Yokukansan inhibits morphine tolerance and physical dependence in mice: the role of α₂A-adrenoceptor.
Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18β-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. tnakaga@pharm.kyoto-u.ac.jp
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T
Nakagawa
K
K
Nagayasu
N
N
Nishitani
H
H
Shirakawa
K
K
Sekiguchi
Y
Y
Ikarashi
Y
Y
Kase
S
S
Kaneko
D018663:Adrenergic Agents / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006153:Guanosine Diphosphate / Q000494:pharmacology; D007554:Isotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000188:drug therapy*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013997:Time Factors; D014326:Tropanes / Q000493:pharmacokinetics
D018663:Adrenergic Agents; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D004365:Drugs, Chinese Herbal; D007554:Isotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; C432869:RTI 112; D018341:Receptors, Adrenergic, alpha-2; D014326:Tropanes; C524644:Yi-Gan San; D006153:Guanosine Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011433:Propranolol