Melatonin induces a state-dependent analgesic effect, but not after chronic administration in rats

Introduction: Temporomandibular disorders are the primary source of nonodontogenic orofacial pain, affecting the patients' quality of life.Pharmacological interventions, including opioids, nonsteroidal anti-inflammatories, steroids, and immunosuppressant drugs, have shown adverse effects, limiting their use.This study aimed to investigate the impact of acute and repeated administration of morphine and/or melatonin on pain thresholds and physiological markers modulated by chronic pain and treatments in a temporomandibular joint arthritis (TMJA) model.Methods: Fifty-nine male Wistar rats (⩬250 g) were randomly assigned to two groups, receiving an intra-temporomandibular joint injection of Complete Freund's Adjuvant (CFA, 1 mg/ml) or saline.After 14 days, treatment with melatonin (50 mg/kg/i.p.) and/or morphine (5 mg/kg/s.c.) was carried out for 8 days.The facial von Frey test was employed to assess mechanical allodynia on experimental days 0 (baseline), 15, and 22.At the end of the protocol, rats were euthanized, and structures (cerebral cortex, pons, and spinal cord) were dissected to determine the levels of BDNF (brain-derived neurotrophic factor), IL-10 (interleukin-10), and TNF-α (tumor necrosis factor alpha).Results: The TMJA group presented facial mechanical allodynia at D15, but not at D22. Melatonin and morphine induced analgesia at D15.The TMJA model increased spinal cord IL-10 and pontine BDNF levels, whereas melatonin decreased pontine BDNF levels and joint inflammation.Conclusion: Morphine and melatonin exhibited acute analgesic effects, yet melatonin failed to maintain the analgesic effect after multiple doses in the TMJA groups.