title: Opioid receptors control viral replication in the airways.
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.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Vahid
authors.initials: V
authors.lastname: Salimi
authors.forename: Marije P
authors.initials: MP
authors.lastname: Hennus
authors.forename: Talat
authors.initials: T
authors.lastname: Mokhtari-Azad
authors.forename: Fazel
authors.initials: F
authors.lastname: Shokri
authors.forename: Riny
authors.initials: R
authors.lastname: Janssen
authors.forename: Hennie M
authors.initials: HM
authors.lastname: Hodemaekers
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Rygiel
authors.forename: Frank E J
authors.initials: FE
authors.lastname: Coenjaerts
authors.forename: Linde
authors.initials: L
authors.lastname: Meyaard
authors.forename: Louis
authors.initials: L
authors.lastname: Bont
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001988:Bronchiolitis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000821:virology*; D016022:Case-Control Studies; D018925:Chemokines / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011957:Receptors, Opioid / Q000235:genetics* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012121:Respiration, Artificial; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000821:virology*; D012137:Respiratory System / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D018925:Chemokines; D015850:Interleukin-6; D009292:Narcotic Antagonists; C529706:OPRD1 protein, human; C485764:OPRM1 protein, human; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C038981:nalmefene