Chest
Original ResearchSigns and Symptoms of Chest DiseasesAntitussive Effects of Memantine in Guinea Pigs
Section snippets
Animals
Male Hartley guinea pigs (200-700 g) (Hilltop Lab Animals, Inc) were studied. All experiments were first approved by the institutional Animal Care and Use Committee.
Citric Acid-Induced Cough
Animals were placed in a transparent chamber (Buxco Research Systems) with a continuous flow of air and exposed to increasing concentrations of citric acid (0.01-0.3 mol/L) delivered by an ultrasonic nebulizer generating aerosol particles of 3 to 6 μm in diameter. Coughs were counted during a 5-min nebulization period and over the
Citric Acid-Induced Cough
Compared with vehicle, 10 mg/kg memantine markedly reduced the number of cumulative coughs evoked by 0.01 to 0.3 mol/L citric acid (P = .012) (Fig 1A, Table 1). At 1 and 3 mg/kg, there was no significant effect of memantine over vehicle. No side effects associated with the 10 mg/kg memantine treatment were apparent. As expected, tripling the dose of memantine to 30 mg/kg similarly reduced cough responses but produced signs of neurologic effects and slight sedation.
In contrast to 10 or 30 mg/kg
Discussion
To our knowledge, this study provides the first evidence that memantine has antitussive activity with significant inhibition of both citric acid- and bradykinin-induced cough in guinea pigs. The degree of inhibition was similar to that seen with baclofen but without the associated sedation and was comparably more effective than high doses of other NMDAR antagonists. Because there was little evidence of significant activity at nicotinic acetylcholine or serotonin receptors, it is most likely
Acknowledgments
Author contributions: Dr Canning had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Dr Smith: contributed to the study design; acquisition, analysis, and interpretation of data; drafting and revisions of the manuscript; and approval of the final version of the manuscript.
Dr Hilton: contributed to the study design; acquisition, analysis, and interpretation of data; revisions of the manuscript; and approval
References (37)
- et al.
Antagonist drug selectivity for radioligand binding sites on voltage-gated and N-methyl-D-aspartate receptor-gated Ca2+ channels
Neurosci Lett
(1989) - et al.
Computer-assisted modeling of multiple dextromethorphan and sigma binding sites in guinea pig brain
Eur J Pharmacol
(1991) - et al.
Dextromethorphan and dextrorphan as calcium channel antagonists
Brain Res
(1988) - et al.
Application and validation of a computerized cough acquisition system for objective monitoring of acute cough: a meta-analysis
Chest
(2001) - et al.
Mechanism of action of memantine
Curr Opin Pharmacol
(2006) - et al.
The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner
Neurosci Lett
(2001) - et al.
Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane
Pharmacol Biochem Behav
(2006) - et al.
Mechanosensitivity of NMDA receptors in cultured mouse central neurons
Neuron
(1994) Central regulation of the cough reflex: therapeutic implications
Pulm Pharmacol Ther
(2009)- et al.
Antitussive effect of the GABA-agonist baclofen
Chest
(1997)
Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms
Gastroenterology
Antitussive activity of sigma-1 receptor agonists in the guinea-pig
Br J Pharmacol
Comparison of the antitussive effects of codeine phosphate 20 mg, dextromethorphan 30 mg and noscapine 30 mg using citric acid-induced cough in normal subjects
Eur J Clin Pharmacol
The effect of inhaled and oral dextromethorphan on citric acid induced cough in man
Br J Clin Pharmacol
Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough
J Int Med Res
Objective evaluation of dextromethorphan and glaucine as antitussive agents
Br J Clin Pharmacol
Restricting cough and cold medicines in children
J Paediatr Child Health
Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents
Arch Pediatr Adolesc Med
Cited by (34)
Potential applications of P2X3 receptor antagonists in the treatment of refractory cough
2023, Respiratory MedicineAntitussive effects of Na<inf>V</inf> 1.7 blockade in Guinea pigs
2021, European Journal of PharmacologyCitation Excerpt :To better address this hypothesis, we monitored heart rate, blood pressure and respiratory rate before and after systemic administration of Compound 801 or its vehicle in anesthetized guinea pigs (Fig. 5). We observed a profound reduction in mean arterial pressure and respiratory rate, with breathing patterns approximating that apparent following bilateral vagotomy and a decrease in blood pressure comparable to that achieved following autonomic ganglia blockade (Chou et al., 2008; Smith et al., 2012). Heart rate was minimally impacted by Compound 801.
Exploring the role of nerves in asthma; insights from the study of cough
2020, Biochemical PharmacologyCitation Excerpt :These include substance P on neurokinin 1 receptors (NK1), neurotrophins on tyrosine receptor kinase (Trk) receptors, and glutamate on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors [55]. In the context of chronic cough, animal studies antagonising the NMDA receptor with memantine reduced cumulative coughs evoked by citric acid and bradykinin [94]. Translation to patients with chronic cough showed a median reduction in cough frequency of 17% but this was statistically non-significant and higher doses of memantine were not tolerated; 10 of the 14 subjects could not tolerate more than the starting dose of 10 mg [95].
Role of reactive oxygen species and TRP channels in the cough reflex
2016, Cell CalciumCitation Excerpt :Inhalation of TRPA1 agonists causes cough in conscious guinea pigs and humans [57,103,104]. Furthermore bradykinin evokes cough in conscious guinea pigs [39,105], which is inhibited by TRPA1 inhibitors [97]. The role of TRPA1 in H2O2-mediated nociceptor activation is concentration dependent: at concentrations lower than 10 mM, H2O2 responses were co-localized to TRPA1-expressing neurons [60,64,89,90] and were abolished by TRPA1 knockout [60,90]; at higher concentrations (up to 120 mM), inhibition of TRPA1 has only a partial inhibitory effect [62], suggesting the involvement of other pathways.
NMDA and GABA receptors as potential targets in cough hypersensitivity syndrome
2015, Current Opinion in PharmacologyCitation Excerpt :Memantine showed no psychotropic effects in animal and human studies [67,75–77]. In guinea pigs, memantine given intraperitoneally at a dose of 10 mg/kg reduced coughs evoked by citric acid and bradykinin aerosols, with a greater cough suppression than compared to dextrometorphan given at a dose of 30 mg/kg or to ketamine at a dose of 30 mg/kg [78]. In a follow-up study in guinea pigs with orally administered memantine, doses of 10 and 30 mg/kg reduced citric-acid induced coughs with comparable results from codeine administration at 30 mg/kg [79•].
Funding/Support: This study was supported by a Medical Research Council Clinician Scientist Fellowship, a Medical Research Council Training Fellowship, and the National Institutes of Health [Grant HL083192].
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).