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 -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.

SIGNIFICANCE STATEMENT 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 associated with descending modulation, and an optimal window of time may exist in the management of chronic orofacial pain.

头端腹内侧髓质 (RVM) 中伤害感受性 ON 细胞和抗伤害性 OFF 细胞的不平衡状况改变了伤害性传递，并在慢性疼痛的发展中发挥重要作用。本研究旨在探讨实验性咬合干扰 (EOI) 诱导的反映口面部痛觉过敏的雄性大鼠模型以及涉及早期和后期 EOI 去除的改良模型中 RVM ON 细胞和 OFF 细胞的神经可塑性机制。我们记录了这些大鼠的机械头缩回阈值、口面部操作行为以及已识别的 RVM ON 细胞和 OFF 细胞的活动。术后第 3 天左右去除 EOI 可以缓解 EOI 引起的口面部痛觉过敏；这种效应可以通过 RVM 内显微注射 α-阿片受体激动剂 U-69593 来抑制。术后第 8 天左右去除 EOI 并不能缓解口面部痛觉过敏，但可以通过 RVM 内微量注射 NK-1（神经激肽-1）受体拮抗剂 L-733060 来逆转这种情况。 ON 细胞和 OFF 细胞的活性在 EOI 的最初 3 和 6 天内都没有变化。当术后第 3 天去除 EOI 时，OFF 细胞反应下降，有助于逆转痛觉过敏。当EOI持续8天或在术后第8天去除时，ON细胞的自发活动和刺激诱发反应增加，有助于维持痛觉过敏。相反，当 EOI 持续 14 d 时，OFF 细胞反应下降，可能参与了持续 EOI 的痛觉过敏的维持。我们的结果表明，RVM 的适应性变化与 EOI 放置和移除后的口面部疼痛相关。

意义声明尽管进行了治疗或消除了潜在的病因，仍有相当一部分患者终生经历慢性口面部疼痛。然而，由于对慢性机制的了解有限，目前的疗法缺乏有效性。使用电生理记录并结合行为测试，我们发现头端腹内侧延髓（RVM）中普遍存在的下行促进参与了后期去除伤害性刺激后口面部痛觉过敏的维持，而RVM普遍存在的下行抑制可能有助于维持口面部痛觉过敏。早期去除伤害性刺激后口面部痛觉过敏的逆转。因此，口面部疼痛的可变临床结果可能与下行调节有关，并且慢性口面部疼痛的治疗可能存在最佳时间窗。