Dogrul Bekir Nihat, Machado Kopruszinski Caroline, Dolatyari Eslami Mahdi, Watanabe Moe, Luo Shizhen, Moreira de Souza Luiz Henrique, Vizin Robson Lilo, Yue Xu, Palmiter Richard D, Navratilova Edita, Porreca Frank
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States.
Department of Biochemistry, University of Washington, Seattle, WA, United States.
Pain. 2025 Jan 1;166(1):153-159. doi: 10.1097/j.pain.0000000000003360. Epub 2024 Jul 26.
Pharmacological ablation of rostral ventromedial medulla (RVM) mu opioid receptor-expressing cells before peripheral nerve injury prevents the development of neuropathic pain. However, whether these neurons are required for the expression of established neuropathic pain is not known. Male Oprm1Cre heterozygous (MOR Cre ) or wild-type (MOR WT ) mice received AAV8-hSyn-DIO-hM4D(Gi)-mCherry in the RVM. After partial sciatic nerve ligation (PSNL), we evaluated pain behaviors and descending control of nociception in response to acute or sustained chemogenetic inhibition of RVM-MOR cells expressing hM4D(Gi). A single systemic administration of hM4D(Gi) agonist clozapine-N-oxide (CNO) reversibly inhibited hind paw tactile allodynia and produced conditioned place preference only in MOR Cre mice with PSNL. Intrathecal CNO also reversibly inhibited PSNL-induced hind paw allodynia, suggesting that the spinal projections from these RVM-MOR cells are critical for manifestation of pain behaviors. Consistent with enhanced descending facilitation from RVM-MOR cells, MOR Cre -hM4D(Gi) mice with PSNL showed diminished descending control of nociception that was restored by systemic CNO. Sustained CNO in drinking water before PSNL prevented expression of chronic pain without affecting acute surgical pain; however, relief of chronic pain required sustained CNO treatment. Thus, in male mice, activity of spinally projecting RVM-MOR cells is required (1) for expression and manifestation of both sensory and affective dimensions of established neuropathic pain and (2) to promote descending facilitation that overcomes apparently intact descending inhibition to maintain chronic pain. Enhanced descending facilitation likely regulates the output signal from the spinal cord to the brain to shape the pain experience and may provide a mechanism for nonopioid management of pain.
在周围神经损伤前对延髓头端腹内侧区（RVM）表达μ阿片受体的细胞进行药物消融可预防神经性疼痛的发生。然而，对于已确立的神经性疼痛的表达而言，这些神经元是否是必需的尚不清楚。雄性Oprm1Cre杂合子（MOR Cre）或野生型（MOR WT）小鼠在RVM中接受了AAV8-hSyn-DIO-hM4D(Gi)-mCherry。在坐骨神经部分结扎（PSNL）后，我们评估了疼痛行为以及对表达hM4D(Gi)的RVM-MOR细胞进行急性或持续性化学遗传抑制后伤害性感受的下行控制。单次全身给予hM4D(Gi)激动剂氯氮平N-氧化物（CNO）可可逆地抑制后爪触觉异常性疼痛，并且仅在PSNL后的MOR Cre小鼠中产生条件性位置偏爱。鞘内注射CNO也可可逆地抑制PSNL诱导的后爪异常性疼痛，这表明来自这些RVM-MOR细胞的脊髓投射对于疼痛行为的表现至关重要。与RVM-MOR细胞增强的下行易化作用一致，PSNL后的MOR Cre -hM4D(Gi)小鼠显示出伤害性感受的下行控制减弱，而全身给予CNO可使其恢复。在PSNL前持续在饮用水中添加CNO可预防慢性疼痛的表达，而不影响急性手术疼痛；然而，慢性疼痛的缓解需要持续的CNO治疗。因此，在雄性小鼠中，脊髓投射的RVM-MOR细胞的活动对于（1）已确立的神经性疼痛的感觉和情感维度的表达和表现以及（2）促进下行易化作用是必需的，该下行易化作用可克服明显完整的下行抑制以维持慢性疼痛。增强的下行易化作用可能调节从脊髓到大脑的输出信号以塑造疼痛体验，并可能为非阿片类药物治疗疼痛提供一种机制。
