title: Effect of increased blood levels of β-endorphin on perception of breathlessness.
abstract: BACKGROUND
  Although opioid receptors are expressed broadly in the CNS and in peripheral sensory nerve endings including bronchioles and alveolar walls of the respiratory tract, it is unknown whether the modulatory effect of endogenous opioids on breathlessness occurs in the CNS or in the peripheral nervous system. The purpose of this investigation was to examine whether increased blood levels of β-endorphin modify breathlessness by a putative effect of binding to peripheral opioid receptors in the respiratory tract.
  
  
  METHODS
  Twenty patients with COPD (10 women and 10 men; age, 70 ± 8 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and unpleasantness of breathlessness ≥ 50 mm on a 100-mm visual analog scale. At two interventions, blood levels of β-endorphin and adrenocorticotropic hormone (ACTH) were measured, ketoconazole (600 mg) or placebo was administered orally, and patients rated the two dimensions of breathlessness each minute during resistive load breathing (RLB).
  
  
  RESULTS
  By inhibiting cortisol synthesis, ketoconazole led to significant increases in β-endorphin (mean change, 20% ± 4%) and ACTH (mean change, 21% ± 4%) compared with placebo. The intensity and unpleasantness ratings of breathlessness and the endurance time during RLB were similar in the two interventions.
  
  
  CONCLUSIONS
  The previously demonstrated modulatory effect of endogenous opioids on breathlessness appears to be mediated by binding to receptors within the CNS rather than to peripheral opioid receptors in the respiratory tract. An alternative explanation is that the magnitude of the β-endorphin response is inadequate to affect peripheral opioid receptors.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT01378520; URL: www.clinicaltrials.gov.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Lebanon, NH. Electronic address: Donald.a.mahler@hitchcock.org.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Mahler
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Lebanon, NH.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Gifford
authors.affiliation: Pulmonary Function and Cardiopulmonary Exercise Laboratories, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Waterman
authors.affiliation: Pulmonary Function and Cardiopulmonary Exercise Laboratories, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ward
authors.affiliation: Department of Kinesiology and the Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kraemer
authors.affiliation: Department of Kinesiology and the Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Kupchak
authors.affiliation: Department of Public Health Sciences, University of North Carolina at Charlotte, Charlotte, NC.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harver
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000368:Aged; D015415:Biomarkers / Q000097:blood; D004417:Dyspnea / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology*; D011957:Receptors, Opioid / Q000502:physiology; D012137:Respiratory System / Q000503:physiopathology; D012720:Severity of Illness Index; D013373:Substance P / Q000097:blood; D016896:Treatment Outcome; D001615:beta-Endorphin / Q000097:blood*
chemical_list: D015415:Biomarkers; D011957:Receptors, Opioid; D013373:Substance P; D001615:beta-Endorphin; D000324:Adrenocorticotropic Hormone; D007654:Ketoconazole