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.