enkephalin--ala(2)-mephe(4)-gly(5)- and Cough

We have previously shown that the caudal nucleus tractus solitarii is a site of action of some antitussive drugs and that the caudal ventral respiratory group (cVRG) region has a crucial role in determining both the expiratory and inspiratory components of the cough motor pattern. These findings led us to suggest that the cVRG region, and possibly other neural substrates involved in cough regulation, may be sites of action of antitussive drugs. To address this issue, we investigated changes in baseline respiratory activity and cough responses to tracheobronchial mechanical stimulation following microinjections (30-50 nl) of some antitussive drugs into the cVRG of pentobarbital-anesthetized, spontaneously breathing rabbits. [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) and baclofen at the lower concentrations (0.5 mM and 0.1 mM, respectively) decreased cough number, peak abdominal activity, and peak tracheal pressure and increased cough-related total cycle duration (Tt). At the higher concentrations (5 mM and 1 mM, respectively), both drugs abolished the cough reflex. DAMGO and baclofen also affected baseline respiratory activity. Both drugs reduced peak abdominal activity, while only DAMGO increased Tt, owing to increases in expiratory time. The neurokinin-1 (NK(1)) receptor antagonist CP-99,994 (10 mM) decreased cough number, peak abdominal activity, and peak tracheal pressure, without affecting baseline respiration. The NK(2) receptor antagonist MEN 10376 (5 mM) had no effect. The results indicate that the cVRG is a site of action of some antitussive agents and support the hypothesis that several neural substrates involved in cough regulation may share this characteristic.

Topics: Abdominal Muscles; Animals; Antitussive Agents; Baclofen; Cough; Diaphragm; Electromyography; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hemodynamics; Male; Microinjections; Neurokinin A; Peptide Fragments; Phrenic Nerve; Physical Stimulation; Piperidines; Rabbits; Reflex; Respiratory Center; Respiratory Mechanics; Solitary Nucleus

We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).

Topics: Alkylation; Animals; Antitussive Agents; Capsaicin; CHO Cells; Cough; Cricetinae; Cricetulus; Male; Mice; Molecular Structure; Naltrexone; Rats; Structure-Activity Relationship

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.

Topics: Animals; Antitussive Agents; Baclofen; Cough; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Naloxone; Neurokinin A; Organophosphorus Compounds; Peptide Fragments; Piperidines; Rabbits; Reflex; Solitary Nucleus

We examined the effect of [D-Ala2]deltorphin II, a selective delta 2-opioid receptor agonist, on the antitussive effect of [D-Ala2, MePhe4,Gly-ol5]enkephalin (DAMGO), a selective mu-opioid receptor agonist. [D-Ala2]deltorphin (3 nmol i.c.v.) had no significant effect on the number of coughs. However, upon i.c.v. pretreatment with [D-Ala2]deltorphin II (3 nmol) the antitussive activity of DAMGO (0.03 nmol) was significantly enhanced. The enhancement of the antitussive activity of DAMGO caused by [D-Ala2]deltorphin II was prevented by a benzofuran derivative of naltrindole (0.1 mg/kg s.c.), a selective delta 2-opioid receptor antagonist. These results suggest that delta 2-opioid receptors may play a synergistic role in antitussive processes that are mediated by mu-opioid receptors.

Topics: Animals; Antitussive Agents; Cough; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oligopeptides; Receptors, Opioid, delta; Receptors, Opioid, mu

The effect of pretreatment with naloxonazine on mu-opioid agonist-mediated antitussive effects was studied in mice. The antitussive effects of [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO) and morphine were significantly antagonized by naloxone pretreatment, 1 mg/kg given i.p. 5 min earlier, but not by naloxonazine pretreatment, 35 mg/kg given s.c. 24 h earlier. In contrast, the antinociceptive effects of these mu agonists, as determined by the tail-flick method, were significantly reduced by pretreatment with both naloxone and naloxonazine. These results suggest that mu 2 rather than mu 1 mechanisms are involved in mu-mediated antitussive effects.

Topics: Analgesics; Animals; Antitussive Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Reaction Time; Receptors, Opioid, mu

Effects of selective mu and delta receptor agonists on capsaicin-induced cough reflex in rats were studied. Intracisternal injection (i.cist.) of a selective mu receptor agonist [D-Ala2,Mephe4,Gly-ol5]enkephalin (DAMGO) produced dose-related depression of coughs over the 0.003-0.03 nmol dose range. The antitussive potency of DAMGO was 100-fold more potent than morphine. The antitussive effects of DAMGO and morphine were significantly reduced by naloxone (1 nmol i.cist.). The selective delta receptor agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), at a dose of 10 nmol (i.cist.), had no significant effect on the number of coughs. When co-administered i.cist., DPDPE (10 nmol) consistently and significantly decreased the antitussive potencies of DAMGO and morphine. The decrease in the antitussive effects of DAMGO and morphine caused by DPDPE were prevented by selective delta receptor antagonist, naltrindole (3 nmol). These results suggest that the antitussive effects of opioids are mediated predominantly by mu receptors, and delta receptors may play an inhibitory role in antitussive processes that are mediated by the mu receptors.

Topics: Aerosols; Animals; Antitussive Agents; Capsaicin; Cisterna Magna; Cough; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Indoles; Injections; Male; Morphinans; Morphine; Naltrexone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu