Role of Neuron-Glial Interaction Mediated by IL-1β in Ectopic Tooth Pain

Abstract

Although many reports have demonstrated that ectopic pain develops in the orofacial region following tooth pulp inflammation, which often causes misdiagnosis and inappropriate treatment for patients with pulpitis, the precise mechanism remains unknown. In the present study, we hypothesized that the functional interaction between satellite glial cells and neurons mediated by interleukin 1β (IL-1β) in the trigeminal ganglion (TG) is involved in ectopic orofacial pain associated with tooth pulp inflammation. The digastric muscle electromyogram (D-EMG) activity elicited by capsaicin administration into the maxillary second molar tooth pulp was analyzed to evaluate the noxious reflex and was significantly increased in rats with inflammation of the maxillary first molar (M1) versus rats injected with saline. A significant increase in the expression of connexin43 (Cx43), a gap junction containing protein, was observed in activated satellite glial cells surrounding second molar-innervating neurons in the TG after M1 pulpitis. Daily administration of Gap26, a Cx43 mimetic peptide and inhibitor, in the TG significantly suppressed the enhancement of capsaicin-induced D-EMG activity and the percentage of Fluoro-Gold (FG)-labeled cells encircled by glial fibrillary acid protein-immunoreactive (IR) + Cx43-IR cells after M1 pulp inflammation ( P < 0.01). The percentage of FG-labeled cells encircled by glial fibrillary acid protein-IR + IL-1β-IR cells, IL-1 type I receptor-IR cells labeled with FG, and TRPV1-IR cells labeled with FG significantly increased after M1 pulp inflammation ( P < 0.01). Daily administration of IL-1ra, an IL-1 receptor antagonist, into the TG significantly reduced the enhancement of capsaicin-induced D-EMG activity and the percentage of TRPV1-IR neurons labeled with FG after M1 pulp inflammation ( P < 0.01). The present findings suggest that satellite glial cell is activated in the TG via activated gap junctions composed of Cx43 following tooth pulp inflammation, which leads to the hyperactivation of remote neurons via IL-1β mechanisms and results in ectopic tooth pulp pain in the adjacent tooth.

Role of Macrophage-Mediated Toll-like receptor 4–Interleukin-1R Signaling in Ectopic Tongue Pain Associated With Tooth Pulp Inflammation

“…TRPV1 expression is potentiated in TG neurons following peripheral in ammation or nerve injury, resulting in the development of mechanical and/or thermal hypersensitivity [31,32]. The activation of IL-1RI by IL-1β facilitates TRPV1 expression and promotes neuronal hyperexcitability [17,19,33]. In the present study, intra-TG injection of IL-1β promoted tongue hypersensitivity to mechanical and heat stimuli and augmented TRPV1 expression.…”

“…Transient receptor potential vanilloid 1 (TRPV1), which is activated by noxious heat (> 43 °C), low extracellular pH (< 6.5), and some irritants, is also considered to contribute to mechanical nociception [18]. TRPV1 expression in sensory neurons increases following the up-regulation of IL-1β production by activated satellite glial cells [19]. Hence, it is likely that the expression of danger -associated molecular patterns induced by the in ammation of the orofacial organ, such as tooth pulp in ammation induced by mandibular rst molar tooth pulp exposure (M1-TPE), also induces TRPV1 expression as well as increases IL-1RΙ expression following TLR4 activation in TG neurons.…”

Connexin 43 expression in satellite glial cells contributes to ectopic tooth-pulp pain

“…These excited neurons can release various molecules into the extracellular space (11,12), that can interact with specific receptors on SGCs in the vicinity of the neurons and induce SGC activation (13). This activation of SGCs can trigger opening of connexin 43 (Cx43)-containing gap junctions that link neighboring SGCs (14). Signals from activated SGCs can be transmitted among SGCs via gap junctions, leading to continuous propagation of SGC activation from the site of injury to uninjured more distant locations (14).…”

“…This activation of SGCs can trigger opening of connexin 43 (Cx43)-containing gap junctions that link neighboring SGCs (14). Signals from activated SGCs can be transmitted among SGCs via gap junctions, leading to continuous propagation of SGC activation from the site of injury to uninjured more distant locations (14). The distantly located and activated SGCs subsequently release molecules that facilitate the excitability of remote neurons innervating uninjured and distant tissues, leading to the development of secondary hyperalgesia (9,11).…”

Activation of trigeminal ganglion satellite glial cells in CFA-induced tooth pulp pain in rats

“…The neuron-glia interaction is a key mechanism in orofacial pain [ 20 , 21 ]. The glial interleukin-1β in SGC plays an important role in ectopic tooth pain in adjacent tooth [ 24 ] and upregulates neuronal sodium channel 1.7 in trigeminal ganglion [ 25 ].…”