Sex differences in antinociceptive response to-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test
Sex differences in antinociceptive response to-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test
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DOI：
10.1097/wnr.0000000000000993
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发表时间：
2018-04-11
期刊：
影响因子：
1.7
通讯作者：
Henderson-Redmond, Angela N.
中科院分区：
文献类型：
--
作者：
LaFleur, Rebecca A.;Wilson, Ronald P.;Henderson-Redmond, Angela N.
大麻素已显示出治疗顽固性疼痛状态的前景，并可能代表疼痛管理的替代药物疗法。越来越多的临床证据表明性在疼痛感知和大麻素反应中的作用。我们研究了表达大麻素1型受体（CB 1 R）的脱敏抗性形式（S426 A/S430 A）的雄性和雌性小鼠对大麻素的敏感性和耐受性。在福尔马林试验中，在用载体或混合的CB 1 R/CB 2 R激动剂、-9-四氢大麻酚（（9）-THC）（1- 6 mg/kg）或CP 55，940（0.06-0.2mg/kg）预处理后，评估小鼠的急性和炎性伤害感受行为。通过福尔马林试验，在长期每日给药后，检查了对6 mg/kg（9）-THC或0.1mg/kg CP 55，940作用的耐受性。与雄性小鼠相比，雌性小鼠对（9）-THC和CP 55，940的敏感性降低。S426 A/S430 A突变增加了两种激动剂在两种性别中的伤害性行为的衰减。与雄性小鼠相比，雌性小鼠对（9）-THC的耐受性延迟，而S426 A/S430 A突变在两种性别中均赋予对（9）-THC的耐受性延迟。与野生型对照相比，雄性S426 A/S430 A突变小鼠也显示出对CP 55，940耐受性的抗性。这项研究表明，两种不同的大麻素激动剂的反应的性别和基因型差异。结果强调了在疼痛和大麻素药理学的临床前研究中包括雄性和雌性小鼠的重要性。
Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management. A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response. We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R). Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, -9-tetrahydrocannabinol ((9)-THC) (1-6mg/kg) or CP 55,940 (0.06-0.2mg/kg). Tolerance to the effects of 6mg/kg (9)-THC or 0.1mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing. Female mice showed decreased sensitivity to the effects of (9)-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to (9)-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to (9)-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls. This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology.