naloxone and Cough

The easily performed "cough-trick" (CT) reduces pain during venipuncture (VP), although the underlying mechanism remains unclear. The aim was to investigate the pain-reducing effect of CT during VP in comparison with two distraction methods, as well as under the influence of naloxone.. 54 healthy male volunteers participated in 3 investigations. Pain during standardized VP with CT was compared to a "weak" distraction (squeezing a rubber ball; investigation 1;. Pain intensity at VP with CT was lower than under "weak" distraction (mean difference 5 mm; 95% CI: 0.5 to 9.6;. Pain-reducing effect of CT during VP is superior to that of simple motor distraction and equivalent to a complex distraction method. This might be due to the activation of segmental pain inhibitory pathways during coughing indicated through the lack of pain reduction due to CT under opioid antagonist blockage.

Topics: Adult; Attention; Cough; Cross-Over Studies; Double-Blind Method; Healthy Volunteers; Humans; Male; Naloxone; Pain; Pain Management; Phlebotomy; Young Adult

The evidence that an infusion of a low dose of naloxone reduces post-operative pain and opioid analgesic consumption is somewhat conflicting. Thus, the aim of the present study was to investigate the effect of an ultra-low dose of naloxone on patient-controlled morphine analgesia.. Ninety patients, 35-55 years old, scheduled for total abdominal hysterectomy, were enrolled in this prospective, randomized, double-blind and placebo-controlled study. Post-operatively, they received either saline (n = 45) or naloxone (n = 45) for 24 h. A standard general anesthesia was administered in both groups. In the recovery room, patients received morphine by a patient-controlled analgesia device. An ultra-low dose of naloxone was infused intravenously at 0.25 μg/kg/h for 24 h in the intervention group. Saline was infused in the control group. Following the surgery, morphine consumption, numeric rating score for pain intensity, nausea and vomiting, pruritus, and requests for antiemetic were recorded at baseline, 30 min, 1, 4, 8,16, 20, and 24 h following their discharge from recovery.. Naloxone reduced morphine consumption over the first 24 post-operative hours significantly compared with the controls (saline) {19.5 [standard deviation (SD) 3.4] mg vs. 27.5 [SD 5.9] mg; P < 0.001}. The incidence and severity of nausea and vomiting was significantly reduced in the naloxone group. The incidence of pruritus and the pain scores at rest and activity were not significantly different.. Following hysterectomy, an ultra-low dose of naloxone infusion proved to reduce morphine consumption as well as the incidence and severity of opioid-induced nausea and vomiting.

Topics: Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Cough; Double-Blind Method; Female; Humans; Hysterectomy; Infusions, Intravenous; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Pain, Postoperative; Postoperative Nausea and Vomiting; Pruritus; Treatment Outcome

The purpose of the study was to compare the analgesic and side effects of two epidurally administered mixtures of bupivacaine and fentanyl with the same drug ratios.. One hundred patients scheduled for colorectal surgery were randomized to receive a thoracic epidural infusion of either bupivacaine 0.12% with fentanyl 2 micrograms/ml or bupivacaine 0.24% with fentanyl 4 micrograms/ml during 48 h postoperatively. The pumps were adjusted to keep the visual analogue scale (VAS) pain score at 3 or less (on a scale of 0-10) with a minimum of adverse effects.. There were no statistically significantly differences between the two groups in VAS pain scores. The average VAS pain score resting varied between 0.5 and 1, and coughing between 1.9 and 3.4. One case of respiratory depression with breathing frequency 7 occurred in each group, but none of the patients required naloxone. One patient in the low concentration group developed partial motor weakness in both legs 36 h postoperatively. Equal drug amounts--bupivacaine 10.8-11 mg/h and fentanyl 18-18.4 micrograms/h--were given in both groups throughout the study.. Both groups had low pain scores with few and comparable adverse effects. It thus seems that the volume is not important when mixtures of bupivacaine and fentanyl in the studies concentrations are infused epidurally at a low thoracic level. Practical reasons favour the higher concentration mixture.

