**Melatonin Plus Folic Acid Treatment Ameliorates Reserpine-Induced Fibromyalgia: An Evaluation of Pain, Oxidative Stress, and Inflammation**

**Roberta Fusco 1,**†**, Rosalba Siracusa 1,**†**, Ramona D'Amico 1,**†**, Alessio Filippo Peritore 1, Marika Cordaro 1, Enrico Gugliandolo 1, Rosalia Crupi 1, Daniela Impellizzeri 1,\*, Salvatore Cuzzocrea 1,2,\* and Rosanna Di Paola 1**


Received: 24 October 2019; Accepted: 5 December 2019; Published: 6 December 2019

**Abstract:** Background: Fibromyalgia is a chronic condition characterized by increased sensory perception of pain, neuropathic/neurodegenerative modifications, oxidative, and nitrosative stress. An appropriate therapy is hard to find, and the currently used treatments are able to target only one of these aspects. Methods: The aim of this study is to investigate the beneficial e ffects of melatonin plus folic acid administration in a rat model of reserpine-induced fibromyalgia. Sprague–Dawley male rats were injected with 1 mg/kg of reserpine for three consecutive days and later administered with melatonin, folic acid, or both for twenty-one days. Results: Administration of reserpine led to a significant decrease in the nociceptive threshold as well as a significant increase in depressive-like symptoms. These behavioral changes were accompanied by increased oxidative and nitrosative stress. Lipid peroxidation was significantly increased, as well as nitrotyrosine and PARP expression, while superoxide dismutase, nonprotein thiols, and catalase were significantly decreased. Endogenously produced oxidants species are responsible for mast cell infiltration, increased expression pro-inflammatory mediators, and microglia activation. Conclusion: Melatonin plus acid folic administration is able to ameliorate the behavioral defects, oxidative and nitrosative stress, mast cell infiltration, inflammatory mediators overexpression, and microglia activation induced by reserpine injection with more e fficacy than their separate administration.

**Keywords:** fibromyalgia; oxidative stress; pain
