Division of Pain Medicine, Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Centre National de la Recherche Scientifique, Ilkirch, Strasbourg, France.
Reg Anesth Pain Med. 2020 Nov;45(11):907-916. doi: 10.1136/rapm-2020-101779. Epub 2020 Sep 14.
The role of peripheral mu-opioid receptors (MOPs) in chronic pain conditions is not well understood. Here, we used a combination of mouse genetics, behavioral assays, and pharmacologic interventions to investigate the contribution of primary afferent MOPs to nociceptive, inflammatory, and neuropathic pain, as well as to opioid analgesia.
We generated conditional knockout mice in which MOPs were selectively deleted in primary sensory neurons. Inflammatory and neuropathic pain states were induced in mutant and control wild-type mice and their behavioral responses to noxious stimuli were compared. Gross motor function was also evaluated. Immunohistochemistry was used to assess MOP expression in the dorsal root ganglia, periaqueductal gray, and small intestine. The effects of MOP agonists DALDA (dermorphin [D-Arg2, Lys4] (1-4) amide) and morphine were evaluated in pain behavior assays, and their effects on neuronal physiology in the dorsal root ganglia were evaluated in whole-cell patch-clamp recordings.
Conditional MOP knockouts and control mice exhibited similar behavioral responses to acute nociceptive stimuli and developed similar inflammation-induced hypersensitivity. Unilateral nerve injury in animals lacking peripheral MOPs induced enhanced, bilateral mechanical allodynia. Subcutaneously administered DALDA was unable to decrease the hypersensitivity induced by inflammation and nerve injury in MOP knockout animals, and morphine's antinociceptive effects were significantly attenuated in the absence of peripheral MOPs.
MOPs in primary sensory neurons contribute to the modulation of neuropathic pain behavior and opioid analgesia. Our observations highlight the clinical potential of peripherally acting opioid agonists in the management of inflammatory and neuropathic pain.
外周μ-阿片受体（MOPs）在慢性疼痛状态中的作用尚未完全阐明。在此，我们采用小鼠遗传学、行为学检测和药理学干预相结合的方法，研究初级传入感觉神经元中的 MOP 对伤害性感受、炎症和神经病理性疼痛以及阿片类镇痛的作用。
我们构建了条件性敲除小鼠，其中 MOP 可在初级感觉神经元中被选择性敲除。在突变型和对照野生型小鼠中诱导炎症和神经病理性疼痛状态，并比较它们对有害刺激的行为反应。同时还评估了总体运动功能。采用免疫组织化学方法检测背根神经节、导水管周围灰质和小肠中 MOP 的表达。在疼痛行为检测中评估 MOP 激动剂 DALDA（强啡肽[D-Arg2，Lys4]（1-4）酰胺）和吗啡的作用，并在全细胞膜片钳记录中评估其对背根神经节神经元生理学的影响。
条件性 MOP 敲除小鼠和对照小鼠对急性伤害性刺激的行为反应相似，且对炎症诱导的超敏反应的发展也相似。在缺乏外周 MOP 的动物中，单侧神经损伤会引起增强的双侧机械性痛觉过敏。皮下给予 DALDA 不能减轻炎症和神经损伤引起的 MOP 敲除动物的过敏反应，而吗啡的镇痛作用在缺乏外周 MOP 时明显减弱。
初级感觉神经元中的 MOP 参与调节神经病理性疼痛行为和阿片类镇痛。我们的观察结果突出了外周作用阿片类激动剂在治疗炎症和神经病理性疼痛方面的临床潜力。
