Beijing Institute of Pharmacology and Toxicology, China.
Addict Biol. 2012 Mar;17(2):392-408. doi: 10.1111/j.1369-1600.2011.00373.x. Epub 2011 Oct 4.
Agmatine, an endogenous ligand for imidazoline receptor, has been shown to prevent opioid dependence, but not much is known about the mechanisms of the effect of agmatine. In the present study, we investigated the function of I1 imidazoline receptor and its candidate protein imidazoline receptor antisera-selected (IRAS)/Nischarin in morphine dependence as well as in the effect of agmatine inhibiting morphine dependence by pharmacological and molecular approaches. Results showed that inhibition of IRAS or Nischarin did not change the development of morphine dependence in vitro and in vivo under the basal condition. Agmatine could reduce the cyclic 3', 5' adenosine monophosphate (cAMP) overshoot at the concentration of 0.01-10 µM in the primary cultured rat hippocampal neurons and attenuated the withdrawal signals and the elevation of FosB and ΔFosB at the dose of 5 mg/kg in the morphine-dependent mice. The effect of agmatine was inhibited by efaroxan (I1 imidazoline receptor non-specific antagonist) and the RNA interference against IRAS or Nischarin. These findings indicate that I1 imidazoline receptor or IRAS/Nischarin mediates the effect of agmatine on morphine dependence and provide evidence that I1 imidazoline receptor may be a new target for treating morphine dependence.
胍丁胺是咪唑啉受体的内源性配体，已被证明可预防阿片类药物依赖，但对胍丁胺作用的机制知之甚少。在本研究中，我们通过药理学和分子方法研究了 I1 咪唑啉受体及其候选蛋白咪唑啉受体抗血清选择（IRAS）/Nischarin 在吗啡依赖中的作用以及胍丁胺抑制吗啡依赖的作用。结果表明，在基础条件下，抑制 IRAS 或 Nischarin 不会改变体外和体内吗啡依赖的发展。胍丁胺可以在浓度为 0.01-10μM 时减少原代培养大鼠海马神经元中环磷酸腺苷（cAMP）的过度增加，并在 5mg/kg 剂量下减轻吗啡依赖小鼠的戒断信号和 FosB 和 ΔFosB 的升高。胍丁胺的作用被 efaroxan（I1 咪唑啉受体非特异性拮抗剂）和针对 IRAS 或 Nischarin 的 RNA 干扰所抑制。这些发现表明，I1 咪唑啉受体或 IRAS/Nischarin 介导了胍丁胺对吗啡依赖的作用，并为 I1 咪唑啉受体可能成为治疗吗啡依赖的新靶点提供了证据。
