Melatonin Abates TMJOA Chronic Pain by MT2R in Trigeminal Ganglion Neurons

Abstract

Temporomandibular joint osteoarthritis (TMJOA) is one of the most common diseases causing chronic pain in the oral and maxillofacial region. So far, there are few ways to relieve the pain of TMJOA. Melatonin (MT) has a good analgesic effect in many diseases, including fibromyalgia, neuropathic pain, chronic headache, and burn pain, with very low acute toxicity and side effects. This study was to investigate the role and mechanism of MT in TMJOA chronic pain. In rats TMJOA chronic pain occurred at day 14 after an intra–temporomandibular joint injection of monosodium iodoacetate, which we previously reported. The enzyme-linked immunosorbent assay results showed that MT levels were higher in the synovial fluid from patients and rats with TMJOA as compared with those from control. Fluorescent retrograde tracing (Dil) identified that upregulation of MT type 2 receptor (MT2R) in trigeminal ganglion (TG) neurons innervating rat temporomandibular joints was accompanied by TMJOA chronic pain. Nociceptive behavior as assessed by von Frey and the Rat Grimace Scale demonstrated that exogenous administration of MT relieved chronic pain in TMJOA rats, whereas blocking MT2R with 4P-PDOT reversed the analgesic effect of MT. Immunofluorescence analysis also confirmed that MT inhibited CGRP and IB4 expression of TG neurons, and this inhibition was reversed by administering the MT2R antagonist in TMJOA rats. By using Fluo-3 AM-based calcium imaging in vitro, MT elicited calcium transients in Dil+ TG neurons, which were significantly abolished by 4P-PDOT. Collectively, this study suggested that MT relieves the TMJOA chronic pain of rats through downregulation of sensitized CGRP+ and IB4+ neurons in TG via MT2R. This will be helpful for health care professionals utilizing MT as an option against TMJOA chronic pain.