Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Abstract

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.

CC Chemokine Family Members’ Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury—A Review of Clinical and Experimental Findings

“…Although, its levels are highest in microglia/macrophages [57,132,[240][241][242][243][244]. CCR2 is preferentially bound by CCL2 [245]; however, several other chemokines, CCL7, CCL8, CCL12, and CCL13 (please see Table 1), can also bind to this receptor [37,239,245,246]. Importantly, CCR2 activation promotes angiogenesis [247] and fracture healing [248] and decreases amyloid plaque formation in Alzheimer's disease models through macrophage-mediated phagocytosis [249,250].…”

“…Further research is needed to determine why this is possible, but it is already known that excessive production of interleukins, such as IL-1β and IL-18, might be key for reducing opioid analgesia in neuropathy [215,216,275]. Several studies have indicated that opioid signaling is connected not only to interleukins but also to chemokines [37,246]. CCR2 is preferentially bound by CCL2 [245], but repeated administration of morphine increases the level of CCL2 in the spinal cord; however, its neutralization by an antibody diminishes the development of morphine tolerance [276].…”

CCL2- and Notch2-mediated Central Sensitization in a Rat Chronic Pelvic Pain Model

“…In a ttw mice model, in vivo depletion of CCL2 in microglia mitigated the severity of chronic spinal compression and related pain (11). In contrast, both INCB3344 and RS504393, specific antagonists of CCR2, improve the CCL-induced nociceptive sensitization (12,13). Altogether, these studies indicate that CCL2/CCR2 signaling pathway plays an important role in the occurrence and/or persistence of pain.…”

Exploring an Intracellular Allosteric Site of CC-Chemokine Receptor 4 from 3D Models, Probe Simulations, and Mutagenesis

“…21 Targeting CCR4 also represents a promising strategy for the treatment of neuropathic pain. 22 Two chemotypes of selective CCR4 NAMs have been identified by random screening that bind to distinct receptor sites. 23 The first chemotype includes basic small lipophilic antagonists (e.g., BMS-397 and Z5367428075), which are predicted to bind to the extracellular side of the receptor, partially overlapping with the orthosteric site.…”

“…It is implicated in cancer pathogenesis and allergic diseases including asthma and dermatitis . Targeting CCR4 also represents a promising strategy for the treatment of neuropathic pain . Two chemotypes of selective CCR4 NAMs have been identified by random screening that bind to distinct receptor sites .…”