Antagonism of substance P and perception of breathlessness in patients with chronic obstructive pulmonary disease

• We investigated whether substance P modulates the perception of breathlessness in patients with chronic obstructive pulmonary disease.
• Aprepitant, an antagonist that blocks neurokinin (NK)-1 receptor signaling, or placebo was administered prior to resistive load breathing.
• Our results do not support a role for the substance P-NK-1 pathway in the perception of breathlessness in patients with COPD.
• With aprepitant, but not with placebo, blood levels of substance P (+54%) and beta-endorphin (+27%) increased.
• The co-transmission of substance P (excitatory) and beta-endorphin (inhibitory) neuropeptides presumably reflects an integrated response.

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 (125 mg) 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 (10 mg) 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.