Overdose of the histamine H3 inverse agonist pitolisant increases thermal pain thresholds


Pitolisant (BF2.649) is a selective inverse agonist for the histamine H3 receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H3-ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models. Behavioral effects of pitolisant and the structural different H3 receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain. Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions. 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. The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H3 receptor-independent.

DOI: 10.1007/s00011-012-0528-5

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@article{Zhang2012OverdoseOT, title={Overdose of the histamine H3 inverse agonist pitolisant increases thermal pain thresholds}, author={Dong Dong Zhang and Marco Sisignano and Claus Dieter Schuh and Kerstin Sander and Holger Stark and Klaus Scholich}, journal={Inflammation Research}, year={2012}, volume={61}, pages={1283-1291} }