Blocking μ-opioid receptor by naltrexone exaggerates oxidative stress and airway inflammation via the MAPkinase pathway in a murine model of asthma.

Opioids regulate various physiological and pathophysiological functions, including cell proliferation, immune function, obesity, and neurodegenerative disorders. They have been used for centuries as a treatment for severe pain, binding to opioid receptors a specific G protein-coupled receptor. Common opioids, like β-endorphin, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), and dynorphins, have analgesic effects. The use of a potent antagonist, like naltrexone hydrochloride, to block the effects of mu Opioid Receptor (μOR) may result in the withdrawal of physiological effects and could potentially impact immune responses in many diseases including respiratory disease. Asthma is a respiratory disease characterized by airway hyperresponsiveness, inflammation, bronchoconstriction, chest tightness, stress generation and release of various cytokines. Airway inflammation leads recruitment and activation of immune cells releasing mediators, including opioids, which may modulate inflammatory response by binding to their respective receptors. The study aims to explore the role of μOR antagonist (naltrexone) in regulating asthma pathophysiology, as the regulation of immune and inflammatory responses in asthma remains unclear. Balb/c mice were sensitized intranasally by 1% TDI and challenged with 2.5% TDI. Naltrexone hydrochloride (1 mg/kg body weight) was administered through intraperitoneal route 1 h before TDI induction. Blocking μOR by naltrexone exacerbates airway inflammation by recruiting inflammatory cells (lymphocytes and neutrophils), enhancing intracellular Reactive oxygen species in bronchoalveolar lavage fluid (BALF), and inflammatory mediator (histamine, Eosinophil peroxidase and neutrophil elastase) in lungs. Naltrexone administration modulated inflammatory cytokines (TNF-α, IL-4, IL-5, IL-6, IL-10, and IL-17A), and enhanced IgE and CRP levels. Naltrexone administration also increased the expression of NF-κB, and phosphorylated p-P38, p-Erk, p-JNK and NF-κB by inhibiting the μOR. Docking study revealed good binding affinity of naltrexone with μOR compared to δ and κ receptors. In future it might elucidate potential therapeutic against many respiratory pathological disorders. In conclusion, μOR blocking by naltrexone regulates and implicates inflammation, bronchoconstriction, and lung physiology.