Inyang Kufreobong E, George Susan R, Laumet Geoffroy
Department of Physiology, Michigan State University, East Lansing, MI, USA.
Department of Medicine and Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Brain Res. 2021 Apr 1;1756:147298. doi: 10.1016/j.brainres.2021.147298. Epub 2021 Jan 29.
The episodic nature of chronic pain can be studied in the rodent model of latent pain sensitization. After remission, central sensitization is opposed by activation of opioid receptors. At the behavioral level, latent pain sensitization is unmasked when pain hypersensitivity is reinstated by opioid receptor (OR) antagonism. Previous studies have focused on inflammatory pain and male rodents. Whether latent pain sensitization occurs in models of chemotherapy-induced neuropathic pain in female and male mice is unknown. The first aim of this study was to investigate whether μ- and δ-OR suppress latent pain sensitization in our model of chemotherapy-induced neuropathic pain in both sexes. Mounting evidence suggests that μ-and δ-ORs form a heteromer and that the heteromer modulates pain sensitivity. Potential implications of the μ-δ OR heteromer in latent pain sensitization have not been fully explored due to a lack of tools to effectively modulate the heteromer. To specifically target the μ-δ OR heteromer, we used a specific interfering peptide blocking the heteromerization. The second aim of this study was to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity. After remission from cisplatin-induced neuropathic pain, antagonism of µ-OR and δOR reinstates pain hypersensitivity in both sexes. After remission from cisplatin-induced neuropathic pain and postoperative pain, disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain.
慢性疼痛的发作性本质可以在潜伏性疼痛致敏的啮齿动物模型中进行研究。缓解后，阿片受体的激活会对抗中枢敏化。在行为水平上，当通过阿片受体（OR）拮抗作用恢复疼痛超敏反应时，潜伏性疼痛致敏就会显现出来。以往的研究主要集中在炎症性疼痛和雄性啮齿动物上。在雌性和雄性小鼠的化疗诱导性神经病理性疼痛模型中是否会发生潜伏性疼痛致敏尚不清楚。本研究的首要目的是调查μ-和δ-阿片受体是否会抑制我们的两性化疗诱导性神经病理性疼痛模型中的潜伏性疼痛致敏。越来越多的证据表明，μ-和δ-阿片受体形成异聚体，并且该异聚体会调节疼痛敏感性。由于缺乏有效调节该异聚体的工具，μ-δ阿片受体异聚体在潜伏性疼痛致敏中的潜在影响尚未得到充分探索。为了特异性靶向μ-δ阿片受体异聚体，我们使用了一种特异性干扰肽来阻断异聚化。本研究的第二个目的是调查在缓解后，μ-δ阿片受体异聚体的破坏是否会恢复疼痛超敏反应。在顺铂诱导的神经病理性疼痛缓解后，μ-阿片受体和δ-阿片受体的拮抗作用会在两性中恢复疼痛超敏反应。在顺铂诱导的神经病理性疼痛和术后疼痛缓解后，μ-δ阿片受体异聚体的破坏会在两性中恢复疼痛超敏反应。综合我们的研究结果表明，μ-δ阿片受体异聚体在各种疼痛模型的缓解中起关键作用，可能代表一个预防疼痛复发和向慢性疼痛转变的新治疗靶点。
