Pharmacological Evidence of the Important Roles of CCR1 and CCR3 and Their Endogenous Ligands CCL2/7/8 in Hypersensitivity Based on a Murine Model of Neuropathic Pain

Cells, 2023 · DOI: 10.3390/cells12010098 · Published: December 26, 2022

Simple Explanation

This research investigates the roles of CCR1 and CCR3, along with their ligands, in neuropathic pain using a mouse model. The study found increased levels of certain chemokines (CCL2/3/4/5/6/7/8/9) in the spinal cord after nerve injury, which suggests these chemokines are involved in neuropathic pain. The researchers also found that blocking the production of CCL2/7/8 or blocking CCR1 and CCR3 receptors reduced pain-like behaviors in the mice. This suggests that these chemokines and their receptors could be potential targets for future pain treatments. The study also examined changes in microglia, astrocytes, and neutrophils, which are types of immune cells in the nervous system. These changes suggest that these cells play a role in the development of neuropathic pain.

Study Duration

28 Days

Participants

373 male and 34 female Albino Swiss mice

Evidence Level

Not specified

Key Findings

1
CCL2/7/8 protein levels were significantly increased in the spinal cord following chronic constriction injury (CCI) of the sciatic nerve, suggesting their involvement in both the development and maintenance of neuropathic pain.
2
Intrathecal injection of CCL2, CCL3, CCL5, CCL7, CCL8, and CCL9 in naive mice induced both mechanical and thermal hypersensitivity, confirming their pronociceptive properties.
3
Inhibition of CCL2/7/8 production by bindarit, as well as blockade of CCR1 and CCR3 by selective and dual antagonists, effectively reduced neuropathic pain-like behavior in mice.

Research Summary

This study comprehensively investigates the roles of CCR1, CCR3, and their endogenous ligands in neuropathic pain using a murine model of chronic constriction injury (CCI). The research identifies time-dependent and long-lasting increases in mRNA levels of CCR1 and CCR3 ligands in the spinal cord after CCI. ELISA results indicate that endogenous ligands of CCR1 and CCR3, particularly CCL2/7/8, are involved in the development and persistence of neuropathic pain. Intrathecal injection of these ligands confirms their strong influence on mechanical and thermal hypersensitivity development. Pharmacological interventions, such as inhibition of CCL2/7/8 production via bindarit and blockade of CCR1 and CCR3 receptors using selective/dual antagonists, effectively reduce neuropathic pain-like behavior, suggesting these chemokines and receptors as potential therapeutic targets.

Practical Implications

Therapeutic Target Identification

CCR1, CCR3, and their ligands, especially CCL2/7/8, may serve as potential therapeutic targets for neuropathic pain treatment.

Drug Development

Development of drugs targeting the CCL2/7/8/CCR1 and CCL7/8/CCR3 signaling pathways could offer new avenues for neuropathic pain management.

Personalized Medicine

Further research should investigate gender-specific differences in chemokine involvement in neuropathic pain to develop personalized treatment strategies.

Study Limitations

1
The study is based on a murine model, and results may not directly translate to human neuropathic pain conditions.
2
The exact mechanisms underlying bindarit's activity remain unexplored, necessitating further research.
3
The study did not investigate the internalization of CCR1 and CCR3 receptors, which could provide further insight into receptor function.

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