Peripheral mechanisms of masseter muscle nociceptor sensitization by Nerve Growth Factor (NGF)

Myofascial temporomandibular disorders (TMD) are common chronic craniofacial conditions that are characterized by pain in the masseter muscle. It has been suggested that nerve growth factor (NGF) may contribute to muscle sensitization in TMD-like pain based on various animal and human studies. Injection of NGF into the masseter muscle of healthy human subjects is not painful but does induce a localized, quick onset (~1 hour) and long lasting mechanical sensitization. It is not known how NGF causes this sensitization. NGF binds to the p75 receptor as well as the tyrosine kinase receptor A (TrkA), both of which are expressed on nociceptive neurons and may increase excitability and neuron sensitization. NGF is also reported to enhance NMDA receptor function on ganglion excitatory synaptic transmission. I hypothesized that human NGF mechanically sensitizes masseter muscle nociceptors by increasing the sensitivity of peripheral NMDA receptors. Co-expression of the NR2B subunit of the NMDA receptor with P75 and TrkA NGF receptors by trigeminal ganglia neurons that innervate the masseter muscle was investigated immunohistochemically. Nociceptor activity was recorded extracellularly from the trigeminal ganglion of anaesthetized female rats. Nociceptor mechanical threshold was assessed before and every 30 minutes for 3 hours after injection of human NGF (25 µg/ml, 10 µl), and in subsequent experiments NGF with TrkA or P75 receptor antibodies. Glutamate (1 M, 10 µl), a NMDA receptor agonist, was injected at the end of each experiment. Approximately 85% of NR2B positive masseter ganglion neurons co-expressed P75 or TrkA receptors, suggesting the potential for interaction. When compared with the vehicle control, it was found that injection of NGF into the masseter muscle did not evoke significant nociceptor discharge but did significantly reduce nociceptor mechanical threshold. There was no effect of NGF on glutamate-evoked nociceptor discharge or glutamate-induced mechanical sensitization. Additional experiments indicated that NGF-induced mechanical sensitization could be partially attenuated by co-administration of TrkA receptor antibodies, but not P75 receptor antibodies. These findings indicate that human NGF-induced sensitization of masseter nociceptors results, in part, from activation of TrkA receptors but does not appear to be mediated through enhanced peripheral NMDA receptor activity.Pharmaceutical Sciences, Faculty ofGraduat