Based on these findings, phosphorylation of p38 MAPK via P2X(7)R may induce tactile allodynia/hyperalgesia, which is most likely mediated by sTNF-α released by microglia.

In this study, the effect of hyperactivity of the lateral pterygoid muscle (LPM) on the temporomandibular joint (TMJ) disk during prolonged clenching was examined with a mathematical model. Finite element models of the TMJ were constructed based on magnetic resonance images from two subjects with or without internal derangement of the TMJ. For each model, muscle forces were used as a loading condition for stress analysis for 10 min clenching. Furthermore, an intermittent increase of the LPM force with intervals of 1 min was applied. In the asymptomatic model, large stresses were found in the central and lateral part of the disk at the onset of clenching. In the retrodiscal tissue, stress relaxation occurred during the first 2 min of clenching. When the force of the LPM increased temporarily, the disk moved anteriorly and returned to its original position afterward. In the symptomatic model, large stresses were observed in both the posterior region of the disk and the retrodiscal tissue throughout clenching. Upon temporary increase of the LPM force, the disk was elongated anteriorly, which appeared to be irreversible. These results indicate that hyperactivity of the LPM may be involved in the progression of disk displacement.

The whisker pad area (WP) is innervated by the second branch of the trigeminal nerve and experiences allodynia and hyperalgesia following transection of the mental nerve (MN; the third branch of the trigeminal nerve). However, the mechanisms of this extra-territorial pain remain unclear. The ionotropic P2X(7) ATP receptor (P2X(7)) in microglia is known to potentiate, via cytokines, the perception of noxious stimuli, raising the possibility that P2X(7) and cytokines are involved in this extra-territorial pain. One day after MN transection (MNT), WP allodynia/hyperalgesia developed, which lasted for > 8 wks. Activation of microglia and up-regulation of P2X(7), membrane-bound tumor necrosis factor (TNF)-α (mTNF-α), and soluble TNF-α (sTNF-α) in the trigeminal sensory nuclear complex (TNC) were evident for up to 6 wks after MNT. Allodynia/hyperalgesia after MNT was blocked by intracisternal administration of etanercept, a recombinant TNF-α receptor (p75)-Fc fusion protein. Intracisternal A438079, a P2X(7) antagonist, also attenuated allodynia/hyperalgesia and blocked up-regulation of mTNF-α and sTNF-α in the TNC. We conclude that sTNF-α released by microglia following P2X(7) activation may be important in both the initiation and maintenance of extra-territorial pain after MNT.