Effects of N-methyl-D-aspartate antagonists on the cough reflex

doi:10.1016/0014-2999(89)90560-8

European Journal of Pharmacology

Volume 168, Issue 2, 13 September 1989, Pages 153-158

https://doi.org/10.1016/0014-2999(89)90560-8 Get rights and content

Abstract

The effects of antagonists of N-methyl-D-aspartate (NMDA) on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i. cist.) injection of MK-801, a non-competitive antagonist of NMDA, significantly decreased the number of coughs in a dose-dependent manner. The competitive antagonists of NMDA, 2-DL-amino-5-phosphonovalerate and 2-DL-amino-7-phosphonoheptanoate, also decreased the number of coughs after i. cist. injection. The antitussive potencies of both the competitive and non-competitive antagonists were similar to that of dextromethorphan. Intraperitoneal injection of MK-801 also decreased the number of coughs in a dose-dependent manner. These data suggest that excitatory amino acid neurotransmitters and NMDA receptors may be involved in the regulation of the cough reflex.

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Cited by (72)

Effect of Tramadol Pretreatment on Sufentanil-Induced Cough
2019, Journal of Perianesthesia Nursing
Citation Excerpt :
The results found that premedication of intravenous tramadol 1 mg/kg infusion could reduce the incidence of sufentanil-induced cough, tramadol also attenuated cough severity. The mechanism may include mu-opioid receptor agonism, NMDA receptor antagonism, serotonin reuptake inhibition, and muscarinic receptor antagonism.16,19,20,22 Administration of opioids in a bolus during general anesthetic induction often induces coughing.1
To investigate the effect of tramadol pretreatment on the incidence and severity of sufentanil-induced cough.
Randomized controlled trial.
Adults of both genders (N = 304; 18 to 65 years old, American Society of Anesthesiologists physical status I to II), scheduled for elective surgery, were randomized into two groups (n = 152): intravenous administration of tramadol 1 mg/kg (group T) or normal saline (group C). Then sufentanil bolus 0.3 mcg/kg was administered intravenously in 5 seconds. The incidence and severity of cough were observed for 1 minute. Mean arterial pressure, heart rate, nausea, vomiting, and truncal rigidity during induction were also recorded.
Patient characteristics were similar between the two groups. The incidence of cough was significantly lower in group T when compared with group C (7.9% vs 18.4%, P < .05); there were nine patients coughing severely in group C, whereas no severe cough occurred in group T (P < .05). The mean arterial pressure, heart rate, and incidences of other side effects were comparable between the two groups.
Pretreatment of intravenous tramadol 1 mg/kg could be a clinically effective intervention for attenuating sufentanil-induced cough.
Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use
2016, Pharmacology and Therapeutics
Citation Excerpt :
Dextromethorphan (DM) has long been used as an over-the-counter cough suppressant, though the molecular mechanism to suppress coughing is not well established (Kamei et al., 1989; Brown et al., 2004; Kim et al., 2009; Canning & Mori, 2010; Young & Smith, 2011).
Dextromethorphan (DM) has been used for more than 50 years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential.
DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology.
This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α₃β₄ subunits, and cause agonist activity at sigma-1 receptors.
Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders
2016, Pharmacology and Therapeutics
Dextromethorphan (DM) is a commonly used antitussive and is currently the only FDA-approved pharmaceutical treatment for pseudobulbar affect. Its safety profile and diverse pharmacologic actions in the central nervous system have stimulated new interest for repurposing it. Numerous preclinical investigations and many open-label or blinded clinical studies have demonstrated its beneficial effects across a variety of neurological and psychiatric disorders. However, the optimal dose and safety of chronic dosing are not fully known. This review summarizes the preclinical and clinical effects of DM and its putative mechanisms of action, focusing on depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinson's disease and autism. Moreover, we offer suggestions for future research with DM to advance the treatment for these and other neurological and psychiatric disorders.
Dextromethorphan inhibits the glutamatergic synaptic transmission in the nucleus tractus solitarius of Guinea pigs
2011, Journal of Pharmacological Sciences
