Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model.
Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model.
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DOI：
10.1016/j.brainres.2012.10.024
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发表时间：
2013-01-15
期刊：
影响因子：
2.9
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Ji F;Wang Z;Ma N;Riley J;Armstead WM;Liu R
由于赫肯诺林是第一种来源于鼠尾草素A的具有诱导脑血管扩张能力的非阿片类μ激动剂，因此我们假设赫肯诺林可以通过μ和κ阿片类受体以及cAMP途径具有相似的血管扩张作用。通过体外竞争结合测定法测定赫克洛因与κ和μ阿片受体的结合亲和力。在配备有闭合颅窗的仔猪中监测脑动脉，并在存在或不存在研究药物的情况下，在注射人工脑脊液（CSF）之前和之后每30秒记录动脉反应：herkinorion，norbinaltorphimine（NTP），一种κ阿片受体拮抗剂，β-funalphimine（β-FNA），一种μ阿片受体拮抗剂，或Rp-8-Br-cAMPS（Rp-cAMPS），蛋白激酶A（PKA）的抑制剂。在赫肯诺林和NTP给药前和给药后10分钟收集CSF样品，用于测量cAMP水平。数据采用重复测量方差分析。我们的研究结果表明，赫克洛因结合κ和μ阿片受体。NTP可完全阻断其舒张血管的作用，而β-FNA则不影响其作用。CSF中的cAMP水平在赫氏菌素给药后升高，但在NTP给药后消失。Herkinorin的脑血管舒张作用也被Rp-cAMPS减弱。总之，作为一种非阿片类κ和μ阿片受体激动剂，赫凯诺林具有扩张脑血管的作用。这种扩张是通过κ阿片受体而不是μ阿片受体介导的。cAMP信号传导在此过程中也起重要作用。
Since herkinorin is the first non-opioid mu agonist derived from salvinorin A that has the ability to induce cerebral vascular dilatation, we hypothesized that herkinorin could have similar vascular dilatation effect via the mu and kappa opioid receptors and the cAMP pathway. The binding affinities of herkinorin to kappa and mu opioid receptors were determined by in-vitro competition binding assays. The cerebral arteries were monitored in piglets equipped with a closed cranial window and the artery responses were recorded before and every 30 s after injection of artificial cerebrospinal fluid (CSF) in the presence or absence of the investigated drugs: herkinorion, norbinaltorphimine (NTP), a kappa opioid receptor antagonist, β-funaltrexamine (β-FNA), a mu opioid receptor antagonist, or Rp-8-Br-cAMPS (Rp-cAMPS), an inhibitor of protein kinase A (PKA). CSF samples were collected before and 10 min after herkinorin and NTP administration for the measurement of cAMP levels. Data were analyzed by repeated-measures analysis of variance. Our results show that herkinorin binds to both kappa and mu opioid receptors. Its vasodilation effect is totally abolished by NTP, but is not affected by β-FNA. The levels of cAMP in the CSF elevate after herkinorin administration, but are abolished with NTP administration. The cerebral vasodilative effect of herkinorin is also blunted by Rp-cAMPS. In conclusion, as a non-opioid kappa and mu opioid receptor agonist, herkinorin exhibits cerebral vascular dilatation effect. The dilatation is mediated though the kappa opioid receptor rather than the mu opioid receptor. cAMP signaling also plays an important role in this process.
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DOI：
10.1124/jpet.108.140079
发表时间：
2008-10
影响因子：
3.5
作者：
Butelman, Eduardo R.;Rus, Szymon;Simpson, Denise S.;Wolf, Angela;Prisinzano, Thomas E.;Kreek, Mary Jeanne
通讯作者：
Kreek, Mary Jeanne
影响因子：
2.9
作者：
DEVINE, JO;ARMSTEAD, WM
通讯作者：
ARMSTEAD, WM
影响因子：
7.3
作者：
Harding, WW;Tidgewell, K;Prisinzano, TE
通讯作者：
Prisinzano, TE
影响因子：
64.8
作者：
Wu, Huixian;Wacker, Daniel;Mileni, Mauro;Katritch, Vsevolod;Han, Gye Won;Vardy, Eyal;Liu, Wei;Thompson, Aaron A.;Huang, Xi-Ping;Carroll, F. Ivy;Mascarella, S. Wayne;Westkaemper, Richard B.;Mosier, Philip D.;Roth, Bryan L.;Cherezov, Vadim;Stevens, Raymond C.
通讯作者：
Stevens, Raymond C.
影响因子：
8.8
作者：
Su D;Riley J;Kiessling WJ;Armstead WM;Liu R
通讯作者：
Liu R