Abstract
Inflammatory orofacial pain, in which substance P (SP) plays an important role, is closely related to the cross-talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs). SGC activation is emerging as the key mechanism underlying inflammatory pain through different signalling mechanisms, including glial fibrillary acidic protein (GFAP) activation, phosphorylation of mitogen-activated protein kinase (MAPK) signalling pathways, and cytokine upregulation. However, in the TG, the mechanism underlying SP-mediated orofacial pain generated by SGCs is largely unknown. In this study, we investigated whether SP is involved in inflammatory orofacial pain by upregulating interleukin (IL)-1β and tumour necrosis factor (TNF)-α from SGCs, and we explored whether MAPK signalling pathways mediate the pain process. In the present study, complete Freund’s adjuvant (CFA) was injected into the whisker pad of rats to induce an inflammatory model in vivo. SP was administered to SGC cultures in vitro to confirm the effect of SP. Facial expression analysis showed that pre-injection of L703,606 (an NK-1 receptor antagonist), U0126 (an inhibitor of MAPK/extracellular signal-regulated kinase [ERK] kinase [MEK] 1/2), and SB203580 (an inhibitor of P38) into the TG to induce targeted prevention of the activation of the NK-1 receptor and the phosphorylation of MAPKs significantly suppressed CFA-induced inflammatory allodynia. In addition, SP promoted SGC activation, which was proven by increased GFAP, p-MAPKs, IL-1β and TNF-α in SGCs under inflammatory conditions. Moreover, the increase in IL-1β and TNF-α was suppressed by L703, 606, U0126 and SB203580 in vivo and in vitro. These present findings suggested that SP, released from TG neurons, activated SGCs through the ERK1/2 and P38 pathways and promoted the production of IL-1β and TNF-α from SGCs, contributing to inflammatory orofacial pain associated with peripheral sensitization.
Highlights
Orofacial pain, referring to a cluster of disorders including trigeminal neuralgia, temporomandibular joint disorders, migraine and orthodontic pain, affects 16% of the general population and causes a dramatic reduction in the quality of life.[1,2] Orofacial inflammation can alter the properties of somatic sensory pathways, resulting in pain abnormalities such as hypersensitivity, hyperalgesia and allodynia.[3]
There was no significant difference among the complete Freund’s adjuvant (CFA)+dimethyl sulfoxide (DMSO), CFA+SP600125 and CFA groups during the entire observation period (Fig. 1, n = 5, P > 0.05), indicating that DMSO is a safe solvent with no side effects and that SP600125 has no therapeutic effect on allodynia in rats
In the CFA+L703, 606, CFA+U0126 and CFA+SB203580 groups, the RGS scores increased on day 1, peaked on day 3 but were still significantly lower than the scores in the CFA group, and returned to baseline on days 5–7 (Fig. 1, n = 5, P < 0.05), meaning that U0126 and SB203580 can attenuate the inflammatory pain mediated by substance P (SP)
Summary
Orofacial pain, referring to a cluster of disorders including trigeminal neuralgia, temporomandibular joint disorders, migraine and orthodontic pain, affects 16% of the general population and causes a dramatic reduction in the quality of life.[1,2] Orofacial inflammation can alter the properties of somatic sensory pathways, resulting in pain abnormalities such as hypersensitivity, hyperalgesia and allodynia.[3]. SGCs play an important role in the peripheral sensitization of the TG.[7] The profound cross-talk network between TG neurons and SGCs is essential to the regulation of inflammatory orofacial pain.[8,9]. Several chemical messengers take part in this process, including substance P (SP), adenosine triphosphate (ATP), calcitonin generelated peptide (CGRP), and γ-aminobutyric acid (GABA).[10,11] For instance, TG neurons synthesize and secrete more SP following peripheral inflammation, which activates the neurokinin (NK)-1 receptors on SGCs to trigger local paracrine mechanisms.[8,12] In the dorsal root ganglion (DRG) of the spinal cord, there is evidence that activated SGCs and the subsequent production of cytokines, such as interleukin (IL)-1β13 and tumour necrosis factor (TNF)α,14,15 contribute to the development and maintenance of chronic neuropathic pain.
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