Thalidomide attenuates the development and expression of antinociceptive tolerance to mu-opioid agonist morphine through L-arginine-iNOS and nitric oxide pathway

[Speaker] Muhammad Imran Khan:1
[Co-author] Vahid Nikoui:2, Jamal Ahmad:3, Bashir Ahmad:3, Amir Rashidian:4, Ahmad-Reza Dehpour:4,5
1:Department of Pharmacy, Kohat University of Science and Technology, 26000 Kohat, KPK, Pakistan, 2:Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran, 3:Khyber Medical University, 28100, KPK, Pakistan, 4:Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, 5:Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

Background: Morphine is a mu-opioid analgesic drug, which is used in 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.
Methods: Male mice after induction of morphine antinociceptive tolerance received thalidomide and tested by hot plate and tail flick tests as well as cell culture, cell viability assay, and NOS gene expression analysis by quantitative reverse transcription-PCR (qRT-PCR).
Results: When thalidomide was administered in a dose of 17.5 mg/kg before each dose of morphine chronically for 5 days, it prevented the development of antinociceptive tolerance. In addition, a single dose of thalidomide (20 mg/kg) attenuated the expression phase of antinociceptive tolerance (P<0.05). The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor, 2 mg/kg) or aminoguanidine (selective inducible NOS inhibitor, 50 mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5 mg/kg) or aminoguanidine (100 mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor, 10 mg/kg) in developmental phase or 20 mg/kg in expression phase also progressively increased the pain threshold (P<0.05). In addition, thalidomide (20 mM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5 mM) in T98G cell line (P<0.05).
Conclusions: 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.

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