OBJECTIVE AND DESIGN: Pitolisant (BF2.649) is a selective inverse agonist for the histamine H(3) receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H(3)-ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models. MATERIALS AND TREATMENTS: Behavioral effects of pitolisant and the structural different H(3) receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain. METHODS: Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions. RESULTS: Clinically relevant doses of pitolisant (10 mg/kg) had no relevant effect on mechanical or thermal pain thresholds in all animal models. Higher doses (50 mg/kg) dramatically increased thermal but not mechanical pain thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In peripheral sensory neurons high concentrations of pitolisant (30-500 μM), but not ciproxifan, partially inhibited calcium increases induced by capsaicin, a selective activator of transient receptor potential vanilloid receptor 1 (TRPV1). High doses of pitolisant induced a strong hypothermia. CONCLUSION: The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H(3) receptor-independent.
OBJECTIVE AND DESIGN: Pitolisant (BF2.649) is a selective inverse agonist for the histamine H(3) receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H(3)-ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models. MATERIALS AND TREATMENTS: Behavioral effects of pitolisant and the structural different H(3) receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain. METHODS: Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions. RESULTS: Clinically relevant doses of pitolisant (10 mg/kg) had no relevant effect on mechanical or thermal pain thresholds in all animal models. Higher doses (50 mg/kg) dramatically increased thermal but not mechanical pain thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In peripheral sensory neurons high concentrations of pitolisant (30-500 μM), but not ciproxifan, partially inhibited calcium increases induced by capsaicin, a selective activator of transient receptor potential vanilloid receptor 1 (TRPV1). High doses of pitolisant induced a strong hypothermia. CONCLUSION: The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H(3) receptor-independent.
Authors: Andrew D Medhurst; Michael A Briggs; Gordon Bruton; Andrew R Calver; Iain Chessell; Barry Crook; John B Davis; Robert P Davis; Andrew G Foley; Teresa Heslop; Warren D Hirst; Stephen J Medhurst; Sandrine Ociepka; Alison Ray; Ciaran M Regan; Becky Sargent; Joanne Schogger; Tania O Stean; Brenda K Trail; Neil Upton; Trevor White; Barry Orlek; David M Wilson Journal: Biochem Pharmacol Date: 2007-01-07 Impact factor: 5.858
Authors: K Rossbach; C Nassenstein; M Gschwandtner; D Schnell; K Sander; R Seifert; H Stark; M Kietzmann; W Bäumer Journal: Neuroscience Date: 2011-06-13 Impact factor: 3.590
Authors: G Meier; J Apelt; U Reichert; S Grassmann; X Ligneau; S Elz; F Leurquin; C R Ganellin; J C Schwartz; W Schunack; H Stark Journal: Eur J Pharm Sci Date: 2001-06 Impact factor: 4.384
Authors: Stephen J Medhurst; Sue D Collins; Andy Billinton; Sharon Bingham; Robert G Dalziel; Amanda Brass; Jennifer C Roberts; Andrew D Medhurst; Iain P Chessell Journal: Pain Date: 2007-12-31 Impact factor: 6.961
Authors: Narender R Gavva; Anthony W Bannon; Sekhar Surapaneni; David N Hovland; Sonya G Lehto; Anu Gore; Todd Juan; Hong Deng; Bora Han; Lana Klionsky; Rongzhen Kuang; April Le; Rami Tamir; Jue Wang; Brad Youngblood; Dawn Zhu; Mark H Norman; Ella Magal; James J S Treanor; Jean-Claude Louis Journal: J Neurosci Date: 2007-03-28 Impact factor: 6.167