Crit Care Med. 2013 Jan;41(1):205-14. doi: 10.1097/CCM.0b013e31826767a8.
Opioid receptors control viral replication in the airways
Vahid Salimi 1, Marije P Hennus, Talat Mokhtari-Azad, Fazel Shokri, Riny Janssen, Hennie M Hodemaekers, Tomasz P Rygiel, Frank E J Coenjaerts, Linde Meyaard, Louis Bont
Objective: Opioids are frequently used during mechanical ventilation for severe viral infection in infancy. Opioid receptors have immunomodulatory properties, but nothing is known about their antiviral effects. We therefore aimed to investigate the role of opioid receptors in virus-induced airway inflammation.
Patients and interventions: Two single nucleotide polymorphisms in OPRM1 and OPRD1 were genotyped in 465 infants with severe respiratory syncytial virus infection and 930 control subjects. Subsequently, the mechanism by which opioid receptors affect clinical outcome in respiratory syncytial virus bronchiolitis was studied in BALB/c mice. Animals were injected daily with nalmefene, a nonselective opioid receptor antagonist, and infected by intranasal inoculation of respiratory syncytial virus 24 hrs after the first dose of nalmefene. The potential therapeutic effect of pharmaceutical opioids was studied using µ (DAMGO), κ (U50488), and Δ (DPDPE) opioid receptor agonists 48 hrs after infection.
Measurements and main results: In our human study, the A118G single nucleotide polymorphism rs1799971 was associated with respiratory syncytial virus disease severity (p = 0.015). In mice, nalmefene treatment increased viral titers and was associated with more pronounced weight loss. Increased viral replication was associated with increased levels of cytokines and chemokines in the bronchoalveolar lavage fluid, enhanced bronchoalveolar cellular influx, and exaggerated lung pathology. Pharmaceutical opioids, in particular DPDPE, did not affect viral replication. They did induce a decreased influx of neutrophils, but an increased influx of lymphocytes and monocytes into the bronchoalveolar lumen during respiratory syncytial virus infection.
Conclusions: Using a human study and an experimental model, we show that opioid receptor signaling has a potential beneficial role in the outcome of respiratory viral disease. We show that opioid receptor signaling is required to control respiratory syncytial virus replication and thereby to control disease severity. However, we also show that caution is required before using pharmaceutical opioids as anti-inflammatory or antiviral treatment of patients with viral respiratory infection.
Biochem Pharmacol. 2001 May 1;61(9):1145-51. doi: 10.1016/s0006-2952(01)00574-3.
Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes
P K Peterson 1, G Gekker, J R Lokensgard, J M Bidlack, A C Chang, X Fang, P S Portoghese
Synthetic kappa-opioid receptor (KOR) agonists have been shown to suppress HIV-1 expression in acutely infected macrophages. In the present study, we examined the effects of the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneaceamide methanesulfonate (U50,488) on HIV-1 expression in CD4+ lymphocytes, the main target cell of this virus. When U50,488 was added to activated CD4+ lymphocytes, HIV-1 expression was inhibited in a concentration- and time-dependent manner with maximal suppression (approximately 60%) at 10(-7) M U50,488. The KOR selective antagonist nor-binaltorphimine (nor-BNI) had no effect by itself on viral expression but blocked the antiviral property of U50,488, suggesting that U50,488 was acting via a KOR-related mechanism. Support for the involvement of KOR was provided by the findings that 34% of activated CD4+ lymphocytes were positive for KOR, using an immunofluorescence technique, and that seven additional synthetic KOR ligands also inhibited HIV-1 expression. The results of this study broaden understanding of the antiviral properties of KOR ligands to include cells outside of the nervous system and suggest a potential role for these agents in the treatment of HIV-1 infection.