ABSTRACT
Licorice has been used as an antitussive and expectorant herbal medicine for a long history. This work evaluated the activities of 14 major compounds and crude extracts of licorice, using the classical ammonia-induced cough model and phenol red secretion model in mice. Liquiritin apioside (1), liquiritin (2), and liquiritigenin (3) at 50â¯mg/kg (i.g.) could significantly decrease cough frequency by 30-78% (pâ¯<â¯.01). The antitussive effects could be partially antagonized by the pretreatment of methysergide or glibenclamide, but not naloxone. Moreover, compounds 1-3 showed potent expectorant activities after 3â¯days treatment (pâ¯<â¯.05). The water and ethanol extracts of licorice, which contain abundant 1 and 2, could decrease cough frequency at 200â¯mg/kg by 25-59% (pâ¯<â¯.05), and enhance the phenol red secretion (pâ¯<â¯.05), while the ethyl acetate extract showed little effect. These results indicate liquiritin apioside and liquiritin are the major antitussive and expectorant compounds of licorice. Their antitussive effects depend on both peripheral and central mechanisms.
Subject(s)
Antitussive Agents/pharmacology , Cough/drug therapy , Expectorants/pharmacology , Glycyrrhiza/chemistry , Phenolsulfonphthalein/metabolism , Plant Extracts/pharmacology , Administration, Oral , Ammonia , Animals , Antitussive Agents/antagonists & inhibitors , Antitussive Agents/chemistry , Cough/chemically induced , Disease Models, Animal , Dose-Response Relationship, Drug , Expectorants/chemistry , Expectorants/isolation & purification , Glyburide/pharmacology , Male , Methysergide/pharmacology , Mice , Mice, Inbred ICR , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Structure-Activity RelationshipABSTRACT
We have previously shown that ionotropic glutamate receptors in the caudal portion of the nucleus tractus solitarii (NTS), especially in the commissural NTS, play a prominent role in the mediation of tracheobronchial cough and that substance P potentiates this reflex. This NTS region could be a site of action of some centrally acting antitussive agents and a component of a drug-sensitive gating mechanism of cough. To address these issues, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30-50 nl) of centrally acting antitussive drugs into the caudal NTS of pentobarbitone-anesthetized, spontaneously breathing rabbits. [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and baclofen decreased baseline respiratory frequency because of increases in the inspiratory time only at the higher concentration employed (5 mM and 1 mM, respectively). DAMGO (0.5 mM) and baclofen (0.1 mM) significantly decreased cough number, peak abdominal activity, peak tracheal pressure, and increased cough-related total cycle duration. At the higher concentrations, these agents suppressed the cough reflex. The effects of these two drugs were counteracted by specific antagonists (10 mM naloxone and 25 mM CGP-35348, respectively). The neurokinin-1 (NK1) receptor antagonist CP-99,994 (10 mM) abolished cough responses, whereas the NK2 receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the caudal NTS is a site of action of some centrally acting drugs and a likely component of a neural system involved in cough regulation. A crucial role of substance P release in the mediation of reflex cough is also suggested.
