Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3

Abstract

Orthodontic tooth movement elicits alveolar bone remodeling and orofacial pain that is manifested by tooth mechanical hyperalgesia. Nerve growth factor (NGF) is upregulated in periodontium and may modulate tooth mechanical hyperalgesia. The objectives were to examine the role of NGF in tooth mechanical hyperalgesia and to elucidate the underlying mechanisms. Tooth mechanical hyperalgesia was induced by ligating closed coil springs between incisors and molars in Sprague–Dawley rats. Retrograde labeling was performed by periodontal administration of fluor-conjugated NGF and the detection of fluorescence in trigeminal ganglia (TG). Lentivirus vectors carrying NGF shRNA were employed to knockdown the expression of NGF in TG. The administration of agonists, antagonists, and virus vectors into TG and periodontium was conducted. Tooth mechanical hyperalgesia was examined through the threshold of biting withdrawal. Our results revealed that tooth movement elicited tooth mechanical hyperalgesia that could be alleviated by NGF neutralizing antibody and that NGF was upregulated in periodontium (mainly in periodontal fibroblasts) and TG. Retrograde labeling revealed that periodontal NGF was retrogradely transported to TG after day 1. Acid-sensing ion channel 3 (ASIC3) and NGF were co-expressed in trigeminal neurons and the percentage of co-expression was significantly higher following tooth movement. The administration of NGF and NGF neutralizing antibody into TG could upregulate and downregulate the expression of ASIC3 in TG, respectively. NGF aggravated tooth mechanical hyperalgesia that could be alleviated by ASIC3 antagonist (APETx2). Moreover, NGF neutralizing antibody mitigated tooth mechanical hyperalgesia that could be recapitulated by ASIC3 agonist (GMQ). NGF-based gene therapy abolished tooth mechanical hyperalgesia and downregulated ASIC3 expression. Taken together, in response to force stimuli, periodontal fibroblasts upregulated the expressions of NGF that was retrogradely transported to TG, where NGF elicited tooth mechanical hyperalgesia through upregulating ASIC3. NGF-based gene therapy is a viable method in alleviating tooth-movement-induced mechanical hyperalgesia.

Immunohistochemical phenotype of sensory neurons associated with sympathetic plexuses in the trigeminal ganglia of adult nerve growth factor transgenic mice

“…Similar perineuronal plexuses around large diameter neurons have also been seen in the affected sensory ganglia after various types of peripheral nerve injury in mice (Lee et al, 1998;Minett et al, 2014;Ramer et al, 1997 and rats (Chung et al, 1993(Chung et al, , 1996(Chung et al, , 1997Jones et al, 1999;Li et al, 2011;McLachlan et al, 1993;Ramer et al, 1999;Zhou et al, 1996). Notably, sympathosensory sprouting has been reported in the human DRG (García-Poblete et al, 2003;Shinder et al, 1999). Though the neurochemical phenotype of those sensory neurons targeted after peripheral nerve injury remains elusive, NGF likely contributes to sympathosensory sprouting seen in NGF transgenic mice, as well as in adult rodents and humans with nerve injury.…”

“…Another ion channel that is widely expressed in the TG is ASIC3, a proton‐gated acid‐sensing ion channel activated by acidosis resulting from tissue injury (Gao et al., 2021; Morgan et al., 2020; Stephan et al., 2018). ASIC3 is potentially involved in nociception and mechanosensation and displays extensive co‐expression with CGRP in TG and DRG neurons (Ichikawa & Sugimoto, 2004; Papalampropoulou‐Tsiridou et al., 2020).…”

NGF-Induced Upregulation of CGRP in Orofacial Pain Induced by Tooth Movement Is Dependent on Atp6v0a1 and Vesicle Release

“…Orofacial pain was induced by ligating closed coil springs between incisors and molars in rats to mimic orofacial pain induced by orthodontic tooth movement, and this orofacial pain rat model has been well documented by previous studies [ 2 , 6 , 11 ]. Specifically, following general anesthesia with pentobarbital sodium (50 mg/kg), rats were placed in supine positions, and the closed coil springs were stretched and activated to deliver force (40 g).…”

“…As an important protein in the process of neurogenesis and neuron growth, nerve growth factor (NGF) plays an important role in orofacial pain modulation [ 9 , 10 ]. Our previous study revealed that the administration of NGF into trigeminal ganglia could exacerbate orofacial pain [ 11 ]. Recent studies have also proved that NGF has been associated with the upregulation of CGRP, leading to neuroinflammatory pain response [ 2 , 12 ].…”

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

“…In rodents, ASIC3 was shown to contribute to orthodontic pain [ 239 , 240 , 241 ], and recent data show that periodontal acidification (around pH 7.0) induced by tooth movement results in mechanical tooth pain hypersensitivity that was partially reversed by an injection of APETx2 in the periodontal tissue in rats [ 242 ]. A genome-wide association study suggests that a genetic variation in the ASIC2 gene could be significantly associated with severe gingival inflammation, linked to periodontitis [ 243 ].…”