title: Antagonism of substance P and perception of breathlessness in patients with chronic obstructive pulmonary disease.
abstract: The objective of this study was to investigate whether substance P, an excitatory neuropeptide, modulates the perception of breathlessness by administering aprepitant, a selective antagonist that blocks neurokinin (NK)-1 receptor signaling. Individual targeted resistive load breathing (RLB) was used to provoke breathlessness. In Study 1, sixteen patients (age, 70±6 years) with chronic obstructive pulmonary disease (COPD) reported similar ratings of breathlessness during RLB between oral aprepitant (125mg) and placebo. After aprepitant, but not with placebo, there were significant increases in blood levels of substance P (+54±39%) and beta-endorphin (+27±17%). A similar design was used in Study 2 except that naloxone (10mg) was administered intravenously prior to RLB to block any effect of endogenous opioids. Nine patients with COPD reported comparable breathlessness ratings during RLB between aprepitant and placebo. Our results do not support a role for the substance P-NK-1 pathway in the perception of breathlessness in patients with COPD. With selective antagonism of NK-1 signaling, there was co-transmission of substance P and beta-endorphin neuropeptides.
authors.affiliation: Section of Pulmonary & Critical Care Medicine Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Electronic address: Donald.a.mahler@hitchcock.org.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Mahler
authors.affiliation: Section of Pulmonary & Critical Care Medicine Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Gifford
authors.affiliation: Section of Pulmonary & Critical Care Medicine Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Aamir
authors.initials: A
authors.lastname: Gilani
authors.affiliation: Pulmonary Function & Cardiopulmonary Exercise Laboratories Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Waterman
authors.affiliation: Pulmonary Function & Cardiopulmonary Exercise Laboratories Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hilton
authors.affiliation: Section of Pulmonary & Critical Care Medicine Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chang
authors.affiliation: Department of Kinesiology and Department of Physiology and Neurobiology University of Connecticut, Storrs, CT, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Kupchak
authors.affiliation: Department of Kinesiology and Department of Physiology and Neurobiology University of Connecticut, Storrs, CT, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kraemer
mesh_terms: D000368:Aged; D000077608:Aprepitant; D004311:Double-Blind Method; D004417:Dyspnea / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D010465:Perception; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000503:physiopathology* / Q000523:psychology; D012119:Respiration / Q000187:drug effects; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D001615:beta-Endorphin / Q000097:blood
chemical_list: D009025:Morpholines; D009292:Narcotic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D000077608:Aprepitant; D013373:Substance P; D009270:Naloxone; D001615:beta-Endorphin
keywords: Aprepitant; Beta-endorphin; Chronic obstructive pulmonary disease; Resistive load breathing; Substance P