Subject(s)
Antitussive Agents/pharmacology , Baclofen/pharmacology , Cough/drug therapy , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Reflex/drug effects , Solitary Nucleus/drug effects , Animals , Antitussive Agents/antagonists & inhibitors , Baclofen/administration & dosage , Baclofen/antagonists & inhibitors , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/administration & dosage , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/antagonists & inhibitors , Male , Naloxone/pharmacology , Neurokinin A/analogs & derivatives , Neurokinin A/pharmacology , Organophosphorus Compounds/pharmacology , Peptide Fragments/pharmacology , Piperidines/pharmacology , Rabbits , Solitary Nucleus/physiologyABSTRACT
Experiments were conducted to characterize the pharmacology of SCH 50911 ((+)-5,5-dimethyl-2-morpholineacetic acid hydrochloride), a structurally novel GABA-B receptor antagonist. Although more potent GABA-B antagonists have been reported, in this study SCH 50911 was compared with CGP 35348, a moderately potent and selective GABA-B antagonist with acceptable in vivo activity. SCH 50911 was more potent to inhibit the binding of GABA to the GABA-B receptor in rat brain (IC50 = 1.1 microM) than CGP 35348 (IC50 = 62 microM). SCH 50911 had no binding affinity for GABA-A, histamine H1, histamine H3, dopamine D1, dopamine D2, serotonin 5-HT2, or muscarinic m1, m2, or m4 receptors. However, SCH 50911 (IC50 = 2.2 microM) was active in a nonspecific muscarinic receptor binding assay, but was devoid of muscarinic agonist or antagonist activity in the isolated guinea pig ileum. SCH 50911 blocked inhibitory responses to baclofen of the guinea pig trachea in a competitive manner (pA2 = 5.8 +/- 0.004). CGP 35348 was 19-fold less potent in this assay (pA2 = 4.6 +/- 0.15). In vivo, SCH 50911 (ED50 = 2.9 mg kg-1, s.c.) and CGP 35348 (ED50 = 5.8 mg kg-1, s.c.) blocked the antitussive effects of baclofen in the guinea pig. In the cat, both SCH 50911 (10 mg kg-1, i.v.) and CGP 35348 (10 mg kg-1, i.v.) shifted the antitussive dose response relationship for baclofen to the right.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
GABA Antagonists/pharmacology , GABA-B Receptor Antagonists , Morpholines/pharmacology , Administration, Oral , Animals , Antitussive Agents/antagonists & inhibitors , Antitussive Agents/pharmacology , Baclofen/antagonists & inhibitors , Baclofen/pharmacology , CHO Cells , Cats , Cholinergic Agents/pharmacology , Cricetinae , GABA Antagonists/administration & dosage , GABA Antagonists/metabolism , Guinea Pigs , Humans , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Male , Morpholines/administration & dosage , Morpholines/metabolism , Muscle Contraction/drug effects , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, GABA-B/metabolism , Trachea/drug effects , Trachea/physiologyABSTRACT
1. The GABA-B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA-B receptor agonists to inhibit the cough reflex. 2. Single intracerebroventricular (i.c.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3-APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug. 4. In the guinea pig, baclofen (3 mg kg-1, s.c.) and 3-APPi (10 mg kg-1, s.c.) inhibited capsaicin-induced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.c.v. administration of the GABA-B receptor antagonist CGP 35348 (10 micrograms). Conversely, the antitussive effect of 3-APPi was unaffected by i.c.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg-1, s.c.) completely blocked the antitussive activity of 3-APPi (10 mg kg-1, s.c.). In separate experiments baclofen alone (1 microg, i.c.v.) inhibited capsaicin-induced cough by 78%. 3-APPi (10 and 100 microg, i.c.v.) had no effect on capsaicin-induced cough in the guinea pig.5. In the cat, potencies (ED50) of the standards and GABA-B agonists by the i.v. route were: codeine(0.34 mg kg-1), BW443C (0.17 mg kg-1), baclofen (0.63 mg kg-1) and 3-APPi (2.3 mg kg-1). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg-1; BW443C, 0.06mg kg-1; baclofen,0.016mg kg-1; and 3-APPi, 0.87 mg kg-1. The EDRs for each drug were: codeine, 26; BW443C, 3;baclofen, 39; and 3-APPi, 3.6 We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action,while 3-APPi inhibits cough by a peripheral site of action.
Subject(s)
Central Nervous System/physiology , Cough/physiopathology , GABA-B Receptor Agonists , Organophosphorus Compounds/pharmacology , Peripheral Nervous System/physiology , Animals , Antitussive Agents/antagonists & inhibitors , Antitussive Agents/pharmacology , Baclofen/antagonists & inhibitors , Baclofen/pharmacology , Capsaicin , Cats , Central Nervous System/drug effects , Codeine/pharmacology , Cough/chemically induced , GABA Agonists/pharmacology , GABA-B Receptor Antagonists , Guinea Pigs , In Vitro Techniques , Injections, Intraventricular , Male , Oligopeptides/pharmacology , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/antagonists & inhibitors , Peripheral Nervous System/drug effectsABSTRACT
When co-administered intracisternally, the selective delta-opioid agonist [D-Pen2,5]enkephalin (DPDPE), which had no significant effect on the cough reflex, consistently and significantly decreased the antitussive potencies of kappa-receptor agonists, U-50,488H and U-62,066E. The decrease in the antitussive effects of these kappa-receptor agonists caused by DPDPE were prevented by selective delta receptor antagonist, naltrindole. These results suggest that delta receptors may play an inhibitory role in antitussive processes that are mediated by the kappa-receptors.
