Melatonin achieves prolonged pain relief by modulating macrophage repolarization from M1 to M2 in the trigeminal ganglion of TMJOA rats

The transient analgesic effect of melatonin (MT) on temporomandibular joint (TMJ) osteoarthritis (OA) chronic pain has been demonstrated, but its long-term efficacy and underlying mechanisms remain unclear. To explore the prolonged analgesic effect of MT on TMJOA pain and to determine whether neuroimmune mechanisms are involved. A rat model of TMJOA pain was established by intra-TMJ injection of monosodium iodoacetate (MIA). Macrophage depletion models were established by intraperitoneal injection of clodronate liposomes. Nociceptive behavior was assessed by measuring the head withdrawal threshold (HWT). Immunofluorescence was employed to evaluate the expression of macrophage markers (F4/80, iNOS, CD206), neuronal sensitization indicators (CGRP, IB4), and inflammatory mediators (IL-1β, TNF-α, IL-10) in the trigeminal ganglion (TG). Calcium imaging was used to assess the activation level of TG neurons. Retrograde tracing was used for the specific labeling of TG neurons innervating the TMJ. Macrophage depletion inhibited MIA-induced TMJOA pain and reversed both the upregulation of CGRP and IB4 expression and the increase in Fluo-3 AM fluorescence intensity in the TG of TMJOA pain model rats. Additionally, after 3 weeks of MT treatment, the HWT in MIA-induced TMJOA rats gradually returned to levels comparable to those in the normal control group and remained stable. Notably, MT treatment repolarized TG macrophages from the M1 to the M2 phenotype in TMJOA model rats, accompanied by a shift in cytokine expression characterized by reduced pro-inflammatory cytokines (IL-1β, TNF-α) and increased anti-inflammatory cytokine (IL-10) expression. MT may exert prolonged analgesic effects in TMJOA pain, which appeared to involve the phenotypic switching of TG macrophages from M1 to M2 and the alleviation of local neuroinflammation.