Systemic administration of 5-HT_2C receptor agonists attenuates muscular hyperalgesia in reserpine-induced myalgia model

Highlights

• Fibromyalgia reduces quality of life in patients by causing chronic pain.

• Reserpine-induced myalgia rat develops fibromyalgia-like muscular hyperalgesia.

• Systemic administration of 5-HT_2C receptor agonists relieves the hyperalgesia.

• 5-HT_2C receptor agonists have therapeutic potential for fibromyalgia.

Abstract

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-HT_2C receptor agonists as novel therapies for treating this disease. Three 5-HT_2C 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-HT_2C receptor antagonist. Our findings demonstrate that 5-HT_2C receptors play a critical role in muscular hyperalgesia in RIM rats and suggest that 5-HT_2C receptor agonists have therapeutic potential for treating chronic pain in patients with fibromyalgia although clinical extrapolation remains to be a future challenge.

Introduction

Fibromyalgia is a prevalent musculoskeletal syndrome characterized by widespread chronic pain. Although the details of pathophysiology remain to be elucidated, evidence suggests that dysfunction of serotonin (5-HT)-mediated pain control may be involved (Russell et al., 1992b, Wolfe et al., 1997). 5-HT is an endogenous transmitter in the descending analgesic neural pathway, which originates in raphe nuclei in the brain stem and projects to the spinal cord (Roberts, 1984). Spinal cord injury-induced nociceptive hypersensitivity is associated with interruption of the serotonergic inhibitory system in rats (Horiuchi et al., 2003). Dysfunction of the serotonergic inhibitory pathway following exposure to intermittent cold stress leads to chronic hyperalgesia in mice (Nishiyori et al., 2010). Intriguingly, the concentration of 5-HT in cerebrospinal fluid is significantly lower in fibromyalgia patients than control subjects, suggesting interruption of the descending analgesic neural pathway in fibromyalgia patients (Russell et al., 1992b).

Although multiple 5-HT receptor subtypes have been characterized in the central nervous system (CNS), five types of 5-HT receptors (5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄ and 5-HT₇), each with several subtypes, have been identified in the spinal cord (Doly et al., 2005, Fonseca et al., 2001, Hoyer et al., 1994, Kidd et al., 1993, Marlier et al., 1991). Some subtypes including 5-HT_1A and 5-HT₇ seem to have an inhibitory role in the pain transmission, while 5-HT₃ subtype has a facilitatory role (Bardin, 2011). Meanwhile, the activation of 5-HT_2C receptors in the spinal cord results in significant analgesic efficacy in several animal pain models. For example, the anti-nociceptive effect of intraperitoneally applied m-chlorophenylpiperazine, a 5-HT₂ receptor agonist (Porter et al., 1999), is abolished by intrathecal administration of 5-HT_2C receptor antagonists in hot-plate and tail-flick tests in mice (Chojnacka-Wójcik et al., 1994). Intrathecal injection of 5-HT_2C receptor agonists also has marked antiallodynic effects in rat models of neuropathic pain (Obata et al., 2004, Nakai et al., 2010). Currently, several 5-HT_2C receptor agonists are being developed for the treatment of CNS-associated symptoms other than chronic pain. For example, lorcaserin is a selective 5-HT_2C receptor agonist over other 5-HT receptor subtypes showing in vitro Ki values of 15 nM for 5-HT_2C, 112 nM for 5-HT_2A and 174 nM for 5-HT_2B (Thomsen et al., 2008)_. It yielded weight loss in a randomized clinical trial in obese and overweight adults (Fidler et al., 2011) or type-2 diabetic patients (O'Neil et al., 2012). YM348 potently and selectively activates 5-HT_2C receptor with Ki values of 0.89, 13 and 2.5 nM for 5-HT_2C, 5-HT_2A and 5-HT_2B receptor, respectively (Kimura et al., 2004), while vabicaserin shows Ki values of 3–22 nM for 5-HT_2C receptor (Dunlop et al., 2011). YM348 has shown potent anti-obese efficacy in preclinical studies (Hayashi et al., 2004), while vabicaserin appears to have antipsychotic potential (Hovelsø et al., 2011). The analgesic potential of these 5-HT_2C receptor agonists, however, has not been determined in either animal models or patients.

The purpose of the present study was to assess the analgesic efficacy of lorcaserin, vabicaserin and YM348 by systemic administration in the reserpine-induced myalgia (RIM) rat which meets validities as an animal model of fibromyalgia (Nagakura et al., 2009, Nagakura et al., 2012). RIM rat develops fibromyalgia-like symptoms including long-lasting muscle hyperalgesia, chronic cutaneous tactile allodynia (face validity). Then, dysfunction of biogenic amine-mediated analgesic control in the central nervous system could underlie the fibromyalgia-like symptoms in RIM rat while deficit in endogenous CNS pain control system is demonstrated in fibromyalgia patients (construct validity). Furthermore, pregabalin and duloxetine, which have been approved for the treatment of fibromyalgia-associated pain, significantly attenuate muscle hyperalgesia in RIM rat (predictive validity). Namely, the current study investigates whether 5-HT_2C receptor agonists have therapeutic potential for chronic pain symptoms, particularly fibromyalgia.