Dextromethorphan (DEX) is a widely used non-opioid antitussive. However, the precise site of action and its mechanism were not fully understood. We examined the effects of DEX on AMPA receptor–mediated glutamatergic transmission in the nucleus tractus solitarius (NTS) of guinea pigs. Excitatory postsynaptic currents (evoked EPSCs: eEPSCs) were evoked in the second-order neurons by electrical stimulation of the tractus solitarius. DEX reversibly decreased the eEPSC amplitude in a concentration-dependent manner. The DEX-induced inhibition of eEPSC was accompanied by an increased paired-pulse ratio. Miniature EPSCs (mEPSCs) were also recorded in the presence of Cd²⁺ or tetrodotoxin. DEX decreased the frequency of mEPSCs without affecting their amplitude. Topically applied AMPA provoked an inward current in the neurons, which was unchanged during the perfusion of DEX. BD1047, a σ-1–receptor antagonist, did not block the inhibitory effect of DEX on the eEPSCs, but antagonized the inhibition of eEPSCs induced by SKF-10047, a σ-1 agonist. Haloperidol, a σ-1 and -2 receptor ligand, had no influence on the inhibitory action of DEX. These results suggest that DEX inhibits glutamate release from the presynaptic terminals projecting to the second-order NTS neurons, but this effect of DEX is not mediated by the activation of σ receptors.
Comparison of the effects of ketamine or lidocaine on fentanyl-induced cough in patients undergoing surgery: A prospective, double-blind, randomized, placebo-controlled study
2010, Current Therapeutic Research - Clinical and Experimental
Background: Fentanyl-induced cough is common but has not been viewed as a serious anesthetic problem. However, the cough may be explosive at times, may require immediate intervention, and may be associated with undesirable increases in intracranial, intraocular, and intra-abdominal pressures. Prevention of fentanylinduced cough in such situations is of paramount importance. Ketamine, at concentrations achieved with standard clinical doses, has a direct relaxant effect on airway smooth muscle.
Objective: This study was designed to assess the effects of ketamine or lidocaine on fentanyl-induced cough.
Methods: This double-blind, randomized, placebo-controlled study was conducted at the Erciyes University Medical School, Kayseri, Turkey. Consecutive adult patients aged 18 to 65 years and classified as American Society of Anesthesiologists physical status I or II who were undergoing elective surgery with general anesthesia were enrolled. Patients were randomly allocated equally into 3 groups to receive lidocaine 1 mg/kg, ketamine 0.5 μg/kg, or placebo intravenously 1 minute before fentanyl administration. Following intravenous fentanyl (1.5 μg/kg over 2 seconds) injection, an observer, unaware of the type of medication given to the patients, recorded the number of episodes of coughing, if any. Any episode of cough was classified as coughing and graded by investigators blinded to treatment as mild (1–2 coughs), moderate (3–4), or severe (≥5). Blood pressure, heart rate, pulse oximetry oxygen saturation (SpO₂), and adverse effects (AEs) were recorded.
Results: A total of 368 patients were approached for inclusion; 300 patients met the inclusion criteria and were enrolled in the study. No patients in the ketamine group had cough. The frequency of cough was significantly lower in the lidocaine (11/100 [11%]; P = 0.024) and ketamine (0/100; P = 0.001) groups compared with the placebo group (23/100 [23%]). The intensity of cough was significantly lower in the lidocaine (mild, 7/100 [7%]; moderate, 4/100 [4%]; P = 0.037) and ketamine (0/100; P < 0.001) groups compared with the placebo group (mild, 10/100 [10%]; moderate, 12/100 [12%]; severe, 1/100 [1%]). Severe cough (≥5) was observed in 1 patient in the placebo group. Incidence and intensity of cough were significantly decreased in the ketamine group compared with the lidocaine group (incidence, P = 0.001; intensity, P = 0.003). There were no significant differences between groups with respect to systolic blood pressure, diastolic blood pressure, heart rate, SpO₂, and AEs.
Conclusion: Intravenous ketamine (0.5 mg/kg) significantly reduced the reflex cough induced by fentanyl compared with lidocaine and placebo, and was well tolerated.
Central regulation of the cough reflex: Therapeutic implications
2009, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Only two excitatory transmitter systems (glutamate, neurokinins) have been identified in the cough reflex pathways of animals and humans (Fig. 2). Glutamate receptor antagonists such as dextromethorphan block cough in multiple species and in response to several different tussive stimuli [4,15,39,68–71]. Similarly, neurokinin receptor antagonists are effective antitussives in guinea pigs, cats, rabbits, dogs and pigs [3–10].
In many species including humans, antagonists of NMDA-type glutamate receptors such as dextromethorphan, when used at sufficient doses, have been found to be relatively safe and effective antitussives. Similarly, now in five different species (guinea pigs, rabbits, cats, dogs and pigs), neurokinin receptor antagonists have also proven to be safe and effective antitussive agents. Both of these classes of drugs act centrally to prevent cough. A brief review of what is known about the central encoding of cough is presented, as are the advantages of centrally acting antitussives. Also discussed are new insights into cough and NMDA receptor signaling that may lead to the development of more effective antitussive agents with limited side effects and broad application in treating cough associated with a variety of aetiologies.

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Effects of N-methyl-D-aspartate antagonists on the cough reflex

Abstract

Brain Res.

Trends Neurosci.

Trends Neurosci.

European J. Pharmacol.

Neurosci. Lett.

European J. Pharmacol.

Neurosci. Lett.

Brain Res.

Jap. J. Pharmacol.

European J. Pharmacol.

Neurosci. Lett.