title: Seizure susceptibility alteration following reversible cholestasis in mice: Modulation by opioids and nitric oxide.
abstract: There is an increasing body of evidence that the central nervous system is affected by cholestatic liver disorders. Cholestasis has been shown to result in a decreased seizure propensity which is believed to be mediated by an increased opioidergic tone and nitric oxide (NO) signaling pathway. In this study, we used a reversible chemically-induced cholestasis model in mice to investigate the changes in seizure susceptibility. The cholestasis was induced by intragastric administration of alpha-naphthylisothiocyanate (ANIT) (100 mg/kg) or vehicle (corn oil). The threshold to generalized clonic seizures induced by timed intravenous infusion of pentylenetetrazole (PTZ) was used as an index of seizure propensity. The role of opioid receptors and NO pathway in the changes of seizure threshold, and the responsiveness to the anticonvulsant effect of opioid agonist, morphine, during and after the resolution of cholestasis was studied in this reversible paradigm of cholestatic disease. A significant increase in cholestasis-related biochemical markers as well as in clonic seizure threshold was observed; it was maximal at day 3 after cholestasis induction and slowly decreased to normal thereafter. Seizure threshold rise was inhibited by chronic administration of the opioid antagonist naltrexone or acute administration of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO production. Co-administration of subeffective doses of L-NAME and naltrexone showed an additive effect. Injection of an anticonvulsant dose of morphine on day 7 after cholestasis induction did not increase seizure threshold, suggestive of a downregulation of receptors even after cholestasis resolution. These data shows that ANIT-induced cholestasis leads to a reversible increased resistance to PTZ-induced seizures through an opioid/NO-mediated pathway, and is probably accompanied by downregulation of opioid receptors.
authors.affiliation: Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran, PO Box 13145-784, Tehran, Iran.
authors.forename: Taha
authors.initials: T
authors.lastname: Gholipour
authors.forename: Kiarash
authors.initials: K
authors.lastname: Riazi
authors.forename: Ali Reza
authors.initials: AR
authors.lastname: Noorian
authors.forename: Ali
authors.initials: A
authors.lastname: Jannati
authors.forename: Hooman
authors.initials: H
authors.lastname: Honar
authors.forename: Behzad
authors.initials: B
authors.lastname: Doratotaj
authors.forename: Hooman Hosseini
authors.initials: HH
authors.lastname: Nik
authors.forename: Ahmad
authors.initials: A
authors.lastname: Shariftabrizi
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000008:administration & dosage / Q000633:toxicity; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002779:Cholestasis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D003314:Corn Oil / Q000008:administration & dosage / Q000737:chemistry; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000633:toxicity; D011957:Receptors, Opioid / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D013997:Time Factors
chemical_list: D015415:Biomarkers; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009569:Nitric Oxide; D015058:1-Naphthylisothiocyanate; D009271:Naltrexone; D009020:Morphine; D003314:Corn Oil; D000469:Alkaline Phosphatase; D001663:Bilirubin; D019331:NG-Nitroarginine Methyl Ester; D010433:Pentylenetetrazole