Miliano Cristina, Chen Irene, Brown Brieann, Murdaugh Laura B, Dong Yuyang, Eddinger Kelly A, Geng Shuo, Li Liwu, Yaksh Tony L, Burton Michael D, Buczynski Matthew W, Gregus Ann M
School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA, United States.
Department of Anesthesiology, University of California San Diego, La Jolla, CA, United States.
Pain. 2025 Jul 10. doi: 10.1097/j.pain.0000000000003711.
Chronic nociplastic pain syndromes are characterized by sensitization of peripheral and central nervous systems and exhibit increased incidence in women. However, nonsteroidal anti-inflammatory drugs are ineffective in mitigating nociplastic pain, and current prescription treatments, such as opioids, anticonvulsants, and antidepressants, provide limited therapeutic benefit for these indications. In the current work, we extended previous studies in rats of central Toll-like receptor 4-dependent pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) lipopolysaccharide (LPS). In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and a modest increase in locomotor activity in response to IT LPS. Congruent with our previous observations in male rats, LPS released spinal 12/15-lipoxygenase (12/15-LOX) metabolites (12/15-LMs) in female C57BL/6N mice. Likewise, 12/15-LOX enzymes are basally expressed in multiple tissues and cell types relevant to nociceptive transmission. Systemic inhibition of 12/15-LOX in female C57BL/6N mice with selective inhibitors ML355 (targeting 12-LOX-p) or ML351 (targeting 15-LOX-1) completely reversed allodynia and grip force deficits. 12/15-LMs also produce tactile allodynia when administered spinally (IT) or peripherally (paw intraplantar) at a subthreshold dose in a hyperalgesic priming model, similar to others' observations with a subthreshold dose of the cyclooxygenase metabolite prostaglandin E2. Collectively, these data suggest that 12/15-LOX enzymes contribute to peripheral and central pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and functional outcome measures.
慢性伤害性感受性疼痛综合征的特征是外周和中枢神经系统致敏，且在女性中的发病率增加。然而，非甾体抗炎药在减轻伤害性感受性疼痛方面无效，目前的处方治疗，如阿片类药物、抗惊厥药和抗抑郁药，对这些适应症的治疗益处有限。在当前的研究中，我们将先前在大鼠中关于中枢Toll样受体4依赖性疼痛超敏反应的研究扩展到雄性和雌性C57BL/6N小鼠，发现鞘内注射（IT）脂多糖（LPS）后雌性小鼠出现了意外的痛觉过敏表型。与先前关于雌性C57BL/6J小鼠的报道相反，雌性C57BL/6N小鼠表现出触觉和冷觉异常性疼痛、握力缺陷，以及对IT LPS的运动活动适度增加。与我们先前在雄性大鼠中的观察结果一致，LPS在雌性C57BL/6N小鼠中释放脊髓12/15-脂氧合酶（12/15-LOX）代谢产物（12/15-LMs）。同样，12/15-LOX酶在与伤害性感受传递相关的多种组织和细胞类型中基础表达。用选择性抑制剂ML355（靶向12-LOX-p）或ML351（靶向15-LOX-1）对雌性C57BL/6N小鼠进行12/15-LOX的全身抑制，完全逆转了异常性疼痛和握力缺陷。在痛觉过敏引发模型中，以阈下剂量脊髓内（IT）或外周（足底内注射）给予12/15-LMs时，也会产生触觉异常性疼痛，这与其他人用阈下剂量的环氧化酶代谢产物前列腺素E2的观察结果相似。总体而言，这些数据表明12/15-LOX酶促成了啮齿动物外周和中枢的疼痛超敏反应，通过多种反射性和功能性结果测量，有可能作为跨性别和物种的可成药靶点进行转化。
