Tumor necrosis factor-Alpha stimulates cytokine expression and transient sensitization of trigeminal nociceptive neurons

Abstract

Objective Elevated levels of tumor necrosis factor-alpha (TNF-α) in the capsule of the temporomandibular joint (TMJ) are implicated in the underlying pathology of temporomandibular disorders (TMD). TMD are a group of conditions that result in pain in the TMJ and/or muscles of mastication, and are associated with significant social and economic burdens. The goal of this study was to investigate the effect of elevated TNF-α levels in the TMJ capsule on nocifensive behavioral response to mechanical stimulation of trigeminal neurons and regulation of cytokines within the trigeminal ganglion. Design Male Sprague-Dawley rats were injected bilaterally in the TMJ capsule with TNF-α and changes in nocifensive head withdrawal responses to mechanical stimulation of cutaneous tissue directly over the capsule was determined using von Frey filaments. Cytokine levels in trigeminal ganglia were determined by protein array analysis at several time points post injection and correlated to nocifensive behavior. Results TNF-α caused a significant increase in the average number of nocifensive responses when compared to naive and vehicle treated animals 2 hours post injection, but levels returned to control levels at 24 hours. Based on array analysis, the levels of eight cytokines were significantly elevated above vehicle control levels at 2 hours following TNF-α injection, but all eight had returned to the vehicle control levels after 24 hours. Conclusions Our findings provide evidence that elevated levels of TNF-α in the joint capsule, which is reported to occur in TMD, promotes nociception in trigeminal ganglia neurons via a mechanism that temporally correlates with differential regulation of several cytokines.

CGRP and the Trigeminal System in Migraine

“…Other studies have shown that CGRP released from TG neurons stimulate production of tumor necrosis factor‐α (TNF‐α) in satellite cells, which then acts on TG neurons to increase both the production and the release of CGRP . Moreover, TNF‐α can acutely sensitize TG neurons directly, as well as evoke the upregulation of several proinflammatory cytokines in these neurons, likely through the TNF‐α receptors . Together, these studies demonstrate that CGRP secreted from TG neurons can increase cytokine production in TG neurons and satellite glial cells and increase its own production and release from neurons, maintaining a sensitized state and enhancing pain …”

“…Moreover, TNF‐α can acutely sensitize TG neurons directly, as well as evoke the upregulation of several proinflammatory cytokines in these neurons, likely through the TNF‐α receptors . Together, these studies demonstrate that CGRP secreted from TG neurons can increase cytokine production in TG neurons and satellite glial cells and increase its own production and release from neurons, maintaining a sensitized state and enhancing pain …”

“…128 Moreover, TNF-α can acutely sensitize TG neurons directly, as well as evoke the upregulation of several proinflammatory cytokines in these neurons, likely through the TNF-α receptors. 129 Together, these studies demonstrate that CGRP secreted from TG neurons can increase cytokine production in TG neurons and satellite glial cells and increase its own production and release from neurons, maintaining a sensitized state and enhancing pain. 124,126,129,130 Central CGRP in Migraine.-As discussed in several recent reviews, it is generally accepted that anti-CGRP therapeutics most likely act peripherally to relieve migraine attacks, since the small-molecule CGRP receptor antagonists and the anti-CGRP antibodies have very little ability to cross the blood-brain barrier.…”

“…129 Together, these studies demonstrate that CGRP secreted from TG neurons can increase cytokine production in TG neurons and satellite glial cells and increase its own production and release from neurons, maintaining a sensitized state and enhancing pain. 124,126,129,130 Central CGRP in Migraine.-As discussed in several recent reviews, it is generally accepted that anti-CGRP therapeutics most likely act peripherally to relieve migraine attacks, since the small-molecule CGRP receptor antagonists and the anti-CGRP antibodies have very little ability to cross the blood-brain barrier. 9,108,[131][132][133][134][135] Nonetheless, a central role of CGRP in migraine is still possible, since several studies reveal a widespread distribution of the neuropeptide and the receptor components CLR and RAMP1 throughout the CNS.…”

Nociceptive behavioural assessments in mouse models of temporomandibular joint disorders

“…Our method was adapted from the 'rat von Frey test method', which has been previously published. 7,54,55 Briefly, before the test, the mice were housed in a special plastic cage, with a slight gap in the middle, for 30 min on 3 consecutive days for acclimation. Then, the orofacial areas directly overlaying the TMJ were carefully shaved under anaesthesia, avoiding the whiskers, 1 day before the starting date of the testing session.…”