Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

Abstract

Neuropathic pain pathophysiology is not fully understood, but it was recently shown that MIP-1 family members (CCL3, CCL4, and CCL9) have strong pronociceptive properties. Our goal was to examine how pharmacological modulation of these chemokines and their receptors (CCR1 and CCR5) influence hypersensitivity after nerve injury in Albino Swiss male mice. The spinal changes in the mRNA/protein levels of the abovementioned chemokines and their receptors were measured using RT-qPCR and ELISA/Western blot techniques in a mouse model of chronic constriction injury of the sciatic nerve. Behavioral studies were performed using the von Frey and cold plate tests after pharmacological treatment with neutralizing antibodies (nAbs) against chemokines or antagonists (CCR1-J113863, CCR5-TAK-220/AZD-5672) alone and in coadministration with morphine on Day 7, when the hypersensitivity was fully developed. Our results showed enhanced protein levels of CCL3 and CCL9 1 and 7 days after nerve injury. The single intrathecal administration of CCL3 or CCL9 nAb, J113863, TAK-220, or AZD-5672 diminished neuropathic pain symptoms and enhanced morphine analgesia. These findings highlight the important roles of CCL3 and CCL9 in neuropathic pain and additionally indicate that these chemokines play essential roles in opioid analgesia. The obtained results suggest CCR1 and CCR5 as new, interesting targets in neuropathy treatment.

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

“…Higher levels of this cytokine are also observed in diabetic neuropathy [19], chemotherapy-induced neuropathic pain [22,95], and a model of partial sciatic nerve ligation [21]. Notably, the neutralization of CCL3 reduces pain-like behavior development in STZ- [19], paclitaxel- [22], CCI- [57], and PSNL-induced [21] neuropathy in mice, which may indicate its significant role in this pathology. Importantly, it is postulated that autoantibodies against CCL3 are biomarkers of type 1 diabetes development [96]; therefore, research on the impact of the modulation of this chemokine on the development of neuropathy should undoubtedly be continued due to its potential therapeutic benefits.…”

“…It was already shown that in a mouse model of diabetic neuropathic pain, strong spinal upregulation of CCL9 is in close association with the development of hypersensitivity [19] and that its neutralization by antibodies reduces pain-related symptoms [19]. Moreover, although in rats [53]/mice [16], increased levels of CCL9 mRNA in the spinal cord and/or DRGs are observed at many time points after injury, the protein level of CCL9 is enhanced between the 1st and 7th days post-CCI [53,57] and 7 days after streptozotocin injection [19]. Therefore, based on published results, we believe that CCL9 plays an important role in the early phase of neuropathic pain development.…”

“…Moreover, maraviroc diminishes microglial and astroglial cell activation, and in consequence, these cells secrete fewer factors whose anti-opioid role has already been documented, such as IL-1β [225], IL-18 [224], CCL3 [15,19,22], and CCL5 [25,26,100]. Importantly, data in the literature indicate that other CCR5 antagonists, i.e., AZD5672 and TAK-220, similar to maraviroc, diminish CCI-evoked neuropathic pain symptoms and enhance morphine-evoked analgesia [57]. Numerous studies clearly indicate that CCR5 is a potential target for drug development in the treatment of neuropathic pain, and maraviroc seems to be a substance worth future research in the clinic.…”

“…The central and peripheral nervous system upregulation of chemokines at the mRNA and protein levels in neuropathic pain models: evidence from mouse and/or rat studies. [14], DRG/CCI [50] YES SC/PSNL [14], SC/STZ [13] CCL2 YES DRG/CCI [50,51], SC, DRG/CCI [52,53], SC/CCI [16] YES SC, DRG/CCI [52], SC/CCI [16], DRG/CCI [51], DRG/OX [18], SC/SCI [54] [55,56], SC/CCI [53,57] YES SC/CCI [16,57], SC/STZ [19] Table 2. Cont.…”

“…Recently, in vitro studies have suggested that microglia and astroglia might be CCL4-producing cells, suggesting that this chemokine may be involved in nociception [56]. To date, only the mRNA level of CCL4 has been shown to be increased after peripheral nerve injury in the spinal cord [16,19,53], while a protein increase has not been observed [16,57]. Similarly, studies conducted in streptozotocin-and chemotherapy-induced neuropathy models have suggested little, if any, participation of CCL4 in pathological nociception [19,97].…”