Activation of mitogen-activated protein kinases in satellite glial cells of the trigeminal ganglion contributes to substance P-mediated inflammatory pain

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.

TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches

“…Besides direct transmission of information from one neuron to the other, activation of satellite glial cells may provide an additional indirect mechanism for the sensitization of other neurons initially not involved in the nociceptive process. Glial cells activated by the initial transmitter release from trigeminal neurons may release inflammatory molecules leading to sensitization of neurons [142]. Glutamate release from satellite glial cells cultured from the trigeminal ganglion was also reported as intraganglionic signaling mechanism [143].…”

Peripheral and Central Mechanisms of Persistent Orofacial Pain

“…GFAP upregulation is observed in the injured trigeminal nerve branch associated with the development of hyperalgesia (Vit et al, 2006; Katagiri et al, 2012). It is believed that neuropeptide such as SP or CGRP is synthesized in TG neurons by various noxious stimuli and is released from neuronal soma as well as peripheral and central terminals, bind their receptors expressed on SGCs, and GFAP expression in SGCs is upregulated after nerve injury or inflammation (Takeda et al, 2005; Vause et al, 2007; Mikuzuki et al, 2017; Zhang et al, 2019). Activated SGCs could release cytokines such as IL-1β in the gap between SGCs and the neuronal soma (Takeda et al, 2007; Lin et al, 2019), that cause acceleration of neuronal excitation.…”

Novel Analgesics with Peripheral Targets

“…P38 inhibitors appeared to be effective in rheumatoid arthritis (PH-797804, discontinued after phase II) [369], the inflammasome was inhibited by CDD-450 (ATI-450, phase II, new ongoing study) [370,371], and pain after nerve injury was reduced by dilmapimod (SB-681323, phase II trials completed several years ago) [372]. JNK contributes to inflammatory pain, also via non-neuronal cells in the DRG [362,373]. Whether MAPK inhibitors prove to be useful as analgesics for patients without need for antitumor therapy or even within this group remains an open question.…”