title: Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway.
abstract: Morphine is a μ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20μM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5μM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS.
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Sattar
authors.initials: S
authors.lastname: Ostadhadi
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Faiza
authors.initials: F
authors.lastname: Mumtaz
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; UQ Center for Clinical Research, Department of Molecular Pathology, University of Queensland, Australia.
authors.forename: Majid
authors.initials: M
authors.lastname: Momeny
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Farima
authors.initials: F
authors.lastname: Moghaddaskho
authors.affiliation: Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Hassanipour
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shahram
authors.initials: S
authors.lastname: Ejtemaei-Mehr
authors.affiliation: Department of Pharmacology, School of Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpour@yahoo.com.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005786:Gene Expression Regulation; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D013792:Thalidomide; D009020:Morphine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II
keywords: Antinociception; Mice; Morphine; Nitric oxide; Thalidomide; Tolerance