| Summary: | Behavioral evidence in rats indicates that injection of tumor necrosis factor alpha (TNFalpha into skeletal muscle results in a prolonged mechanical sensitization without gross inflammation. The present series of studies were conducted to test the idea that injection of TNFalpha causes mechanical sensitization of skeletal muscle through a peripheral mechanism that involves lowering of the mechanical threshold (MT) of muscle nociceptors without inflammation. In- vivo extracellular electrophysiological recording was used to assess the effect of TNFalpha (1 or 0.1microgram) and other drugs on the excitability and MT of masseter muscle nociceptors. Expression of TNFR1 (P55) and TNFR2 (P75) receptors by the masseter muscle and trigeminal ganglion neurons that innervate that muscle was determined by Western blot and immunohistochemical methodologies, respectively. The Evans blue dye technique and thermal camera recordings were used to assess inflammation in muscle tissues. Enzyme-linked immunoassays and glutamate biosensor probes were used to measure muscle concentrations of prostaglandin (PG) E2 and nerve growth factor, and glutamate, respectively. Intramuscular injection of 1mg TNFalpha did not excite nociceptors, but did significantly decrease MT compared to vehicle control. There was no evidence of gross inflammation 3 hours after injection of TNFalpha. Co-injection of TNFalpha with P55 or P75 receptor antibodies attenuated TNFalpha-induced mechanical sensitization. P55 and P75 receptors were expressed by 29% and 62% of masseter nociceptors, respectively. PGE2 and glutamate concentrations were significantly changed 3 hours after TNFalpha injection into the masseter muscle. Injection of diclofenac, a cycloxygenase inhibitor that attenuates prostaglandin synthesis, partially reversed the TNFalpha-induced decreases in the MT of masseter muscle nociceptors, while vehicle control, DL-2-amino-5-phophonovaleric acid, a competitive NMDA receptor antagonist, and a tyrosine kinase A receptor antibody, which blocks NGF-induced masseter muscle nociceptor sensitization, did not significantly alter nociceptor MT. These findings indicate that TNFalpha-induced mechanical sensitization of masseter nociceptors is mediated, in part, by increased PGE2 levels through activation of peripheral P55 and P75 receptors. Over all, these results suggest that injection of TNFalpha into skeletal muscle could be used as a model of myofascial trigger points to study the peripheral pain mechanisms of masticatory muscle pain.
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