Neuronal Activities in the Rostral Ventromedial Medulla Associated with Experimental Occlusal Interference-Induced Orofacial Hyperalgesia

The imbalanced conditions of pronociceptive ON-cells and antinociceptive OFF-cells in the rostral ventromedial medulla (RVM) alter nociceptive transmission and play an important role in the development of chronic pain. This study aimed to explore the neuroplastic mechanisms of the RVM ON-cells and OFF-cells in a male rat model of experimental occlusal interference (EOI)-induced nociceptive behavior reflecting orofacial hyperalgesia and in modified models involving EOI removal at early and later stages. We recorded the mechanical head withdrawal thresholds, orofacial operant behaviors, and the activity of identified RVM ON-cells and OFF-cells in these rats. EOI-induced orofacial hyperalgesia could be relieved by EOI removal around postoperative day 3; this effect could be inhibited by intra-RVM microinjection of the κ-opioid receptor agonist U-69593. EOI removal around postoperative day 8 did not relieve the orofacial hyperalgesia, which could, however, be reversed by intra-RVM microinjection of the NK-1 (neurokinin-1) receptor antagonist L-733060. The activity of ON-cells and OFF-cells did not change during both the initial 3 and 6 d of EOI. When EOI was removed on postoperative day 3, OFF-cell responses decreased, contributing to the reversal of hyperalgesia. When EOI lasted for 8 d or was removed on postoperative day 8, spontaneous activity and stimulus-evoked responses of ON-cell increased, contributing to the maintained hyperalgesia. In contrast, when the EOI lasted for 14 d, OFF-cell responses decreased, possibly participating in the maintenance of hyperalgesia with persistent EOI. Our results reveal that adaptive changes in the RVM were associated with orofacial pain following EOI placement and removal. A considerable proportion of patients experience chronic orofacial pain throughout life despite the therapies given or removal of potential etiologic factors. However, current therapies lack effectiveness because of limited knowledge of the chronicity mechanisms. Using electrophysiological recording, combined with a behavioral test, we found that the prevailing descending facilitation in the rostral ventromedial medulla (RVM) participates in the maintenance of orofacial hyperalgesia following late removal of nociceptive stimuli, while the prevailing descending inhibition from the RVM may contribute to the reversal of orofacial hyperalgesia following early removal of nociceptive stimuli. Thus, variable clinical outcomes of orofacial pain may be associa