雌性动物比雄性动物更快地获得对1，2，9-四氢大麻酚的耐受性。然而，目前尚不清楚S426 A/S430 A突变是否改变了化疗诱发的慢性神经性疼痛小鼠对THC的镇痛耐受性，以及这种耐受性是否在男性和女性之间存在差异。使用4次每周一次的5 mg/kg顺铂注射使雄性和雌性S426 A/S430 A突变体和野生型同窝出生的小鼠神经病变，随后评估对6和/或10 mg/kg NH 9-THC的抗异常性疼痛作用的耐受性。雌性获得耐受性的抗异常性疼痛的效果，6和10毫克/公斤的109-四氢大麻酚比男性更快。相反，S426 A/S430 A突变并没有改变雄性或雌性小鼠对THC的耐受性。CB 1 R拮抗剂利莫那班预处理后阻断了β 9-THC的抗异常性疼痛作用，CB 2 R反向激动剂SR 144528预处理后部分阻断了β 9-THC的抗异常性疼痛作用。我们的研究结果表明，在神经病慢性疼痛模型中，GRK/β-抑制蛋白-2脱敏途径的破坏不影响对β-THC的敏感性和/或耐受性。
Tolerance to the pain-relieving effects of cannabinoids limits the therapeutic potential of these drugs in patients with chronic pain. Recent preclinical research with rodents and clinical studies in humans has suggested important differences between males and females in the development of tolerance to cannabinoids. Our previous work found that male mice expressing a desensitization resistant form (S426A/S430A) of the type 1 cannabinoid receptor (CB1R) show delayed tolerance and increased sensitivity to the antinociceptive effects of delta-9-tetrahydrocannabinol (∆9-THC). Sex differences in tolerance have been reported in rodent models with females acquiring tolerance to ∆9-THC faster than males. However, it remains unknown whether the S426A/S430A mutation alters analgesic tolerance to ∆9-THC in mice with chemotherapy-evoked chronic neuropathic pain, and also whether this tolerance might be different between males and females. Male and female S426A/S430A mutant and wild-type littermates were made neuropathic using four once-weekly injections of 5 mg/kg cisplatin and subsequently assessed for tolerance to the anti-allodynic effects of 6 and/or 10 mg/kg ∆9-THC. Females acquired tolerance to the anti-allodynic effects of both 6 and 10 mg/kg ∆9-THC faster than males. In contrast, the S426A/S430A mutation did not alter tolerance to ∆9-THC in either male or female mice. The anti-allodynic effects of ∆9-THC were blocked following pretreatment with the CB1R antagonist, rimonabant, and partially blocked following pretreatment with the CB2R inverse agonist, SR144528. Our results show that disruption of the GRK/β-arrestin-2 pathway of desensitization did not affect sensitivity and/or tolerance to ∆9-THC in a chronic pain model of neuropathy.
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影响因子：
3.3
作者：
Guindon J;Deng L;Fan B;Wager-Miller J;Hohmann AG
通讯作者：
Hohmann AG
影响因子：
7.4
作者：
ARNER, S;MEYERSON, BA
通讯作者：
MEYERSON, BA
影响因子：
45.3
作者：
GREGG, RW;MOLEPO, JM;STEWART, DJ
通讯作者：
STEWART, DJ
影响因子：
3.3
作者：
Deng L;Guindon J;Vemuri VK;Thakur GA;White FA;Makriyannis A;Hohmann AG
通讯作者：
Hohmann AG
影响因子：
5.3
作者：
Authier, N;Gillet, JP;Coudore, F
通讯作者：
Coudore, F