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

Abstract

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.

• Authors: Dong Dong Zhang, Marco Sisignano, Claus Dieter Schuh, Kerstin Sander, Holger Stark, Klaus Scholich
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 61 Issue 11 Pg. 1283-91 (Nov 2012) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 22820944 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histamine Agonists
• Histamine H3 Antagonists
• Imidazoles
• Piperidines
• pitolisant
• ciproxifan
• Calcium

Topics

• Animals
• Behavior, Animal (drug effects)
• Calcium (metabolism)
• Cells, Cultured
• Ganglia, Spinal (drug effects, metabolism)
• Histamine Agonists (toxicity)
• Histamine H3 Antagonists (pharmacology)
• Hot Temperature
• Hypothermia (chemically induced)
• Imidazoles (pharmacology)
• Mice
• Pain (physiopathology)
• Pain Threshold (drug effects)
• Piperidines (toxicity)
• Psychomotor Performance (drug effects)