Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Cracow, Poland.
Molecules. 2023 Jul 30;28(15):5766. doi: 10.3390/molecules28155766.
Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients' quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal-glial-immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.
神经病理性疼痛是一种全球性的致残疾病，影响着全球数以百万计的人。大量研究表明，这种类型的疼痛是一种慢性疾病，其机制复杂，且往往随着时间的推移而恶化，导致患者的生活质量显著下降，并出现抑郁、残疾和睡眠障碍等问题。目前使用的镇痛药在治疗神经病变方面效果不够理想，并且由于需要高剂量，可能会引起许多副作用。近年来，许多研究人员指出趋化因子不仅在神经病变的发展和维持中起着重要作用，而且在镇痛药的有效性中也起着重要作用。目前，已知约有 50 种趋化因子通过位于神经元、神经胶质和免疫细胞表面的 20 种不同的七跨膜 G 蛋白偶联受体发挥作用。近年来的数据清楚地表明，比最初认为的更多的趋化因子（CCL1/2/3/5/7/8/9/11、CXCL3/9/10/12/13/14/17；XCL1、CX3CL1）具有致痛作用；因此，通过使用中和抗体阻断其作用、抑制其合成或阻断其受体可以缓解神经病理性疼痛。其中一些趋化因子（CCL1/2/3/7/9/XCL1）已被证明能够降低神经病变中阿片类药物的疗效，针对它们的中和抗体可以恢复吗啡和/或丁丙诺啡的镇痛作用。最新的研究提供了无可置疑的证据，表明趋化因子受体是治疗药物的有希望的靶点；趋化因子受体拮抗剂可以缓解不同病因的疼痛，其中大多数能够增强阿片类药物的镇痛作用，例如，阻断 CCR1（J113863）、CCR2（RS504393）、CCR3（SB328437）、CCR4（C021）、CCR5（马拉维若/阿片类药物 AZD5672/TAK-220）、CXCR2（NVPCXCR220/SB225002）、CXCR3（NBI-74330/AMG487）、CXCR4（AMD3100/AMD3465）和 XCR1（vMIP-II）。最近的研究表明，趋化因子受体的多靶点拮抗剂，如 CCR2/5（cenicriviroc）、CXCR1/2（reparixin）和 CCR2/CCR5/CCR8（RAP-103），也是非常有效的止痛药。基于通过改变趋化因子家族的活性来调节神经元-神经胶质-免疫相互作用的多方向策略，可以显著改善患有神经病理性疼痛的患者的生活质量。然而，趋化因子家族的成员仍然是被低估的治疗疼痛的药理学靶点。本文综述了相关文献，并就趋化因子及其受体在神经病理性疼痛中的作用提供了新的见解。
