Mechanism of neuropathic pain still remain to be undiscovered. However, more and more studies performed on animals indicate that the blockade of chemokine receptors via the use of their antagonists may have bring beneficial effects in the treatment of neuropathic pain through affecting various cell types which activation, infiltration and/or proliferation is highly observed during neuropathy. That is why the aim of the present study was to investigate the effect of CC chemokine receptor type 1 (CCR1) and type 3 (CCR3) antagonists on pain-related behavior and level of protein markers of microglia/macrophages and neutrophils and moreover to compare effect of substances in male and female animals. 

 

Experiments were performed on Wistar rats and Albino Swiss mice. To induce symptoms of neuropathic pain, the sciatic nerve was ligated using chronic constriction injury model (CCI, 4-fold ligation in rat, 3-fold ligation in mouse) according to the published methods [1-4]. Repeated administration of  J113863 (CCR1 antagonist) [1] and SB328437 (CCR3 antagonist) [2] were performed on male rats for 7 following days after CCI. Behavioral tests measuring mechanical and thermal hypersensitivity were performed and after that tissue from spinal cord and dorsal root ganglia (DRG) were collected for protein analysis of microglia/macrophages and neutrophils markers. Moreover, comparison of the effectiveness of blockade of CCR1 and CCR3 in neuropathic pain were measured between genders, after single injection of J113863, SB328437 and UCB35625 (CCR1/CCR3 antagonist) on day 12 after CCI [3].

 

First of all, CCI induced strong mechanical and thermal hypersensitivity as measured 7-12 days after CCI. J113863 and SB328437 were able to reduce both kind of hypersensitivity after their repeated administration [1,2]. Secondly, CCI evoked strong upregulation of IBA-1 (microglia/macrophages) and MPO (neutrophils) protein levels measured on day 7th in the spinal cord and DRG. J113863 significantly reduced IBA-1 level compared to vehicle- treated group, while SB328437 protects against CCI evoked upregulation of MPO in the spinal cord. Both CCR1 and CCR3 antagonists inhibit increase of the MPO level in the DRG following CCI, but not IBA-1 [1,2]. Additionally, comparison of the % of the maximal possible effect (%MPE) had revealed differences in the effectiveness of J113863 between genders, showing its better effectiveness in male animals [3]. 

Current studies indicate an important role of modulation of CCR1 and CCR3 to achieve the decrease of pain-like behavior in CCI-subjected animals. Impact of selected antagonists on highly activated glial and immune cells during neuropathy may be the reason of such a good analgesic effect observed. Interestingly, the studies show different mechanism of action of J113863 which affects more microglia/macrophages and SB328437 which influences the level of neutrophils. However, in both cases analgesic effect was observed what indicates CCR1 and CCR3 as a good targets for future pain therapy. 

[1]  doi:10.1111/imm.13172

[2]  doi:10.3389/fimmu.2021.781310

[3]  doi.org/10.3390/cells12010098

[4]  doi: 10.1016/0304-3959(88)90209-6

 

Selectected substances are not available for patients, however we believe that chemokine receptor antagonists will be taken into consideration for clinical trials in the terms of neuropathic pain because of its good analgesic effects in the animal models. 

Consent to the use of laboratory animals was issued by the II Ethical Committee of the Maj Institute of Pharmacology Polish Academy of Sciences (213/2021; 116/2021; 75/2017; 97/2022; 1277/2015; 246/2022; 317/2022).

The research was funded by the National Science Centre, Poland grants, OPUS 22 2021/43/B/NZ7/00230 and statutory funds from the Maj Institute of Pharmacology Polish Academy of Sciences.