- 作者: Minoru Narita; Hirokazu Mizoguchi; Michiko Narita; Nae J. Dun; Bang H. Hwang; Takash Endoh; Tomohiko Suzuki; Hiroshi Nagase; Tsutomu Suzuki; Leon F. Tseng
- 作者服務機構: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisc., USA Department of Toxicology, Hoshi University, Tokyo, Japan; Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tenn., Department of Anatomy, Indiana University School of Medicine, Indianapolis, Ind., USA; Basic Research Laboratories, Toray Industries, Kamarura, Japan
- 中文摘要: --
- 英文摘要: The midbrain perfaqueductal gray matter (PAG) is animportant brain region for the coordination of μ-opioid-induced pharmacological actions. The present study wasdesigned to determine whether newly isolated μ-opioidpeptide endomorphins can activate G proteins throughμ-opioid receptors in the PAG by monitoring the bindingto membranes of the non-hydrolyzable analog of GTP,guanosine-5'-O-(3-[ S]thio)triphosphate ([ S]GTPγS).An autoradiographic [ S]GTPγS binding study showedthat both endomorphin-1 and -2 produced similar ana-tomical distributions of activated G proteins in themouse midbrain region. In the mouse PAG, endomor-phin-1 and -2 at concentrations from 0.001 to 10 μMincreased [ S]GTRγS binding in a concentration-depen-dent manner and reached a maximal stimulation of 74.6±3.8 and 72.3±4.0%, respectively, at 10 μM. In con-trast, the synthetic selective μ-opioid receptor agonist[D-AIa ,NHPhe ,Gly-ol]enkephalin (DAMGO) had a muchgreater efficacy and produced a 112.6±5.1%increase ofthe maximal stimulation. The receptor specificity of en-domorphin-stimulated [ S]GTPγS binding was verifiedby coincubating membranes with endomorphins in thepresence of specific μ-, δ- or κ-opioid receptor antago-nists. Coincubation with selective μ-opioid receptor an-tagonists β-funaltrexamine or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH (CTOP) blocked both endomorphin-1and-2-stimulated [ S]GTPγS binding. In contrast, nei-ther δ- nor κ-opioid receptor antagonist had any effect onthe [ S]GTPγS binding stimulated by either endomor-phin-1 or -2. These findings indicate that both endomor-phin-1 and -2 increase [ S]GTPγS binding by selectivelystimulating μ-opioid receptors with intrinsic activity lessthan that of DAMGO and suggest that these new endoge-nous ligands might be partial agonists for μ-opioidreceptors in the mouse PAG.
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- 英文關鍵字: --