In 2008, the National Institute of Dental and Craniofacial Research indicated that approximately 10 million Americans suffer from temporomandibular joint disorders (TMJD). Orofacial pain disorders not only impair the quality of life, but also seriously inhibit the health of the patient by impairing a person's ability to eat and drink. Reports have shown that patients with myofascial TMJD experience bilateral thermal hypersensitivity in the trigeminal region (Fernandez-de-las-Penas et al 2010). Our previous studies have shown that complete Freund's adjuvant (CFA)-induced masseter muscle inflammation and microinjection of the pro-inflammatory cytokine interleukin-1&beta (IL-1&beta) into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc) induce contralateral orofacial hyperalgesia in rat models. Furthermore, ventral Vi/Vc second order neurons project to the rostral ventromedial medulla (RVM) (Sugiyo et al 2005), a critical site for descending pain modulation, and substance P (SP) and its neurokinin-1 (NK-1) tachykinin receptor in the RVM are involved in descending pain facilitation (LaGraize et al 2010). We hypothesize that the development of bilateral deep tissue orofacial hyperalgesia after unilateral inflammation involves neuron-glial interactions in the ipsilateral Vi/Vc transition zone, the SP/NK-1 receptor signaling in the RVM, and subsequent activation of RVM 5-HT containing neurons terminating in the contralateral Vi/Vc transition zone. The results showed that 1) microinjection of the IL-1 receptor antagonist into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia, 2) lesions to the ipsilateral Vc did not prevent the development of contralateral hyperalgesia, 3) ibotenic acid lesion of RVM neurons prevented the development of IL-1&beta-induced contralateral hyperalgesia, 4) intra RVM post-treatment injection of the NK-1 receptor antagonists attenuated CFA-induced bilateral hyperalgesia and IL-1&beta-induced bilateral hyperalgesia, 5) serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia, and 6) inhibition of 5-HT3 receptors in the contralateral Vi/Vc attenuated CFA-induced contralateral hyperalgesia. These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms involving the Vi/Vc-RVM circuitry.