title: Overdose of the histamine H₃ inverse agonist pitolisant increases thermal pain thresholds.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H(3) receptor-independent.
authors: Institute of Clinical Pharmacology, pharmazentrum frankfurt, ZAFES, Hospital of the Goethe-University Frankfurt, Theodor Stern Kai 7, Frankfurt, Germany.
authors: Dong Dong
authors: DD
authors: Zhang
authors: Marco
authors: M
authors: Sisignano
authors: Claus Dieter
authors: CD
authors: Schuh
authors: Kerstin
authors: K
authors: Sander
authors: Holger
authors: H
authors: Stark
authors: Klaus
authors: K
authors: Scholich
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D017442:Histamine Agonists / Q000633:toxicity*; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D006358:Hot Temperature; D007035:Hypothermia / Q000139:chemically induced; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D010146:Pain / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects*; D010880:Piperidines / Q000633:toxicity*; D011597:Psychomotor Performance / Q000187:drug effects
chemical_list: D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D010880:Piperidines; C516975:pitolisant; C115705:ciproxifan; D002118:Calcium