u-50488 and Cough

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

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.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Cough; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Indoles; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; 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