title: Role of benzodiazepine-GABAA receptor complex in attenuation of U-50,488H-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin in mice.
abstract: In the present study, the role of benzodiazepine-GABAA receptor complex in the attenuation of U-50,488H (U50), a selective kappa opioid agonist-induced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin (GTS) was investigated using the mice tail-flick test. The intraperitoneal (i.p.) treatment of GTS (100 and 200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently attenuated the U50 (40 mg/kg, i.p.)-induced analgesia. GTS (0.001-10 microg/ml) did not alter binding of [3H]naloxone to mice whole brain membrane. The attenuation effect of GTS (100 mg/ kg) and diazepam (0.5 mg/kg) on U50-induced analgesia was blocked by flumazenil (0.1 mg/kg, i.p.), a benzodiazepine receptor antagonist, and picrotoxin (1 mg/kg, i.p.), a GABAA-gated chloride channel blocker. However, bicuculline (1 mg/kg, i.p.), a GABAA receptor antagonist blocked the attenuation effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on U50-induced analgesia. Chronic treatment (day 4-day 6) of GTS (50-200 mg/kg) and diazepam (0.1-1 mg/kg) dose-dependently inhibited the tolerance to U50-induced analgesia. Flumazenil (0.1 mg/kg) and picrotoxin (1 mg/kg) on chronic treatment blocked the inhibitory effect of GTS (100 mg/kg) and diazepam (0.5 mg/kg) on tolerance to U50-induced analgesia. On the other hand, chronic treatment of bicuculline (1 mg/kg) blocked the inhibitory effect of diazepam (0.5 mg/kg) but not GTS (100 mg/kg) on tolerance to U50-induced analgesia. In conclusion, the findings suggest that GTS attenuates U50-induced analgesia and inhibits tolerance to its analgesia and this action involves benzodiazepine receptors and GABAA-gated chloride channels.
authors: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Nagar, India.
authors: Kumar V S
authors: KV
authors: Nemmani
authors: P
authors: P
authors: Ramarao
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004361:Drug Tolerance; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D036145:Ginsenosides; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010146:Pain / Q000517:prevention & control; D017288:Pain Threshold / Q000187:drug effects; D005894:Panax; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology*; D013623:Tail / Q000187:drug effects
chemical_list: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D018712:Analgesics, Non-Narcotic; D001640:Bicuculline; D003975:Diazepam; D004365:Drugs, Chinese Herbal; D005442:Flumazenil; D036145:Ginsenosides; D010852:Picrotoxin; D011963:Receptors, GABA-A; D017473:Receptors, Opioid, kappa; D012503:Saponins