Morphine-induced Straub tail reaction in mice treated with serotonergic compounds

• Published in: European journal of pharmacology 2016-11, Vol.791, p.1-7
• Main Authors: Belozertseva, Irina V., Dravolina, Olga A., Tur, Margarita A., Semina, Marina G., Zvartau, Edwin E., Bespalov, Anton Yu
• Format: Article
• Language: English
• Subjects: 5-HT2 receptor; Animals; Cyproheptadine; Dose-Response Relationship, Drug; Drug Inverse Agonism; Kinetics; Locomotion - drug effects; Male; Mice; Morphine - pharmacology; Muscle Spasticity - chemically induced; Muscle Spasticity - diet therapy; Muscle Spasticity - drug therapy; Muscle Spasticity - physiopathology; Receptor, Serotonin, 5-HT2C - metabolism; SB206553; Serotonin 5-HT2 Receptor Agonists - pharmacology; Serotonin 5-HT2 Receptor Agonists - therapeutic use; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Serotonin 5-HT2 Receptor Antagonists - therapeutic use; Straub tail reaction; Transient spasticity
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.08.014

Constitutively active 5-HT2 receptors have been suggested to contribute to motoneuronal excitability, muscle spasms and spasticity. Accordingly, 5-HT2C receptor inverse agonists have been demonstrated in pilot experiments to reduce spasticity in animal model of spasticity and patients with spinal cord injuries. Thus, 5-HT2C receptor inverse agonists may represent a novel class of anti-spasticity agents justifying a search for compounds with robust 5-HT2C receptor inverse agonist activity either among the existing medications or via a dedicated drug discovery program. Morphine-induced Straub tail response in mice is regarded as a model of transient spasticity that may be suitable for supporting such drug discovery efforts. Subcutaneous injection of morphine (10–60mg/kg) induced a dose-dependent Straub tail reaction in male Swiss mice with maximum response obtained 15–30min after the morphine administration. When given prior to morphine, 5-HT2B/2C receptor inverse agonists cyproheptadine (1–10mg/kg, i.p.) and SB206553 (0.3–3mg/kg, i.p.) diminished Straub tail reaction dose-dependently without affecting spontaneous locomotor activity. In contrast, 5-HT2B/2C receptor antagonist methysergide (1–5.6mg/kg, i.p.) and 5-HT2C receptor antagonist SB242084 (1–5.6mg/kg, i.p.) as well as 5-HT2A receptor inverse agonist pimavanserin (1–10mg/kg, i.p.) had no appreciable effects on Straub tail response. Taken together, the findings indicate that constitutive activity of 5-HT2B/2C receptor may be involved in the mechanisms of morphine-induced spasticity. Thus, morphine-induced Straub tail response may be evaluated further as a candidate higher throughput test to identify 5-HT2C receptor inverse agonists with anti-spasticity effects in vivo.