Blockage of the fractalkine pathway reduces hyperalgesia and prevents morphological glial alterations—Comparison between inflammatory and neuropathic orofacial pain in male rats

Abstract

AbstractThis study aimed to evaluate the effects of inhibitors of the fractalkine pathway in hyperalgesia in inflammatory and neuropathic orofacial pain in male rats and the morphological changes in microglia and satellite glial cells (SGCs). Rats were submitted to zymosan‐induced arthritis of the temporomandibular joint or infraorbital nerve constriction, and treated intrathecally with a P2X7 antagonist, a cathepsin S inhibitor or a p‐38 mitogen‐activated protein kinase (MAPK) inhibitor. Mechanical hyperalgesia was evaluated 4 and 6 h following arthritis induction or 7 and 14 days following nerve ligation. The expression of the receptor CX3CR1, phospho‐p‐38 MAPK, ionized calcium‐binding adapter molecule‐1 (Iba‐1), and glutamine synthetase and the morphological changes in microglia and SGCs were evaluated by confocal microscopy. In both inflammatory and neuropathic models, untreated animals presented a higher expression of CX3CR1 and developed hyperalgesia and up‐regulation of phospho‐p‐38 MAPK, which was prevented by all drugs (p < .05). The number of microglial processes endpoints and the total branch length were lower in the untreated animals, but the overall immunolabeling of Iba‐1 was altered only in neuropathic rats (p < .05). The mean area of SGCs per neuron was significantly altered only in the inflammatory model (p < .05). All morphological alterations were reverted by modulating the fractalkine pathway (p < .05). In conclusion, the blockage of the fractalkine pathway seemed to be a possible therapeutic strategy for inflammatory and neuropathic orofacial pain, reducing mechanical hyperalgesia by impairing the phosphorylation of p‐38 MAPK and reverting morphological alterations in microglia and SGCs.