1606 - 5-HT2C Receptor Agonists Attenuate Muscle Pain in a Rat Model of Fibromyalgia

Monday, November 7, 2011: 2:45 PM
W190a (McCormick Place West)
Shinichi Ogino, Mina Tsukamoto, Yukinori Nagakura, Tomonari Watabiki, Yasuaki Shimizu and Hiroyuki Ito, Astellas Pharma Inc., Tsukuba, Japan
Presentation Number: 1606

Background/Purpose: Fibromyalgia (FM) is a chronic disorder believed to involve the dysfunction of biogenic amine-mediated pain control and is characterized by widespread pain, muscle tenderness, and decreased pain threshold to pressure and other stimuli. Interruption of 5-hydroxytryptamine (5-HT) transmission, a main neurotransmitter in the descending pain inhibitory system, results in hypersensitivity of the spinal nociceptive neurons. 5-HT2C receptors are present in the dorsal horn of the spinal cord and mediate 5-HT-induced analgesia in animal pain models. Here, we examined the effects of several 5-HT2C receptor agonists on muscle hyperalgesia using the reserpine-induced FM model rats.

Method: Reserpine (1 mg/kg) was administered subcutaneously once daily for three consecutive days to male SD rats. Muscle pressure threshold of the gastrocnemius muscle was determined using the Randall-Selitto test, and extracellular 5-HT content in the spinal cord was measured using a microdialysis system. The effect of 5-HT2C (lorcaserin, vabicaserin, and YM348), 5-HT1A (buspirone), and 5-HT2A (TCB-2) agonists on muscle pressure threshold was evaluated 5 days after the final injection of reserpine. In addition, the effect of the 5-HT2C receptor selective antagonist SB242084 was examined by injecting the agent 15 min before the administration of lorcaserin.

Result: Reserpine treatment significantly reduced extracellular content of 5-HT in the spinal cord and the muscle pressure threshold in rats. Lorcaserin (1 and 3 mg/kg, p.o.), vabicaserin (1 and 3 mg/kg, s.c.), and YM348 (0.1 and 0.3 mg/kg, p.o.) dose-dependently and significantly attenuated the reserpine-induced decrease in muscle pressure threshold, while no effect was observed with either buspirone (10 mg/kg, i.p.) or TCB-2 (2 mg/kg, i.p.). The analgesic effect of lorcaserin was significantly reversed by pretreatment with SB242084.

Conclusion: Our findings indicate that 5-HT2C receptors play a critical role in pain transmission in the reserpine-induced muscle hyperalgesia and suggest the therapeutic potential of 5-HT2C receptor agonists in treating FM.

Keywords: 5-HT, animal models, fibromyalgia and pain

Disclosure: S. Ogino, Astellas Pharma Inc, 3 ; M. Tsukamoto, Astellas Pharma Inc, 3 ; Y. Nagakura, Astellas Pharma Inc, 3 ; T. Watabiki, Astellas Pharma Inc, 3 ; Y. Shimizu, Astellas Pharma Inc, 3 ; H. Ito, Astellas Pharma Inc, 3 .