Morphine modulates inducible nitric oxide synthase expression and reduces pulmonary oedema induced by a-naphthylthiourea Mustafa Comert a , Emine Yilmaz Sipahi b, T , Huseyin Ustun c , Fulden Isikdemir b , Gamze Numanoglu d , Figen Barut d , Hanife Altunkaya e , Yetkin Ozer e , Ferruh Niyazi Ayoglu f , Tunc Hakan Sipahi g , Ishak Ozel Tekin h , Z. Nur Banoglu b a Department of General Surgery, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey b Department of Pharmacology, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey c Department of Pathology, Ankara Hospital, Ankara, Turkey d Department of Pathology, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey e Department of Anaesthesiology, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey f Department of Public Health, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey g Department of Family Physician, Ankara, Turkey h Department of Immunology, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey Received 24 January 2005; accepted 28 January 2005 Available online 17 March 2005 Abstract This study was designed to investigate the possible participation of morphine in pulmonary oedema induced by a-naphthylthiourea (ANTU), which is a well-known noxious chemical agent in the lung. Injection of ANTU (15 mg/kg i.p.) produced pulmonary oedema as indicated by an increase in lung weight/body weight ratio and pleural effusion reaching a maximum within 4 h in rat. Administration of morphine prior to ANTU significantly inhibited to pulmonary oedema with a dose-dependent manner. The protective effect of morphine is prevented by peripheral opioid receptor antagonist, naloxone methiodide. ANTU-treated rats were shown positive by inducible nitric oxide synthase immunohistochemical staining. There was no staining in the control group. On the other hand, the degree of staining was markedly reduced in tissue sections by morphine. These results suggest that previous administration of subcutaneous morphine has preventive effect on ANTU-induced pulmonary inflammatory reaction and its effect mediated via peripheral opioid receptors. Application of naloxone with ANTU has no effect on the lung parameters indicating that endogenous opioids do not modulate ANTU-induced damage. D 2005 Elsevier B.V. All rights reserved. Keywords: a-Naphthylthiourea; Morphine; Naloxone methiodide; Pulmonary oedema; Inflammation 1. Introduction Alpha-naphthylthiourea is a chemical agent largely used as a rodenticide which produces a dose and time-dependent inflammatory reaction characterized by pulmonary oedema secondary to permeability changes in the lung micro- vasculature (Richter, 1952). Morphological studies with light and electron microscopy indicate that the capillary endothelial cell of the lung is the primary cellular target of ANTU toxicity (Cunningham and Hurley, 1972; Meyrick et al., 1972). Injury to the endothelium appears as blebbing and scalloping of the cell surface with eventual loss of the endothelial barrier. This loss of endothelial barrier integrity results in increased capillary permeability and the produc- tion of an interstitial and alveolar oedema (Pine et al., 1976). The exact mechanisms of ANTU on pulmonary tissue are not clearly demonstrated. It has been speculated that vasoactive substances originating from the pulmonary vascular bed and airways may contribute to the pulmonary 0014-2999/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.01.038 T Corresponding author. Zonguldak Karaelmas Universitesi, Tip Fakultesi Egitim Bloklari, Farmakoloji A.D., 67600 Kozlu-Zonguldak, Turkey. Tel.: +90 372 2610243; fax: +90 372 2610155. E-mail address: dresipahi@yahoo.com (E. Yilmaz Sipahi). European Journal of Pharmacology 511 (2005) 183– 189 www.elsevier.com/locate/ejphar