The TRPV1 antagonist SB705498 significantly reduced capsaicin-induced coughing in guinea pigs and lowered expression of the neuropeptides substance P, CGRP, and neurokinin A in both lung and brain tissue.
Three neuropeptides reduced in lung and brainTRPV1 blockade with SB705498 reduced substance P, CGRP, and neurokinin A in both lung and brain tissue (all p<0.05), demonstrating that the anti-cough effect involves suppression of neurogenic inflammation at multiple levels.
What the researchers found
In capsaicin-induced cough guinea pig model (N=10 per group, 4 groups):
- Both inhaled and oral SB705498 significantly reduced cough numbers (p<0.001) and prolonged cough incubation periods (p<0.001) compared to saline control
- Codeine (positive control) also significantly reduced coughing
- SB705498 reduced expression of three neuropeptides in lung and brain tissue (all p<0.05): substance P (SP), calcitonin gene-related peptide (CGRP), and neurokinin A (NKA)
- No lung or brain parenchymal inflammation was observed in any group (safety signal)
- Both routes of SB705498 administration (inhaled and oral) were effective
Why it matters
Chronic cough is one of the most common reasons for doctor visits, affecting up to 10% of adults in some populations. Current antitussives are often ineffective or have significant side effects (like sedation from codeine). TRPV1 antagonists represent a mechanistically targeted approach that addresses the root cause — nerve hypersensitivity — rather than just suppressing the cough reflex centrally. The finding that neuropeptide levels decrease in both lungs and brain suggests the drug modulates the cough pathway at multiple levels.
How the study worked
Guinea pigs with capsaicin-inducible cough were randomized into four groups (N=10 each): saline inhalation (negative control), codeine injection (positive control), SB705498 inhalation, and SB705498 oral administration. After treatment, capsaicin cough challenge was repeated and cough numbers and incubation periods were recorded. ELISA and immunohistochemistry measured substance P, CGRP, and neurokinin A expression in lung and brain tissues. H&E staining assessed tissue pathology.
What this study cannot tell us
Guinea pigs are the standard model for cough research but may not perfectly predict human cough responses. The capsaicin-induced cough model represents acute cough hypersensitivity rather than the complex pathology of chronic unexplained cough in humans. The study did not assess long-term safety or efficacy. SB705498 has known tolerability issues in human trials (TRPV1 antagonists can cause hyperthermia), which were not evaluated in this short-term study. The brain tissue neuropeptide changes are interesting but the functional significance for centrally mediated cough suppression needs further investigation.
How to read the evidence
This is a well-controlled preclinical animal study using the gold-standard guinea pig cough model with randomized treatment groups, positive and negative controls, and comprehensive neuropeptide analysis. However, all findings are in animals, and TRPV1 antagonists have faced challenges in human clinical development.
When this study was published
Published in 2018, this study is about 7 years old. TRPV1 antagonist development for cough has continued, with newer compounds being designed to avoid hyperthermia while retaining anti-cough efficacy. The P2X3 receptor antagonist gefapixant (targeting a different cough pathway) has since been approved in some countries.
The bigger picture
Substance P, CGRP, and neurokinin A are the same neuropeptides involved in migraine, pain, and inflammatory conditions throughout the body. Their reduction by TRPV1 blockade in the context of cough connects airway sensory neurology to the broader neuropeptide pharmacology field. TRPV1 antagonists have been explored for pain management but faced setbacks due to hyperthermia side effects. This study suggests inhalation delivery could provide local effects without systemic side effects — a strategy relevant to other TRPV1-targeted conditions.
Questions still open
- Could inhaled TRPV1 antagonists avoid the hyperthermia side effect seen with systemic administration?
- Would TRPV1 blockade be effective in patients with chronic cough from different causes (reflux, asthma, post-viral)?
- Are the reductions in substance P and CGRP in brain tissue clinically meaningful, or are they too small to affect cough centrally?
Common questions
Why do people cough from capsaicin, and what does this have to do with chronic cough?
How are substance P and CGRP involved in chronic cough?
Read the original research
The research of the possible mechanism and the treatment for capsaicin-induced cough.
Pulmonary pharmacology & therapeutics, 49, 1-9
Citation
Zhang, Li; Sun, Tieying; Liu, Longteng; Wang, Lifang. (2018). The research of the possible mechanism and the treatment for capsaicin-induced cough.. Pulmonary pharmacology & therapeutics, 49, 1-9. https://doi.org/10.1016/j.pupt.2017.12.008