Abstract
BackgroundNeuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2)-chemokine C-C motif receptor 2 (CCR2) signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain.MethodsThe inferior alveolar nerve and mental nerve transection (IAMNT) was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP), and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing.ResultsIAMNT induced persistent (>21 days) heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH) from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 μg) significantly attenuated IAMNT-induced heat hyperalgesia.ConclusionThe data suggest that CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial–neuronal interaction. Targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia.
Highlights
Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown
Time course of inferior alveolar nerve and mental nerve transection (IAMNT)-induced heat hyperalgesia After two days habituation, the basal headwithdrawal latency (HWL) of the whisker pad to heat stimulus was tested for naïve, IAMNT and sham-operated mice and they showed similar latencies (Naïve, 12.4 ± 0.7 seconds; IAMNT, 12.9 ± 0.8 seconds; Sham, 12.1 ± 0.7 seconds)
These results indicate that IAMNT induces persistent trigeminal neuropathic pain
Summary
Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2)-chemokine C-C motif receptor 2 (CCR2) signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain. The mechanisms by which nerve injury develops neuropathic pain have remained largely unknown. It was generally believed that only neurons and their neural circuits were responsible for the development and maintenance of neuropathic pain. In recent years, it is increasingly dorsal root ganglion (DRG), spinal cord, and brain [17,18,19,20] and contribute to chronic pain processing [16]. Whether CCL2-CCR2 signaling is involved in trigeminal neuropathic pain remains unknown
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