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Inflammation Research

Erschienen in:

01.11.2012 | Original Research Paper

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

verfasst von: Dong Dong Zhang, Marco Sisignano, Claus Dieter Schuh, Kerstin Sander, Holger Stark, Klaus Scholich

Erschienen in: Inflammation Research | Ausgabe 11/2012

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Abstract

Objective and design

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.

Materials and treatments

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.

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 H₃ receptor-independent.

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Titel: Overdose of the histamine H3 inverse agonist pitolisant increases thermal pain thresholds
verfasst von: Dong Dong Zhang
Marco Sisignano
Claus Dieter Schuh
Kerstin Sander
Holger Stark
Klaus Scholich
Publikationsdatum: 01.11.2012
Verlag: SP Birkhäuser Verlag Basel
Erschienen in: Inflammation Research / Ausgabe 11/2012
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-012-0528-5

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Abstract

Objective and design

Materials and treatments

Methods

Results

Conclusion

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