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

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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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Abbreviations

DRG:

Dorsal root ganglions

H3 :

Histamine receptor 3

i.p.:

Intraperitoneal

i.th:

Intrathecal

PWL:

Paw withdrawal latency

SNI:

Spared nerve injury

TRP:

Transient receptor potential receptors

TRPV1:

Transient receptor potential vanilloid receptor 1

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Acknowledgments

This work was supported by DFG (German Research Association) grants SCHO817-2 and SCHO817-2, the LOEWE Lipid Signaling Forschungszentrum Frankfurt (LiFF), the LOEWE NeFF and the European COST Action BM0860.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, pharmazentrum frankfurt, ZAFES, Hospital of the Goethe-University Frankfurt, Theodor Stern Kai 7, Frankfurt, Germany

    Dong Dong Zhang, Marco Sisignano, Claus Dieter Schuh & Klaus Scholich

  2. Institute of Pharmaceutical Chemistry, ZAFES/LiFF/NeFF, Goethe University Frankfurt, Max von Laue Str. 9, Frankfurt, Germany

    Kerstin Sander & Holger Stark

Authors
  1. Dong Dong Zhang
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  2. Marco Sisignano
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Correspondence to Holger Stark or Klaus Scholich.

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Responsible Editor: Andras Falus.

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Zhang, D.D., Sisignano, M., Schuh, C.D. et al. Overdose of the histamine H3 inverse agonist pitolisant increases thermal pain thresholds. Inflamm. Res. 61, 1283–1291 (2012). https://doi.org/10.1007/s00011-012-0528-5

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  • DOI: https://doi.org/10.1007/s00011-012-0528-5

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