N/OFQ modulates orofacial pain induced by tooth movement through CGRP-dependent pathways

Abstract

Background Nociceptin/orphanin FQ (N/OFQ) has been revealed to play bidirectional roles in orofacial pain modulation. Calcitonin gene-related peptide (CGRP) is a well-known pro-nociceptive molecule that participates in the modulation of orofacial pain. We aimed to determine the effects of N/OFQ on the modulation of orofacial pain and on the release of CGRP. Methods Orofacial pain model was established by ligating springs between incisors and molars in rats for the simulation of tooth movement. The expression level of N/OFQ was determined and pain level was scored in response to orofacial pain. Both agonist and antagonist of N/OFQ receptor were administered to examine their effects on pain and the expression of CGRP in trigeminal ganglia (TG). Moreover, gene therapy based on the overexpression of N/OFQ was delivered to validate the modulatory role of N/OFQ on pain and CGRP expression. Results Tooth movement elicited orofacial pain and an elevation in N/OFQ expression. N/OFQ exacerbated orofacial pain and upregulated CGRP expression in TG, while UFP-101 alleviated pain and downregulated CGRP expression. N/OFQ-based gene therapy was successful in overexpressing N/OFQ in TG, which resulted in pain exacerbation and elevation of CGRP expression in TG. Conclusions N/OFQ exacerbated orofacial pain possibly through upregulating CGRP.

The effect of physical interventions on pain control after orthodontic treatment: A systematic review and network meta-analysis

“…CGRP is a neuropeptide found in the periodontal tissue and is responsible for promoting pain after surgery [ 53 ]. Studies have focused on regulating CGRP through targets such as TRPV1 and nociceptin/orphanin FQ [ 54 ]. Evidence-based medical research has also shown that high-frequency vibrations can accelerate orthodontic tooth movement by promoting the differentiation of osteoblasts, fibroblasts, and osteoclasts and increasing bone remodeling; thereby accelerating the process [ 55 , 56 ].…”

Role of neuropeptides in orofacial pain: A literature review

“…Notably, unlike other members of the opioid family, nociceptin/orphanin FQ (N/OFQ) has been revealed to play bidirectional roles in the modulation of orofacial pain, exhibiting either pro-or anti-nociceptive effects. 45 Periodontal administration of UFP-101, a N/OFQ receptor antagonist, could alleviate orofacial pain induced by experimental tooth movement in rats, which suggested that periodontal N/OFQ receptors were involved in orofacial pain. 46 Subsequently, these investigators speculated that N/OFQ increased orofacial pain induced by tooth movement by upregulating CGRP.…”

“…46 Subsequently, these investigators speculated that N/OFQ increased orofacial pain induced by tooth movement by upregulating CGRP. 45…”

“…Periodontal administration of UFP‐101, a N/OFQ receptor antagonist, could alleviate orofacial pain induced by experimental tooth movement in rats, which suggested that periodontal N/OFQ receptors were involved in orofacial pain 46 . Subsequently, these investigators speculated that N/OFQ increased orofacial pain induced by tooth movement by upregulating CGRP 45 …”

Nociceptor mechanisms underlying pain and bone remodeling via orthodontic forces: toward no pain, big gain

“…Orthodontic tooth movement upregulates the P2X3 receptor in the TG, while an inhibitor of P2X3 reduces orthodontic pain-like behaviors in rats ( 62 ). Orthodontic tooth movement in rats upregulates the nociceptin/orphanin FQ-opioid receptor-like receptor pathway in the TG, which exacerbates pain-like behaviors and likely mediates P2X3 upregulation in TG neurons ( 122 , 123 ). Interestingly, the exposure of mice to static magnetic fields decreases orthodontic pain-like behaviors, accompanied by a decrease in the expression of P2X3 ( 124 ), supporting the roles of P2X3 in orthodontic pain.…”