Elsevier

Pharmacological Reports

Volume 62, Issue 1, January–February 2010, Pages 139-149
Pharmacological Reports

Local pulmonary opioid network in patients with lung cancer: a putative modulator of respiratory function

https://doi.org/10.1016/S1734-1140(10)70251-6Get rights and content

Abstract

Recently, there has been growing interest in the opioid regulation of physiological respiratory function. However, evidence for a local opioid network that includes endogenous opioid peptides and their receptors is scarce. Tissue samples from patients with lung cancer were examined by immunohistochemistry to identify the components of the opioid network: β-endorphin (END); its precursor, proopiomelanocortin (POMC); the key processing enzymes prohormone convertase 1 and 2; carboxypeptidase E; and END’s corresponding opioid receptor, the u-opioid receptor (MOR). Additionally, we tested pulmonary function parameters in a patient with advanced lung cancer after inhalation of nebulized morphine. Confocal immunofluorescence microscopy revealed that the opioid precursor POMC colocalizes with its active peptide END, key processing enzymes and MOR in alveolar macrophages, sub-mucosal glands, cancerous cells, and pulmonary neuroendocrine cells within the bronchial epithelium. In addition, MOR was identified on sensory nerve endings within the bronchial epithelium. Furthermore, nebulized morphine improved pulmonary function parameters in advanced lung cancer. These findings provide evidence of a local opioid network in functionally important anatomical structures of the respiratory system; this network consists of all the machinery required for POMC processing into active peptides, such as END, and contains the receptors for END. Our findings indicate a need for further clinical trials to elucidate the modulatory function of peripheral endogenous opioids in the human lung.

Introduction

Recently, there has been growing interest in the local opioid regulation of the tracheobronchial mucociliary clearance [31, 38] and the smooth muscle broncho-constrictive response of the lung [3, 40]. Inhalation of β-endorphin (END) modulates the mucociliary clearance in dogs in a naloxone-reversible manner [38]. Opioid peptides also inhibit bronchial smooth muscle contractions induced by parasympathetic nerve stimulation; in turn, local naloxone antagonizes this inhibition suggesting an opioid receptor specific mechanism [15, 31]. Some clinical trials have indicated that patients might benefit from inhalation of nebulized opioids, but other clinical trials have not [18]. However, particularly terminally ill patients, such as those with lung cancer or end stage lung disease, seem to have significant relief from their dyspnea after treatment with nebulized opioids [8, 11, 13]. More recently, Mahler et al. demonstrated that endogenous opioids al-levate dyspnea during treadmill exercise in patients with chronic obstructive pulmonary disease [21].

Opioid peptides, their precursors and their receptors are located within the central nervous system. However, similar to other non-neuronal tissues, such as the gut, spleen, and skin [25, 27, 37], lung or lung cancer cell lines also contain some components of the opioid system. There is evidence for END in cell lines from human lung cancer [22, 32] and for opioid receptor binding sites in both human lung [5, 9] and lung carcinoma cell lines [22]. However, it is unknown if these components of the opioid system associate with functionally important anatomical structures of the respiratory system, such as submucosal bronchial glands, pulmonary neuroendocrine cells (PNECs), and the nerve fibers ofthe bronchial epithelium.

Posttranslational processing of proopiomelano-cortin (POMC) into the functionally active peptide END requires key enzymes such as carboxypeptidase E (CPE) and prohormone convertase 1 (PC1) and 2 (PC2) [4, 20, 27]. In contrast with the extensively studied, classical posttranslational processing of POMC in the pituitary gland [35], little is known about opioid peptide localization and processing within the human lung.

Because of the increasing interest in the opioid system of the lung, we systematically examined different areas of lung tissue from lung cancer patients for the expression of the precursor POMC; its processing enzymes PC1, PC2, and CPE; the POMC-derived active peptide END; and END’s corresponding opioid receptor (µ-opioid receptor, MOR). To illustrate local opioid effects, particularly in a terminally ill patient with lung cancer, we examined pulmonary function parameters after the inhalation of nebulized morphine. From these experiments, we hoped to provide a comprehensive neuroanatomical basis for a local opioid network regulating respiratory functions in the human lung.

Section snippets

Patients and preparation of human lung tissue

The study followed the International Guidelines of Declaration of Helsinki (World Medical Association: http://www.wma.net) and was approved by the Ethics Committee of the Nicolaus Copernicus University in Toruń, Poland. Human lung tissue samples were obtained from 16 lung cancer patients undergoing lobec-tomy or pneumectomy at the Department of Thoracic Surgery and Lung Disease of the Oncology Center in Bydgoszcz, Poland (Tab. 1). All patients were informed of the purpose of the study and gave

Anatomical and histological identification of END-IR cells in different areas of human lung tissue

Light microscope pictures with END immunoreactiv-ity showed END-IR cells within the anatomical and histological structure of human lung tissue. END im-munoreactivity was observed in sparse solitary cells within the bronchial epithelium (Fig. 1A), in alveolar macrophage-like cells accumulating within the alveolar lumen (Fig. 1B), and in cancerous cells infiltrating the lung tissue (Fig. 1C). There was no significant im-munoreactivity without the primary antibody or with an antibody against END

Discussion

Using a systematic approach, we were able to demonstrate within the lung tissue of lung cancer patients an endogenous opioid network that contained the essential components required for END synthesis and processing and contained the opioid receptors for END. Specifically, we showed the following: 1) identification of END-IR cells within different anatomical and histological structures of the human lung; 2) colocal-ization of the opioid precursor POMC with END, PC1, PC2 and CPE within alveolar

Acknowledgments

We are gratefulto Mrs. Ute Oedekoven’s for technicalassistance, Dr. Jan Sir for his contribution in microscopy, and Ms. Marzena Sykutera for her help in tissue preparation. We gratefully acknowledge the gift of antibodies and recombinant antigens from Drs. NG Seidah, Quebec, Canada; DF Steiner, University of Chicago, IL; and N Birch, University of Auckland, New Zealand (anti-PCI, anti-PC2, recombinant PC1 and PC2); Drs. Y Peng Loh and L Fricker, Albert Einstein College, NY [anti-CPE and

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    These authors contributed equally to this work.

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