Evidence for the involvement of nitric oxide in cholestasis-induced itch associated response in mice.
Cholestasis is a major systemic disorder associated with distressing pruritus (itch). Nitric oxide (NO) is a neurotransmitter, assumed to be involved in pruritus. Based on over-production of NO in cholestatic liver diseases, this project aimed to investigate involvement of NO in cholestasis-related itch in mice. To achieve this, cholestasis was induced by bile duct ligation (BDL). Our results showed that BDL mice elicited significant itch on fifth and seventh day after the procedure. This scratching behavior was inhibited by intraperitoneal (IP) treatment of mice with non-selective NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME; 3mg/kg) and inducible NOS (iNOS) inhibitor aminoguanidine (AG; 100mg/kg). The inhibitory effects of l-NAME and AG were reversed by pretreatment with l-arginine (100mg/kg). Administration of l-NAME, AG and l-arginine per se, in BDL and SHAM mice did not produce scratching behaviors. In addition, intradermal injection of l-arginine at dose of 300 nmol/site significantly increased itch in BDL mice. Furthermore, nitrite levels in skin and serum of BDL animals significantly increased after 7 d of operation and administration of NOS inhibitors decreased this enhancement. l-arginine injection reversed the effects of NOS inhibitors on reduction of nitrite levels in the skin and serum of BDL mice. Finally, cutaneous iNOS expression increased in BDL mice 7 d after surgery. Taken together, our study showed for the first time that BDL, as a model of acute cholestasis in rodents, induces NO over-production by activating NOS enzymes, especially iNOS, which contribute to pruritus.
Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Sattar
S
Ostadhadi
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Arash
A
Foroutan
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Majid
M
Momeny
Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Abbas
A
Norouzi-Javidan
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
Ehsan
E
Azimi
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Nastaran
N
Kordjazy
Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpoura@sina.tums.ac.ir.
Ahmad Reza
AR
Dehpour
D000818:Animals; D002779:Cholestasis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011537:Pruritus / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
Cholestasis; Inducible nitric oxide synthase (iNOS); Itch; Mice; Nitric oxide (NO)