Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions.
Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions.
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炎症性疼痛，例如关节炎疼痛，是一个日益严重的健康问题。炎性疼痛通常使用阿片类药物和环氧合酶 (COX) 抑制剂治疗，但两者均受到副作用的限制。最近，resolvins 是一种新型脂质介质家族，包括衍生自 omega-3 多不饱和脂肪酸的 RvE1 和 RvD1，在治疗与炎症相关的疾病方面显示出显着的功效。在此，我们报告外周（足底内）或脊髓（鞘内）施用 RvE1 或 RvD1（0.3-20 ng）可有效减少足底内注射福尔马林、角叉菜胶或完全弗氏佐剂诱导的小鼠炎症疼痛行为，而不影响基础疼痛感知。鞘内 RvE1 还可以抑制鞘内辣椒素和 TNF-α 引起的自发性疼痛和热以及机械过敏。 RvE1 通过减少中性粒细胞浸润、爪水肿和促炎细胞因子表达发挥抗炎作用。 RvE1 还通过抑制 ERK 信号通路，消除 TRPV1 和 TNF-α 诱导的兴奋性突触后电流增加以及 TNF-α 诱发的脊髓背角神经元 NMDA 受体过度活跃。因此，我们证明了消退素在使脊髓突触可塑性正常化方面的新作用，这与产生疼痛超敏反应有关。鉴于消退素的显着功效以及众所周知的阿片类药物和 COX 抑制剂的副作用，消退素可能代表治疗炎性疼痛的新型镇痛药。
Inflammatory pain, such as arthritis pain, is a growing health problem. Inflammatory pain is generally treated with opioids and cyclooxygenase (COX) inhibitors, but both are limited by side effects. Recently, resolvins, a novel family of lipid mediators including RvE1 and RvD1 derived from omega-3 polyunsaturated fatty acid, show remarkable potency in treating disease conditions associated with inflammation. Here we report that peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 or RvD1 (0.3–20 ng) potently reduces inflammatory pain behaviors in mice induced by intraplantar injection of formalin, carrageenan or complete Freund’s adjuvant, without affecting basal pain perception. Intrathecal RvE1 also inhibits spontaneous pain and heat and mechanical hypersensitivity evoked by intrathecal capsaicin and TNF-α. RvE1 plays anti-inflammatory roles via reducing neutrophil infiltration, paw edema, and proinflammatory cytokine expression. RvE1 also abolishes TRPV1- and TNF-α-induced excitatory postsynaptic current increase and TNF-α-evoked NMDA receptor hyperactivity in spinal dorsal horn neurons, via inhibition of ERK signaling pathway. Thus, we demonstrate a novel role of resolvins in normalizing spinal synaptic plasticity that has been implicated in generating pain hypersensitivity. Given the remarkable potency of resolvins and well known side effects of opioids and COX inhibitors, resolvins may represent novel analgesics for treating inflammatory pain.
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