Involvement of ERK Phosphorylation of Trigeminal Spinal Subnucleus Caudalis Neurons in Thermal Hypersensitivity in Rats with Infraorbital Nerve Injury

To evaluate the involvement of the mitogen-activated protein kinase (MAPK) cascade in orofacial neuropathic pain mechanisms, this study assessed nocifensive behavior evoked by mechanical or thermal stimulation of the whisker pad skin, phosphorylation of extracellular signal-regulated kinase (ERK) in trigeminal spinal subnucleus caudalis (Vc) neurons, and Vc neuronal responses to mechanical or thermal stimulation of the whisker pad skin in rats with the chronic constriction nerve injury of the infraorbital nerve (ION-CCI). The mechanical and thermal nocifensive behavior was significantly enhanced on the side ipsilateral to the ION-CCI compared to the contralateral whisker pad or sham rats. ION-CCI rats had an increased number of phosphorylated ERK immunoreactive (pERK-IR) cells which also manifested NeuN-IR but not GFAP-IR and Iba1-IR, and were significantly more in ION-CCI rats compared with sham rats following noxious but not non-noxious mechanical stimulation. After intrathecal administration of the MEK1 inhibitor PD98059 in ION-CCI rats, the number of pERK-IR cells after noxious stimulation and the enhanced thermal nocifensive behavior but not the mechanical nocifensive behavior were significantly reduced in ION-CCI rats. The enhanced background activities, afterdischarges and responses of wide dynamic range neurons to noxious mechanical and thermal stimulation in ION-CCI rats were significantly depressed following i.t. administration of PD98059, whereas responses to non-noxious mechanical and thermal stimulation were not altered. The present findings suggest that pERK-IR neurons in the Vc play a pivotal role in the development of thermal hypersensitivity in the face following trigeminal nerve injury.