Fibromyalgia is a prevalent musculoskeletal disorder characterized by chronic widespread pain that significantly reduces quality of life in patients. Due to the lack of consistently effective treatment, the development of improved therapies for treating fibromyalgia is necessary. As dysfunction of serotonergic analgesic control appears to be involved in the pathophysiology of fibromyalgia, the present study explored the potential of 5-HT2C receptor agonists as novel therapies for treating this disease. Three 5-HT2C receptor agonists (lorcaserin, vabicaserin and YM348) that have been suggested to be useful in the treatment of several central nervous system diseases, including obesity and schizophrenia, were used. The effect of systemic administration of these agents on the muscular hyperalgesia that develops in the reserpine-induced myalgia (RIM) rat, a putative animal model of fibromyalgia, was investigated. RIM rats exhibited decreased muscle pressure thresholds. Microdialysis experiments showed that the concentration of serotonin (5-HT) in the spinal cord of RIM rats was significantly lower than that of controls. Lorcaserin (0.3–3 mg/kg p.o.), vabicaserin (0.3–3 mg/kg s.c.) and YM348 (0.03–0.3 mg/kg p.o.) recovered the muscle pressure threshold. The effect of lorcaserin was reversed by the pretreatment with SB242084, a 5-HT2C receptor antagonist. Our findings demonstrate that 5-HT2C receptors play a critical role in muscular hyperalgesia in RIM rats and suggest that 5-HT2C receptor agonists have therapeutic potential for treating chronic pain in patients with fibromyalgia although clinical extrapolation remains to be a future challenge.