Subject(s)
Antitussive Agents/antagonists & inhibitors , Indoles/pharmacology , Morphinans/pharmacology , Naltrexone/analogs & derivatives , Narcotic Antagonists/pharmacology , Pyrrolidines/pharmacology , Receptors, Opioid/drug effects , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer , Animals , Antitussive Agents/pharmacology , Cough/drug therapy , Enkephalin, D-Penicillamine (2,5)- , Enkephalins/antagonists & inhibitors , Enkephalins/pharmacology , Male , Pyrrolidines/antagonists & inhibitors , Rats , Rats, Inbred Strains , Receptors, Opioid/physiology , Receptors, Opioid, delta , Receptors, Opioid, kappa , Reflex/drug effectsABSTRACT
The influence of drugs which modify the concentration of brain monoamines on the size of the 50% antitussive dose (AtD50) of morphine (M), dihydrocodeine (DC) and dextromethorphan (DX) was investigated in male Sprague-Dawley rats. The puncture electrode-induced cough method was used for inducing cough. The AtD50 was calculated by the "up and down" method. All drugs were injected i.p. Concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the whole brain were measured by means of high performance liquid chromatography with electro-chemical detection. The values for the AtD50 of M, DC and DX were 1.22, 1.44, and 6.06 mg/kg, respectively. Reserpine (2.5 mg/kg/day, 2 days) produced depression of more than 80% in levels of NE, DA and 5-HT in the brain. This treatment resulted in a substantial reduction in the antitussive effect of the cough suppressants, as evidenced by an increase in the AtD50 of M, DC and DX. p-Chlorophenylalanine (PCPA; 300 mg/kg, 24 hr) specifically produced a reduction of more than 70% in the level of 5-HT in the brain. The PCPA-treated rats also displayed an inhibition of the antitussive effect. The AtD50 in reserpine- and PCPA-treated rats was 2- and 4-fold higher, respectively, than the AtD50 for normal rats. alpha-Methyl-p-tyrosine (300 mg/kg, 5 hr) produced a significant reduction in the levels of NE and DA in the brain, but the antitussive effects of M, DC and DX were not altered. These results suggest that 5-HT in the brain may play an important role in the mechanism of action of antitussive drugs.
Subject(s)
Antitussive Agents/pharmacology , Brain Chemistry/drug effects , Dopamine/physiology , Norepinephrine/physiology , Serotonin/physiology , Animals , Antitussive Agents/antagonists & inhibitors , Cough/physiopathology , Dose-Response Relationship, Drug , Electric Stimulation , Fenclonine/pharmacology , Male , Methyltyrosines/pharmacology , Rats , Rats, Inbred Strains , Reserpine/pharmacology , alpha-MethyltyrosineABSTRACT
Effects of naloxone on the cough depressant action of antitussive drugs were investigated in pentobarbital anesthetized male and female cats. Respiration and cough reflex were measured using a pneumotachograph via a cannula inserted into the trachea. The cough reflex was elicited by electrical stimuli to the superior laryngeal nerve. An i.v. administration of morphine (1 mg/kg) significantly inhibited the cough reflex for at least 60 min. The antitussive effect of morphine was antagonized by naloxone (400 micrograms/kg). The inhibitory effect of morphine on the respiratory frequency was also antagonized by naloxone. The cough reflex was significantly inhibited by fominoben (5 mg/kg, i.v.) and dextromethorphan (3 mg/kg, i.v.). However, the respiratory frequency was increased by these two drugs. An i.v. administration of naloxone prevented the antitussive effects and the excitatory effects in respiratory frequency of fominoben and dextromethorphan. The present study suggests that the cough depressant actions of antitussive drugs may be mediated by endogenous opiates and/or by neurotransmitters which are modified by endogenous opiates.