Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared with wild-type mice, Comt +/− mice undergoing repeated swim stress and molar extraction surgery intervention exhibited pronounced multisite body pain and depressive-like behavior lasting >3 months. Comt +/− mice undergoing the intervention also exhibited enhanced activity of primary afferent nociceptors innervating hindpaw and low back sites and increased plasma concentrations of norepinephrine and pro-inflammatory cytokines interleukin-6 (IL-6) and IL-17A. The pain and depressive-like behavior were of greater magnitude and longer duration (≥12 months) in females versus males. Furthermore, increases in anxiety-like behavior and IL-6 were female-specific. The effect of COMT genotype × stress interactions on pain, IL-6, and IL-17A was validated in a cohort of 549 patients with CPPCs, demonstrating clinical relevance. Last, we assessed the predictive validity of the model for analgesic screening and found that it successfully predicted the lack of efficacy of minocycline and the CB2 agonist GW842166X, which were effective in spared nerve injury and complete Freund’s adjuvant models, respectively, but failed in clinical trials. Yet, pain in the CPPC model was alleviated by the beta-3 adrenergic antagonist SR59230A. Thus, the CPPC mouse model reliably recapitulates clinically and biologically relevant features of CPPCs and may be implemented to test underlying mechanisms and find new therapeutics.

中文翻译：

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慢性原发性疼痛的小鼠模型，整合了临床相关的遗传脆弱性、压力和轻微损伤

慢性原发性疼痛 (CPPC) 影响着超过 1 亿美国人，其中主要是女性。它们仍然没有得到有效的治疗，很大程度上是因为缺乏具有转化相关性的有效动物模型。在这里，我们描述了一个 CPPC 小鼠模型，该模型整合了临床相关遗传（儿茶酚-O-甲基转移酶；COMT 敲低）和环境（应激和损伤）因素。与野生型小鼠相比，康特 +/-接受反复游泳应激和拔牙手术干预的小鼠表现出明显的多部位身体疼痛和抑郁样行为，持续>3个月。康特 +/-接受干预的小鼠还表现出支配后爪和腰部部位的初级传入伤害感受器活性增强，以及去甲肾上腺素和促炎细胞因子白细胞介素 6 (IL-6) 和 IL-17A 的血浆浓度增加。与男性相比，女性的疼痛和抑郁样行为更严重，持续时间更长（≥12 个月）。此外，焦虑样行为和 IL-6 的增加是女性特有的。 COMT 基因型 × 应激相互作用对疼痛、IL-6 和 IL-17A 的影响在 549 名 CPPC 患者的队列中得到验证，证明了临床相关性。最后，我们评估了该模型用于镇痛筛查的预测有效性，发现它成功预测了米诺环素和 CB2 激动剂 GW842166X 的疗效缺乏，这两种药物分别在幸存神经损伤和完全弗氏佐剂模型中有效，但在临床中失败试验。然而，β-3 肾上腺素能拮抗剂 SR59230A 可以减轻 CPPC 模型中的疼痛。因此，CPPC 小鼠模型可靠地概括了 CPPC 的临床和生物学相关特征，并可用于测试潜在机制并寻找新的治疗方法。