Background and aims: Chemokine signaling has been implicated in the pathogenesis of neuropathic pain. Thus, the aim of our study was to investigate the roles of CXCR2 and CXCR3 antagonists on neuropathic pain symptoms and opioid effectiveness.
Methods: Chronic Constriction Injury (CCI) model of neuropathic pain was used. The pharmacological tools were injected intrathecally, and pain behavior was evaluated by von Frey/cold plate tests. Analysis of mRNA/protein expression was performed by qRT-PCR/Western blotting. The co-localization of CXCR2/CXCR3 with neural/glial cells was visualized by immunofluorescence. 
Results: Our results demonstrated that each of the CXCR2 (CXCL1-3) and CXCR3 (CXCL4, CXCL9-11, CCL21) ligands induced hypersensitivity reactions in naive animals and the effect occurring shortly after administration is associated with the neural location of CXCR2 and CXCR3, as confirmed by immunofluorescence. Furthermore, the neutralizing antibodies against CCI-upregulated CXCL3, CXCL9, CXCL10, CCL21 and a selective antagonists of the CXCR2 (NVP-CXCR2-20) and CXCR3 (NBI-74330) reduced the neuropathic pain-related behavior. Interestingly, in contrast to NVP-CXCR2-20, the NBI-74330 also enhanced morphine analgesic potency, diminished the spinal microglial markers and pronociceptive factors in CCI-exposed animals. 
Conclusions: Our data provide new evidence that CXCR2 and CXCR3 are a promising target for diminishing neuropathic pain. Importantly, the pharmacological modulation of neuroimmunological interactions via CXCR3 may represent a new strategy for effective polytherapy with opioids. 
Acknowledgments: Supported by the National Science Centre, Poland OPUS-11-2016/21/B/NZ4/00128, PRELUDIUM-12-2016/23/N/NZ7/00356, statutory funds of the Institute of Pharmacology PAS Department of Pain Pharmacology. Piotrowska supported by the Foundation for Polish Sciences, the L`Oreal-UNESCO For Women in Science program in Poland.

COMPARISON OF ANTINOCICEPTIVE EFFECTS OF CXCR2 AND CXCR3 RECEPTOR ANTAGONISTS AND THEIR INFLUENCE ON OPIOIDS ANALGESIA OF NEUROPATHIC PAIN MODEL