Topics: Aged; Analgesia, Epidural; Analgesics, Opioid; Anesthetics, Local; Bupivacaine; Buprenorphine; Colon; Cough; Fentanyl; Follow-Up Studies; Humans; Infusion Pumps; Injections, Intravenous; Leg; Middle Aged; Muscle Weakness; Naloxone; Narcotic Antagonists; Pain Measurement; Pain, Postoperative; Rectum; Respiration

In a double-blind study patients given a single dose of doxapram 1-5-2-0 mg/kg combined with morphine postoperatively had a significantly lower incidence of reflex postoperative cough and expectoration of purulent sputum than patients given morphine alone. They also had significantly higher arterial oxygen tensions five days postoperatively. Smaller differences were found with naloxone combined with morphine.

Topics: Adolescent; Adult; Clinical Trials as Topic; Cough; Doxapram; Female; Humans; Lung Diseases; Male; Middle Aged; Morphine; Naloxone; Oxygen; Postoperative Complications; Sputum

Arabinogalactan is a polysaccharide isolated from the roots of the medicinal plant Withania somnifera L. It contains 65% arabinose and 18% galactose. The aim of the present study was to evaluate the antitussive activity of arabinogalactan in conscious, healthy adult guinea pigs and the role of the opioid pathway in the antitussive action. A polysaccharide extract was given orally in a dose of 50 mg/kg. Cough was induced by an aerosol of citric acid in a concentration 0.3 mol/L, generated by a jet nebulizer into a plethysmographic chamber. The intensity of cough response was defined as the number of cough efforts counted during a 3-min exposure to the aerosol. The major finding was that arabinogalactan clearly suppressed the cough reflex; the suppression was comparable with that of codeine that was taken as a reference drug. The involvement of the opioid system was tested with the use of a blood-brain barrier penetrable, naloxone hydrochloride, and non-penetrable, naloxone methiodide, to distinguish between the central and peripheral mu-opioid receptor pathways. Both opioid antagonists acted to reverse the arabinogalactan-induced cough suppression; the reversion was total over time with the latter antagonist. We failed to confirm the presence of a bronchodilating effect of the polysaccharide, which could be involved in its antitussive action. We conclude that the polysaccharide arabinogalactan from Withania somnifera has a distinct antitussive activity consisting of cough suppression and that this action involves the mu-opioid receptor pathways.

Topics: Animals; Antitussive Agents; Citric Acid; Codeine; Cough; Galactans; Guinea Pigs; Male; Naloxone; Narcotic Antagonists; Plant Extracts; Plant Roots; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Withania

Opioid receptors which are involved in cough generation are abundantly expressed in the brainstem. Codeine is a potent μ-opioid receptor agonist. In the present study we examined the effects of naloxone, a μ-opioid receptor antagonist, on mechanically-induced tracheobronchial cough and on the cough suppressing effect of codeine in six pentobarbitone anesthetized spontaneously breathing rabbits. A single dose of naloxone (0.4 mg/kg) followed by a single dose of codeine (7 mg/kg) were administered intravenously. The number and amplitude of cough and sneeze reflexes were examined sequentially; before and after naloxone, and then after codeine. We found that neither did naloxone alone nor codeine given after prior naloxone pretreatment appreciably affect coughing or sneezing. Likewise, there were no significant differences in the diaphragm and abdominal muscles electromyographic moving averages, or the inspiratory and expiratory esophageal pressure amplitudes. However, we detected a tendency for the rise in expiratory motor drive during coughing and sneezing after injection of naloxone. The respiratory rate was significantly higher after naloxone in comparison with control (P < 0.001). No significant differences in arterial blood pressure were observed. We conclude that the failure of codeine to suppress the cough reflex on the background of naloxone pretreatment confirms the involvement of μ-opioid mechanism in the central antitussive effect of codeine.

Topics: Abdominal Muscles; Analgesics, Opioid; Animals; Antitussive Agents; Blood Pressure; Codeine; Cough; Diaphragm; Electromyography; Naloxone; Narcotic Antagonists; Rabbits; Receptors, Opioid, mu; Respiratory Muscles; Respiratory Rate; Sneezing

