We previously developed a rat dental occlusal interference model of facial pain that was produced by bonding a crown onto the right maxillary first molar and was reflected in sustained facial hypersensitivity that was suggestive of the involvement of central sensitization mechanisms. The aim of the present study was to investigate potential central mechanisms involved in the occlusal interference-induced facial hypersensitivity. A combination of behavioral, immunohistochemical, Western blot and electrophysiological recording procedures was used in 98 male adult Sprague-Dawley rats that either received the occlusal interference or were sham-operated or naive rats. Immunohistochemically labeled astrocytes and microglia in trigeminal subnucleus caudalis (Vc) showed morphological changes indicative of astrocyte and microglial activation after the occlusal interference. Prolonged upregulation of p38 MAPK and ERK was also documented in Vc after placement of the occlusal interference, and was expressed in both neurons and glial cells at time points when rats showed peak mechanical facial hypersensitivity. The i.t. administration of the p38 MAPK inhibitor SB203580 to the medulla significantly inhibited the occlusal interference-induced hypersensitivity, and the ERK inhibitor PD98059 produced an even stronger effect. Central sensitization of functionally identified Vc nociceptive neurons following placement of the occlusal interference was also documented by extracellular electrophysiological recordings, and i.t. administration of PD98059 could reverse the neuronal central sensitization. These novel findings suggest that central mechanisms including central sensitization of trigeminal nociceptive neurons and non-neuronal processes involving MAPKs play significant roles in the production of occlusal interference-induced facial pain. Perspective Central mechanisms including trigeminal nociceptive neuronal sensitization, non-neuronal processes involving glial activation and MAPKs play significant roles in occlusal interference-induced facial pain. These mechanisms may be involved in clinical manifestations of facial pain that have been reported in patients with an occlusal interference.

Background Currently, there is a lack of effective therapy for chronic pain. Increasing evidence has shown that chemokines and their correlative receptors involved in the neuron–glial cell cross‐talk could contribute to the pathogenesis of neuropathic pain. Our previous studies suggested that CXCR3 expression was elevated in the spinal dorsal horn after nerve injury. Objectives In this study, we aimed to explore the role of CXCR3 signalling in chronic pain modulation. Methods Reverse transcription quantitative PCR and Western blotting were used to measure the expression of CXCR3 and its ligands in the spinal cord following chronic constriction injury (CCI) of the sciatic nerve. Cxcr3 ‐knockout mice were used to observe the effect of the receptor on pain‐related behaviour and microglial activation. Immunohistochemistry was used to investigate the expression of two activation markers for spinal microglia, Iba‐1 and phosphorylated‐p38 (p‐p38) in these mice. Results The expression of CXCR3 and its ligand CXCL11 was upregulated in the lumbar dorsal horn of the spinal cord in CCI models. In Cxcr3 ‐knockout mice, CCI‐induced tactile allodynia and thermal hyperalgesia were observed to be alleviated during the early stage of pain processing. Meanwhile, the expression of the glial activation markers, namely, Iba‐1 and p‐p38, was decreased. Conclusion Our results demonstrate that CXCR3 could be a key modulator involved in pain modulation of the spinal cord; therefore, CXCR3‐related signalling pathways could be potential targets for the treatment of intractable pathological pain.