Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA; Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA; Alcohol and Drug Abuse Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA; Southeast Louisiana VA Healthcare System (SLVHCS), New Orleans, LA, 70119, USA.
Neuropharmacology. 2022 Jun 1;210:109032. doi: 10.1016/j.neuropharm.2022.109032. Epub 2022 Mar 16.
Chronic inflammatory pain represents one of the largest subsets of chronic pain diagnoses, which affect nearly a quarter of individuals in the United States and cost nearly $600 billion dollars annually. Chronic pain leads to persistent sensory hypersensitivities, as well as emotional and cognitive disturbances. Evidence suggests that melanocortin 4 receptors (MC4Rs) mediate pain-signaling and pain-like behaviors via actions at various nodes in the pain-neural axis, but the field lacks a complete understanding of the potential role of MC4Rs in chronic inflammatory pain in males and females. The central amygdala (CeA) expresses high quantities of MC4R and receives pain-related information from the periphery, and in vivo CeA manipulations alter nociceptive behavior in pain-naïve and in animals with chronic pain. Here, we tested the hypothesis that MC4Rs in the CeA modulate thermal nociception and mechanical sensitivity, as well as pain avoidance, in male and female Wistar rats, using a model of chronic inflammatory pain (Complete Freud's Adjuvant; CFA). First, we report that CFA produces long-lasting hyperalgesia in adult male and female Wistar rats, and long-lasting pain avoidance in male Wistar rats. Second, we report that MC4R antagonism in the CeA reduces thermal nociception and mechanical sensitivity in male and female Wistar rats treated with CFA. Finally, we report that MC4R antagonism in the CeA reduces pain avoidance in male, and that this effect is not due to drug effects on locomotor activity. Our results indicate that a model of chronic inflammatory pain produces long-lasting increases in pain-like behaviors in adult male and female Wistar rats, and that antagonism of MC4Rs in the CeA reverses those effects.
慢性炎症性疼痛是慢性疼痛诊断中最大的亚类之一，影响了美国近四分之一的人群，每年耗费近 6000 亿美元。慢性疼痛会导致持续的感觉过敏，以及情绪和认知障碍。有证据表明，黑素皮质素 4 受体（MC4Rs）通过在疼痛神经轴的各个节点上的作用来介导疼痛信号和类似疼痛的行为，但该领域缺乏对 MC4Rs 在男性和女性慢性炎症性疼痛中的潜在作用的全面理解。中央杏仁核（CeA）表达大量的 MC4R，并从外周接收与疼痛相关的信息，体内 CeA 操作会改变疼痛敏感和慢性疼痛动物的伤害性行为。在这里，我们使用慢性炎症性疼痛模型（完全弗氏佐剂；CFA）测试了以下假设，即 CeA 中的 MC4Rs 调节雄性和雌性 Wistar 大鼠的热痛觉和机械敏感性，以及疼痛回避。首先，我们报告 CFA 会在成年雄性和雌性 Wistar 大鼠中产生持久的痛觉过敏，并在雄性 Wistar 大鼠中产生持久的疼痛回避。其次，我们报告 MC4R 在 CeA 中的拮抗作用可降低 CFA 治疗的雄性和雌性 Wistar 大鼠的热痛觉和机械敏感性。最后，我们报告 MC4R 在 CeA 中的拮抗作用可减少雄性大鼠的疼痛回避，而这种效应不是由于药物对运动活动的影响。我们的研究结果表明，慢性炎症性疼痛模型会导致成年雄性和雌性 Wistar 大鼠产生持久的类似疼痛行为增加，而 CeA 中 MC4Rs 的拮抗作用可逆转这些效应。
