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Published on: February 13, 2018
Overdose of the histamine H₃ inverse agonist pitolisant increases thermal pain thresholds
Dong Dong Zhang1, Marco Sisignano, Claus Dieter Schuh
1Institute of Clinical Pharmacology, pharmazentrum frankfurt, ZAFES, Hospital of the Goethe-University Frankfurt, Theodor Stern Kai 7, Frankfurt, Germany.
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.
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