The purpose of this work was to search for potential drugs with potent antitussive and expectorant activities as well as a low toxicity, but without addictive properties. Cholic acid-verticinone ester (CA-Ver) was synthesized based on the clearly elucidated antitussive and expectorant activities of verticinone in bulbs of Fritillaria and different bile acids in Snake Bile. In our previous study, CA-Ver showed a much more potent activity than codeine phosphate. This study was carried out to investigate the central antitussive mechanism and the addictive evaluation of CA-Ver.. Testing on a capsaicin-induced cough model of mice pretreated with naloxone, a non-selective opioid receptor antagonist, was performed for the observation of CA-Ver's central antitussive mechanism. We then took naloxone-induced withdrawal tests of mice for the judgment of CA-Ver's addiction. Lastly, we determined the opioid dependence of CA-Ver in the guinea pig ileum.. The test on the capsaicin-induced cough model showed that naloxone could block the antitussive effect of CA-Ver, suggesting the antitussive mechanism of CA-Ver was related to the central opioid receptors. The naloxone-urged withdrawal tests of the mice showed that CA-Ver was not addictive, and the test of the opioid dependence in the guinea pig ileum showed that CA-Ver had no withdrawal response.. These findings suggested that CA-Ver deserved attention for its potent antitussive effects related to the central opioid receptors, but without addiction, and had a good development perspective.

Topics: Animals; Antitussive Agents; Capsaicin; Cevanes; Cholic Acids; Cough; Disease Models, Animal; Drug Interactions; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Naloxone; Opioid-Related Disorders; Receptors, Opioid; Substance Withdrawal Syndrome

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

To seek a novel and potent antitussive drug based on Shedan-Chuanbei powder, a complex of traditional Chinese medicine preparation for cough therapy.. Verticinone-cholic acid (Ver-CA) salt, a novel, salifying derivative of verticinone and cholic acid, both of which are the major bioactive components in Shedan-Chuanbei powder, was synthesized. We then evaluated the antitussive activity and the acute toxicity of the salt.. The new compound, with good solubility in water, has much more potent antitussive activity in comparison with the same dose of single verticinone and single cholic acid. The administration 3 mg/kg of Ver-CA could result in over 50% reduction of a citric acid-induced cough. Pretreatment with naloxone (0.8 mg/kg, ip) can only partially antagonize its antitussive effect. On the other hand, glybenclamide (3 mg/kg, ip), an ATP-sensitive K+ channel blocker, can also significantly reduce the antitussive effect of Ver-CA. A further acute toxicity study showed that the LD(50) values of Ver-CA were 3 times that of verticinone.. Based on the studies of pharmacology and acute toxicity, the salt has a synergic and attenuated toxicity compared with single verticinone and cholic acid. Moreover, the present study also suggests that Ver-CA, a potential novel antitussive agent, may exert its antitussive effect via both the peripheral (modulated by ATP-sensitive K+ channels) and central mechanisms (modulated by the opioid receptor).

Topics: Animals; Antitussive Agents; Cevanes; Cholic Acid; Cough; Dose-Response Relationship, Drug; Drug Compounding; Female; Glyburide; Guinea Pigs; KATP Channels; Male; Mice; Molecular Structure; Naloxone; Narcotic Antagonists; Random Allocation

The antitussive effects of endomorphin-1 and endomorphin-2, endogenous mu-opioid receptor agonists, on capsaicin-induced coughs were examined in mice. Endomorphin-2, at doses of 3, 10 and 30 microg, i.c.v., dose-dependently inhibited the number of capsaicin-induced coughs. However, the same doses (3, 10 and 30 microg) of endomorphin-1 injected with i.c.v. had no significant effects on the number of capsaicin-induced coughs. The antitussive effect of endomorphin-2 was significantly reduced by beta-funaltrexamine, a mu(1)/mu(2)-opioid receptor antagonist, but not naloxonazine, a selective mu(1)-opioid receptor antagonist. Furthermore, the antitussive effect of endomorphin-2 was also partially but significantly reduced by nor-binaltorphimine, a selective kappa-opioid receptor antagonist. These results indicate that the administration of the endogenous mu-opioid ligand endomorphin-2, but not endomorphin-1, into the brain produces an antitussive effect via mainly naloxonazine-insensitive mu-opioid receptors, namely mu(2)-opioid receptors and partially kappa-opioid receptors.

