Laboratory Investigations

Opioid Receptors Control Viral Replication in the Airways*

Salimi, Vahid PhD¹; Hennus, Marije P. MD²; Mokhtari-Azad, Talat PhD¹; Shokri, Fazel PhD³; Janssen, Riny PhD⁴; Hodemaekers, Hennie M. BAppSc⁴; Rygiel, Tomasz P. PhD⁵; Coenjaerts, Frank E. J. PhD⁶; Meyaard, Linde PhD⁵; Bont, Louis MD, PhD^2,5

Author Information

¹ Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

² Department of Pediatric Intensive Care, Wilhelmina Children’s Hospital Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.

³ Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

⁴ Laboratory for Health Protection Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

⁵ Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

⁶ Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.

*See also p. 361.

Supported, in part, by Tehran University of Medical Sciences (132/9591) and by the Association for International Cancer Research (AICR 07-008) (Dr. Rygiel). The European Federation of Immunological Societies and European Society for Paediatric Infectious Diseases supported Dr. Salimi to be trained at Florence University and Utrecht University.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Critical Care Medicine 41(1):p 205-214, January 2013. | DOI: 10.1097/CCM.0b013e31826767a8

Abstract

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.