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

Mahler, Donald A.; Gifford, Alex H.; Gilani, Aamir; Waterman, Laurie A.; Hilton, Jennifer; Chang, Andrew S.; Kupchak, Brian R.; Kraemer, William J.

doi:10.1016/j.resp.2014.02.008

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…To investigate the possible role of substance P in the perception of dyspnea, 125 mg of aprepitant, a selective antagonist that blocks NK-1 receptor signaling, was administered orally in a randomized placebo-controlled trial. 24 Th e results showed that antagonism of the substance P-NK-1 pathway did not aff ect the perception of breathlessness as reported by patients with COPD during RLB. 24 Neuroimaging studies, particularly PET imaging and functional MRI, have provided "a window" into brain activation under experimental conditions in which dyspnea has been provoked.…”

Section: Neural Inputs That Reach the Somatosensory Cortex And Contrimentioning

confidence: 78%

“…24 Th e results showed that antagonism of the substance P-NK-1 pathway did not aff ect the perception of breathlessness as reported by patients with COPD during RLB. 24 Neuroimaging studies, particularly PET imaging and functional MRI, have provided "a window" into brain activation under experimental conditions in which dyspnea has been provoked. The overall data support a cortical-limbic network for dyspnea perception.…”

Section: Neural Inputs That Reach the Somatosensory Cortex And Contrimentioning

confidence: 78%

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Recent Advances in Dyspnea

Mahler

O’Donnell

2015

Chest

Self Cite

115

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Section: Neural Inputs That Reach the Somatosensory Cortex And Contrimentioning

confidence: 78%

Section: Neural Inputs That Reach the Somatosensory Cortex And Contrimentioning

confidence: 78%

Recent Advances in Dyspnea

Mahler

O’Donnell

2015

Chest

Self Cite

115

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“…Use of an antagonist of SP (aprepitant, orally administered 125 mg daily) in a cohort of stable COPD patients (n=16, mean age 70 years) paradoxically increased serum SP levels compared to untreated stable COPD patients and no improvements in lung function and the perception of breathlessness were seen [575]. Another similar and more recent study confirmed these data (NCT01854177).…”

Section: Modulation Of Antimicrobial Peptides In Treatment Of Copdmentioning

confidence: 72%

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD

Nucera

Bello

Shen

et al. 2021

CMC

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: Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung resulting generally from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors [such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end product (RAGE) or toll-like receptors (TLRs)] in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in pre-clinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes, be-cause there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential anti-inflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of a typical chemokines in COPD pathophysiology and thereby improve COPD management.

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“…However, we acknowledge that the respiratory discomfort experienced by our subjects, although dominated by “air hunger,” was multimodal (Table 1 ). From the perspective of future pharmacological approaches to the treatment of dyspnea and, more specifically, targeting non-opioid mechanisms to alleviate respiratory discomfort (e.g., Mahler et al, 2014 ), the available evidence suggests that substances interfering with C-fibers should be more active on the “work/effort” component of dyspnea and substances with a central nervous system target should be more active on the “air hunger” component of dyspnea.…”

Section: Discussionmentioning

confidence: 99%

Interactions Between Dyspnea and the Brain Processing of Nociceptive Stimuli: Experimental Air Hunger Attenuates Laser-Evoked Brain Potentials in Humans

et al. 2015

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Dyspnea and pain share several characteristics and certain neural networks and interact with each other. Dyspnea-pain counter-irritation consists of attenuation of preexisting pain by intercurrent dyspnea and has been shown to have neurophysiological correlates in the form of inhibition of the nociceptive spinal reflex RIII and laser-evoked potentials (LEPs). Experimentally induced exertional dyspnea inhibits RIII and LEPs, while “air hunger” dyspnea does not inhibit RIII despite its documented analgesic effects. We hypothesized that air hunger may act centrally and inhibit LEPs. LEPs were obtained in 12 healthy volunteers (age: 21–29) during spontaneous breathing (FB), ventilator-controlled breathing (VC) tailored to FB, after inducing air hunger by increasing the inspired fraction of carbon dioxide -FiCO2- (VCCO2), and during ventilator-controlled breathing recovery (VCR). VCCO2 induced intense dyspnea (visual analog scale = 63% ± 6% of full scale, p < 0.001 vs. VC), predominantly of the air hunger type. VC alone reduced the amplitude of the N2-P2 component of LEPs (Δ = 24.0% ± 21.1%, p < 0.05, effect-size = 0.74) predominantly through a reduction in P2, and the amplitude of this inhibition was further reduced by inducting air hunger (Δ = 22.6% ± 17.9%, p < 0.05, effect-size = 0.53), predominantly through a reduction in N2. Somatosensory-evoked potentials (SEPs) were not affected by VC or VCCO2, suggesting that the observed effects are specific to pain transmission. We conclude that air hunger interferes with the cortical mechanisms responsible for the cortical response to painful laser skin stimulation, which provides a neurophysiological substrate to the central nature of its otherwise documented analgesic effects.

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

Cited by 9 publications

References 34 publications

Recent Advances in Dyspnea

Recent Advances in Dyspnea

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD

Interactions Between Dyspnea and the Brain Processing of Nociceptive Stimuli: Experimental Air Hunger Attenuates Laser-Evoked Brain Potentials in Humans

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