Topics: Animals; Antitussive Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naloxone; Naltrexone; Oligopeptides; Receptors, Opioid, kappa; Receptors, Opioid, mu

Angiotensin Converting Enzyme Inhibitors (ACEI) like captopril and enalapril, can induce persistant cough in man. Noscapine, an antitussive alkaloid, can be used to suppress ACEI-induced cough. Some workers have suggested a role for bradykinin in precipitation of ACE-induced cough. Work carried out in our laboratory has shown noscapine to be a non-competitive inhibitor of bradykinin in guinea pig ileum. It is therefore possible that noscapine suppresses cough by blocking the effect of bradykinin receptor activation in the airways. Guinea pigs were placed in a cough-chamber connected to an air pump and a pressure transducer. Capsaicin was sprayed into the chamber and cough was recorded as a distinctive change in air pressure inside the cough-chamber. Animals treated with 1 mg/kg captopril and enalapril for 7 days, showed increased cough response. Ten microgram/kg FR190997, a non-peptide agonist of the bradykinin B2 receptor, also increased the cough response. Noscapine at 0.5, 1 and 2 mg/kg was able to reverse the effects of ACEI and FR190997. Naloxone, a specific opioid receptor inhibitor, did not block the antitussive effects of noscapine in enalapril or FR190997 treated guinea pigs. This antitussive effect of noscapine is not mediated via the mu, kappa or delta opioid receptors. It is therefore possible that noscapine exerts its antitussive action by interfering with the bradykinin cough mediation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antitussive Agents; Bradykinin; Capsaicin; Captopril; Cough; Dose-Response Relationship, Drug; Drug Interactions; Enalapril; Guinea Pigs; Male; Naloxone; Narcotic Antagonists; Noscapine; Quinolines; Receptor, Bradykinin B2

We investigated whether inhaled pinacidil and moguisteine inhibit capsaicin-induced coughs in guinea pigs. Inhaled pinacidil (15 - 60 microg/ml), an ATP-sensitive K+ channel opener, and moguisteine (15 - 60 microg/ml) each dose-dependently inhibited the number of capsaicin-induced coughs. The antitussive effects of pinacidil and moguisteine were significantly antagonized by pretreatment with glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel blocker. However, pretreatment with naloxone methiodide (10 mg/kg, s.c.) had no significant effect on the antitussive effects of either pinacidil or moguisteine. On the other hand, inhaled dihydrocodeine (15 - 60 microg/ml) also dose-dependently suppressed the number of capsaicin-induced coughs. The antitussive effect of inhaled dihydrocodeine was significantly antagonized by pretreatment with naloxone methiodide (10 mg/kg, s.c.), but not by glibenclamide (10 mg/kg, i.p.). These results indicate that inhaled pinacidil and moguisteine both attenuate capsaicin-induced coughs. Pinacidil and moguisteine may exert their antitussive effects through the activation of ATP-sensitive K+ channels in the tracheobronchial tract. Furthermore, it is possible that ATP-sensitive K+ channels may be involved in the antitussive effects of peripherally acting non-narcotic antitussive drugs.

Topics: Adenosine Triphosphate; Administration, Inhalation; Animals; Antitussive Agents; Capsaicin; Codeine; Cough; Dose-Response Relationship, Drug; Drug Antagonism; Glyburide; Guinea Pigs; Male; Naloxone; Pinacidil; Potassium Channels; Thiazoles; Thiazolidines

In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor.

Topics: Animals; Carbazoles; Cell Line; CHO Cells; Cloning, Organism; Codeine; Cough; Cricetinae; Dextromethorphan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Humans; Hydrocodone; Levallorphan; Male; Naloxone; Narcotic Antagonists; Protein Binding; Pyridines; Pyrroles; Pyrrolidines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

Antinociceptive and antitussive effects of morphine were studied in DA-bg/bg (Beige) rats. Intraperitoneal administration of morphine (10 mg/kg) produced a marked antinociceptive effect, in the tail-flick test, in Beige rats and DA rats, a progenitor strain rats. There was no significant difference in the peak antinociceptive effect of morphine between Beige rats and DA rats. The antinociceptive effect of morphine in both Beige rats and DA rats was significantly reduced following pretreatment with a low dose (0.3 mg/kg, i.p.) of naloxone or naltrexonazine (1 mg/kg, s.c.), a selective mu 1-opioid receptor antagonist. Morphine suppressed coughs dose dependently at doses between 0.3-3 mg/kg, i.p., in Beige rats and between 0.1-1.0 mg/kg, i.p., in DA rats. The antitussive potency of morphine in Beige rats was less than that in DA rats. The antitussive effect of morphine was significantly antagonized by pretreatment with naloxone (0.3 mg/kg, i.p.) in both Beige rats and DA rats. However, pretreatment with naltrexonazine (1 mg/kg, s.c.), a selective mu 1-opioid receptor antagonist, had no effect on the antitussive effect of morphine. These results suggest that Beige rats are hyporesponsive to the mu 2-opioid receptor-mediated antitussive effect, but not to the mu 1-opioid receptor-mediated antinociceptive effect.

