title: Elevation of pentylenetetrazole-induced seizure threshold in cholestatic mice: interaction between opioid and cannabinoid systems.
abstract: OBJECTIVE
  Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure.
  
  
  METHODS
  The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB(1) receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined.
  
  
  RESULTS
  Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level.
  
  
  CONCLUSIONS
  Both opioid and cannabinoid CB(1) receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.
authors.affiliation: Department of Pharmacology, Tehran Medical Unit, Islamic Azad University of Medical Sciences, Tehran, Iran.
authors.forename: Hamed
authors.initials: H
authors.lastname: Shafaroodi
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ghasemi
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001652:Bile Ducts / Q000601:surgery; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002779:Cholestasis / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008026:Ligation; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism*; D010433:Pentylenetetrazole; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D063385:Cannabinoid Receptor Modulators; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011957:Receptors, Opioid; C103505:AM 251; D009271:Naltrexone; D010433:Pentylenetetrazole