**1. Introduction**

Fibromyalgia is a chronic clinical condition characterized by chronic widespread pain, fatigue, depression, and sleep disturbances [1–3]. It is widely distributed: 2–5.8% of the population of industrial countries are a ffected by it [4]. Although aspects of the pathophysiology are still unclear, evidence of involvement of neurotransmitter, genetics, autonomic nervous system (ANS) dysfunction, neuroendocrine dysfunctions, and cerebral psychophysiological abnormalities have been demonstrated [5,6]. Fibromyalgia is considered a non-inflammatory disorder stress-related with dysfunction of the hypothalamic-pituitary-adrenocortical axis [7–9]. Furthermore, changes in inflammatory actors [10,11], modified balance in anti- and pro-inflammatory cytokines [12,13], and

increases in toxic metabolites of lipid peroxidation and oxidative stress [14–16] have been detected. Recent evidences have shown that fibromyalgia syndrome involves the neuropathic pain condition [17]. Hyperalgesia and allodynia are common signs in fibromyalgia [18–20]. Sleep deprivation can produce these features [21], in conjunction with inflammation, mitochondrial dysfunction, and oxidative stress, with the result of peripheral nerve damage [22]. Functional brain-imaging studies have displayed compelling evidence for changes in the pain process in fibromyalgia correlating with patients' allodynia or hyperalgesia [23]. Treatment of fibromyalgia requires a pharmacological approach focused on all symptoms with an emphasis on pain. Several pieces of evidence indicate that melatonin can be useful and suitable in fibromyalgia treatment thanks to its di fferent properties [24–26]. It is a highly conserved indoleamine with chronobiological features [27]. Additionally, its anti-inflammatory, antidepressant, analgesic, and sedative activities have been reported [28–31]. To date, the pathophysiology of the syndrome also shows an important oxidative component [32]. It has long been shown that folic acid can improve the function of the immune system and has important antioxidant properties [33]. It exerts both indirect and direct antioxidant e ffects, such as protection against oxidative modification of low-density lipoproteins [34], free radical scavenging [35], and activation of cellular antioxidant defense [36,37]. Based on these findings, the aim of this study is to evaluate the e ffect of folic acid and melatonin administration on a fibromyalgia rat model and compare it with the single administrations of the two substances.