Topics: Analgesics, Opioid; Animals; Capsaicin; Cough; Female; Male; Morphine; Naloxone; Naltrexone; Pain; Rats; Rats, Inbred Strains; Species Specificity

The effect of buprenorphine on the antitussive effect of morphine was examined in mice. Buprenorphine at doses of 0.1, 0.3 and 1 mg/kg given i.p. alone have no effects on the % inhibition in the number of capsaicin-induced coughs. However, pretreatment with the same doses of buprenorphine for 2 hr significantly attenuated the antitussive effect of morphine (3 mg/kg, i.p.). Naloxonazine, a selective mu 1-opioid receptor antagonist, had no effect of buprenorphine on antitussive effect of morphine. These results suggest that buprenorphine antagonizes the antitussive effect of morphine via the activation of mu 1-opioid receptors.

Topics: Animals; Antitussive Agents; Buprenorphine; Capsaicin; Cough; Injections, Intraperitoneal; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Receptors, Opioid, mu; Time Factors

1. The antitussive effects of moguisteine have been compared with codeine in several experimental models of cough in guinea-pigs and dogs. 2. Moguisteine and codeine dose-dependently (respective ED50 values are given in parentheses) inhibited cough induced in guinea-pigs by 7.5% citric acid aerosol (25.2 and 29.2 mg kg-1, p.o.), by 30 microM capsaicin aerosol (19.3 and 15.2 mg kg-1, p.o.), by mechanical stimulation (22.9 and 26.4 mg kg-1, p.o.) and by tracheal electrical stimulation (12.5 and 13.9 mg kg-1, p.o.). 3. Moguisteine was effective against cough induced by tracheal electrical stimulation in dogs (ED50 17.2 mg kg-1, p.o.); codeine was not tested because of its emetic effect. 4. After repeated dosing (12-15 days), moguisteine did not induce tolerance in either guinea-pigs or dogs. 5. Moguisteine did not interact with opiate receptors, since it did not show affinity for [3H]-naloxone binding sites and furthermore naloxone (5 mg kg-1, s.c.) did not antagonize its antitussive effects. 6. Moguisteine had no antitussive effect after i.c.v. administration (20 micrograms), whilst codeine (2-10 micrograms) and dextromethorphan (2.5-20 micrograms) were highly effective. 7. Our findings demonstrate that moguisteine is a novel peripherally acting non-narcotic antitussive agent, the mode of action of which remains to be elucidated fully.

Topics: Aerosols; Animals; Antitussive Agents; Binding, Competitive; Capsaicin; Citrates; Citric Acid; Codeine; Cough; Dogs; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Injections, Intraventricular; Male; Naloxone; Physical Stimulation; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Thiazoles; Thiazolidines

The antitussive effects of SR 48968, a non-peptide tachykinin NK2 receptor antagonist, were investigated on citric acid-induced cough in the unanesthetized guinea-pig and compared with the effects of codeine. SR 48968 (0.01-0.3 mg/kg i.p.) inhibited in a dose-dependent manner the number of coughs induced by inhalation of an aqueous solution of citric acid with an ED50 of 0.1 mg/kg (0.17 mumol/kg). Under similar conditions, the codeine ED50 was 8 mg/kg (27 mumol/kg). Naloxone, an opioid receptor antagonist, abolished the effects of codeine but did not modify the effects of SR 48968. These data suggest that NK2 receptor stimulation might play an important role in the regulation of the cough reflex and that SR 48968 could be a potential antitussive agent.

Topics: Animals; Antitussive Agents; Benzamides; Citrates; Citric Acid; Codeine; Cough; Dose-Response Relationship, Drug; Female; Guinea Pigs; Injections, Intraperitoneal; Male; Naloxone; Piperidines; Receptors, Neurokinin-2

The effects of acute treatment with captopril, an angiotensin converting enzyme inhibitor, on the capsaicin-induced cough reflex were examined in rats. Intraperitoneal injection of captopril in doses of 3 and 10 mg/kg decreased the number of coughs dose-dependently. Although the peak effect was similar to that of morphine (0.5 mg/kg), the duration of captopril's effect (10 mg/kg) was longer than that of morphine. Furthermore, while pretreatment with naloxone significantly decreased the duration of the antitussive effect of captopril, it had no significant effect on the early-phase (within 60 min) effect of captopril. These results suggest that the mechanism which underlies the antitussive effect of captopril involves mediation by both nonopioid and opioid systems.

Topics: Animals; Antitussive Agents; Capsaicin; Captopril; Cough; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; Rats; Rats, Sprague-Dawley

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

The effect of pentazocine on the capsaicin-induced cough reflex in rats was investigated. Intraperitoneal injection of pentazocine, in doses from 1 to 10 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of pentazocine (10 mg/kg, i.p.) was significantly reduced by prior injection of naloxone (0.3 mg/kg, i.p.), but it was unaffected by Mr-2266 BS (5 mg/kg, i.p.), an antagonist of kappa-opioid receptors. The antinociceptive potency of pentazocine (30 mg/kg, i.p.), as determined by the formalin test, was significantly reduced by pretreatment with Mr-2266 BS (5 mg/kg, i.p.), whereas naloxone (0.3 mg/kg, i.p.) had no significant effect on the antinociceptive effect of pentazocine. The antitussive effects of pentazocine (3 mg/kg) and morphine (0.1 mg/kg) were significantly enhanced in rats treated chronically with naloxone (5 mg/kg/day, 5 days), whereas the antitussive effect of U-50,488 H (1 mg/kg, i.p.), a selective kappa-opioid agonist, was not enhanced in these rats. By contrast, the antinociceptive effect of morphine (0.01 mg/kg, i.p.) was significantly enhanced in rats that had been pretreated chronically with naloxone. However, the antinociceptive effects induced by pentazocine (3 mg/kg, i.p.) and U-50,488 H (1 mg/kg, i.p.) were unchanged. These results suggest that pentazocine-induced antitussive effects in rats are mediated via stimulation of mu-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antitussive Agents; Benzomorphans; Capsaicin; Cough; Dose-Response Relationship, Drug; Drug Interactions; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Morphine; Naloxone; Pentazocine; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu

1. Comparisons were made between the doses required of aerosol and intraperitoneally administered morphine, dextromethorphan, codeine and the specific peripherally acting mu-receptor agonist DALDA (H-Tyr-D-Arg-Phe-Lys-NH2) to suppress citric acid-induced coughing in conscious guinea pigs. 2. Estimated ID50s for inhibition of numbers of coughs induced by an aerosol of 5% citric acid were 1.0 and 2.4 mg/kg for intraperitoneally administered morphine and dextromethorphan, respectively. 3. The estimated ID50s after inhalation of morphine and dextromethorphan as aerosols were approximately 2.2 and approximately 12 micrograms/kg, respectively. 4. Aerosilized codeine (approximately 72 micrograms/kg, n = 5) significantly inhibited coughing by 62 +/- 23% whereas 3 mg/kg, i.p. was required to significantly reduce coughing by a similar degree (60 +/- 6%, n = 7). 5. Inhalation of DALDA (approximately 7.2 micrograms/kg, n = 7) also significantly inhibited coughing. 6. The antitussive effect of inhaled morphine (approximately 7.2 micrograms/kg, n = 11) was inhibited after administration of 3 mg/kg of either naloxone hydrochloride or naloxone methylbromide intraperitoneally. 7. The results support the hypothesis that effects at a peripheral site can make a major contribution to the antitussive actions of these drugs.

Topics: Administration, Inhalation; Animals; Antitussive Agents; Citrates; Citric Acid; Codeine; Cough; Dextromethorphan; Female; Guinea Pigs; Injections, Intraperitoneal; Morphine; Naloxone; Narcotics; Oligopeptides; Oxymorphone; Peripheral Nerves

Dextromethorphan-containing cold/cough preparations are frequently prescribed and bought over the counter for use in children. Although generally considered safe, dextromethorphan has been shown to cause CNS side effects, including hyperexcitability, increased muscle tone, and ataxia. Two deaths have been reported with intentional dextromethorphan overdose. A literature review, brief review of pharmacology, and report of two cases of adverse reactions to dextromethorphan-containing preparations are presented.

Topics: Child, Preschool; Cough; Dextromethorphan; Drug Overdose; Emergency Service, Hospital; Female; Humans; Infant, Newborn; Male; Naloxone

The authors studied relationship between the antitussic and analgesic activity of substances. The antitussic effect of codeine, tilidine, tramadol and pentazocine has been studied in nonanesthetized healthy cats. The drugs except tilidine, were administered intraperitoneally in a dose of 10 mg/kg body weight. Tilidine was administered intramuscularly in the same dose. Cough induced in nonanesthetized cats by mechanical irritation of laryngopharyngeal and tracheobronchial areas was evaluated by changes of the lateral tracheal pressure. A significant decrease of the subsequent cough parameters was observed after the application of codeine, tilidine, tramadol and pentazocine. Naloxone given 5 min before the application of the drug has not prevented the cough-suppressing effect due to codeine. Naloxone alone administered in a dose of 1 mg/kg body weight has not significantly influenced the experimentally-induced cough reflex in nonanesthetized cats.

Topics: Analgesia; Analgesics; Animals; Antitussive Agents; Cats; Codeine; Cough; Female; Male; Naloxone; Pentazocine; Tilidine; Tramadol

Topics: Analgesia; Animals; Antitussive Agents; Brain; Cell Membrane; Cough; Cyclohexanes; Cyclohexenes; Guinea Pigs; Hypothalamus; Morphine; Naloxone; Norepinephrine; Rats; Synaptosomes; Yohimbine

Effects of opioids and opioid antagonists on citric acid-induced cough and reflex bronchoconstriction have been examined in conscious guinea pigs. Airway reflexes produced by inhaled citric acid are mediated by capsaicin sensitive sensory neurons, and we examined particularly the possibility that inhibitory effects of opioids can be exerted locally in the airway. As expected, systemically administered codeine (1-10 mg/kg), meperidine (3-30 mg/kg) and morphine (1-10 mg/kg) dose-dependently inhibited cough and bronchoconstriction. However, inhalations of nebulized codeine (10-100 mg/ml) and morphine (10-30 mg/ml) also produced these effects. The potency and rapid onset of action of inhaled codeine suggest that it exerted its effects without first being metabolized to morphine. The opioid receptor antagonist naloxone completely (10-100 micrograms/kg), and nalorphine (a mixed agonist/antagonist) (1-3 mg/kg) partly, inhibited codeine's antitussive and antibronchoconstrictor effects. Nalorphine alone (3-30 mg/kg) inhibited citric acid induced reflexes, whereas naloxone was without effect. Prior inhalation of a quaternary opioid receptor antagonist, levallorphan methyl iodide (10 mg/ml), abolished the inhibitory effects of inhaled codeine (30 mg/ml). The present data suggest that inhibition of cough and reflex bronchoconstriction can be produced by opioids, acting on mu and kappa receptors located in the guinea pig tracheobronchial tree. The possible existence in the airways of a unique opioid receptor mediating inhibition of cough (as described in the central nervous system) cannot be excluded.

Topics: Animals; Bronchi; Citrates; Citric Acid; Codeine; Cough; Female; Guinea Pigs; Male; Meperidine; Morphine; Nalorphine; Naloxone; Receptors, Opioid; Reflex

The effects of highly selective agonists of kappa-opioid receptors, namely U-50,488H and U-62,066E, on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i.cist.) injection of U-50,488H and of U-62,066E significantly decreased the number of coughs in a dose-dependent manner. The antitussive potency of i.cist. injection of these two kappa-opioid agonists was similar to that of morphine. Intraperitoneal (i.p.) injection of U-50,488H and of U-62,066E also decreased the number of coughs, again in a dose-dependent manner. The antitussive effects of U-50,488H and U-62,066E were blocked by norbinaltorphimine, an antagonist of kappa-opioid receptors. Methysergide, administered i.cist. (3 nmol), antagonized the antitussive effects of U-50,488H and U-62,066E. However, ketanserin had no effect on the antitussive effects of these kappa-opioid agonists. These data suggest that U-50,488H and U-62,066E exert their antitussive effect on rats through stimulation of kappa-opioid receptors. Furthermore, with respect to the antitussive effects of kappa-opioid agonists, the system that involves 5-HT1 receptors may be more important than the system that involves 5-HT2 receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antitussive Agents; Cisterna Magna; Cough; Injections; Ketanserin; Male; Methysergide; Morphine; Naloxone; Naltrexone; Pyrrolidines; Rats; Rats, Inbred Strains; Reflex

Topics: Animals; Cats; Codeine; Cough; Dextropropoxyphene; Female; Male; Mice; Naloxone; Pain

Naloxone at doses of 200 micrograms X kg-1 increases cough, in experiments carried out on dogs. With stimuli of the same intensity, after naloxone, a significant increase in the number of coughs in each fit, is observed. Changes in the first cough burst, compared with spontaneous respiration at rest, are statistically significant and they contribute to define the characteristics of the cough burst. The increase of cough by naloxone blockade of endorphinic neurons of the respiratory center shows that usually the activity of these inhibitory neurons, tonically depresses the tussive response. The antitussive opiates would seem to operate by activating these inhibitory synapses.

Topics: Animals; Cough; Dogs; Electromyography; Endorphins; Lung Volume Measurements; Naloxone; Reflex; Respiratory Center; Stimulation, Chemical

Topics: Animals; Antitussive Agents; Binding, Competitive; Cats; Codeine; Cough; Dose-Response Relationship, Drug; Guinea Pigs; Medulla Oblongata; Naloxone; Narcotics; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Receptors, sigma; Stereoisomerism

Possible opiate-related descending influences from the periaqueductal gray matter (PAG) and nucleus raphe magnus (NRM) were tested on the activity of neural systems involved in respiration and related reflex functions in cats. Stimulation of PAG and NRM could powerfully suppress the simple buccopharyngeal reflexes of jaw-opening and tongue-protrusion and the more complex reflexes of coughing and swallowing; respiration in contrast appeared to be only weakly influenced. The reflexly induced responses of 57 single reflex interneurons recorded in the solitary tract nucleus (NST) could also be markedly suppressed by PAG and NRM conditioning stimulation. In contrast, the rhythmic activity of 30 respiratory neurons in NST was not abolished by PAG and NRM stimuli but most did show a decrease in the peak firing frequency of each rhythmic burst. The suppressive effect of PAG and NRM stimulation on the reflexes and NST reflex interneurons could be reduced by the intravenous administration of naloxone. These studies indicate that neuronal functions associated with respiration and respiratory-related activities can be suppressed by descending influences from PAG and NRM that are in part opiate-related. The observations add to the accumulating evidence that the raphe system is implicated in functions other than pain and its control, and they may also be relevant to clinical observations of opiate-induced effects on respiration and the cough reflex.

Topics: Animals; Brain Stem; Cats; Cerebral Aqueduct; Cough; Deglutition; Dental Pulp; Electric Stimulation; Evoked Potentials; Interneurons; Medulla Oblongata; Naloxone; Neural Inhibition; Neurons; Raphe Nuclei; Receptors, Opioid; Reflex; Respiration; Tongue

Butorphanol (levo-N-cyclobutylmethyl-3, 14-dihydroxy morphinan), a potent analgetic agent of the narcotic antagonist type with a low abuse potential in laboratory animals, was evaluated for antitussive activity in unanesthetized guinea-pigs and dogs. Subcutaneously, it was over 100 times more active than codeine, dextromethorphan and dl-pentazocine and about 20 times more active than morphine in the guinea-pig, while in the dog it was 100, 10 and 4 times more active than codeine, dl-pentazocine and morphine, respectively. Orally, butorphanol was 15-20 times more active than either codeine or dextromethrophan in both species. Naloxone reversed the antitussive effects of butorphanol, codeine, morphine and dl-pentazocine while those of dextromethorphan were not antagonized. The antitussive effect of butorphanol and morphine lasted about 4 hr and both compounds were longer acting than codeine. Butorphanol was also shown to be as effective against cough of pathological origin as against experimentally induced cough in the dog.

Topics: Animals; Antitussive Agents; Bronchitis; Cough; Cyclobutanes; Dogs; Electric Stimulation; Guinea Pigs; Male; Morphinans; Naloxone; Time Factors; Tracheitis