Armstead W M
Department of Anesthesia and Pharmacology, The University of Pennsylvania , USA.
Brain Res. 1997 Feb 7;747(2):252-8. doi: 10.1016/s0006-8993(96)01284-x.
The present study was designed to investigate the role of activation of Kca+2 channels and cAMP in opioid-induced pial artery dilation in newborn pigs equipped with closed cranial windows. Methionine enkephalin, an endogenous mu agonist, elicited dilation that was modestly attenuated by the Kca+2 channel antagonist, iberiotoxin (10(-7) M) (7 +/- 1, 11 +/- 1 and 16 +/- 1 vs. 4 +/- 1, 7 +/- 1, and 11 +/- 1% for methionine enkephalin 10(-10), 10(-8), 10(-6) M in the absence and presence of iberiotoxin, respectively). Dilator responses to leucine enkephalin and dynorphin, endogenous delta and kappa agonists, as well as the synthetic analogues DAMGO, DPDPE, deltorphin and U50488H all were similarly attenuated by iberiotoxin. Dilation in response to methionine enkephalin was accompanied by increased CSF cAMP concentration (1170 +/- 21, 1358 +/- 22, 1473 +/- 26, and 1575 +/- 24 fmol/ml for control, 10(-10), 10(-8), 10(-6) M methionine enkephalin, respectively). Methionine enkephalin-induced dilation was attenuated by Rp 8-bromo cAMPs (10(-5) M), a cAMP antagonist (7 +/- 1, 11 +/- 1 and 17 +/- 1 vs. 2 +/- 1, 4 +/- 1, and 7 +/- 1% for methionine enkephalin 10(-10), 10(-8), and 10(-6) M in the absence and presence of Rp 8-bromo cAMPs, respectively). Dilation by the other endogenous and synthetic opioid analogues was also accompanied by elevated CSF cAMP and attenuated by Rp 8-bromo cAMPs. Additionally, dilation produced by the cAMP analogue, 8-bromo cAMP, was blunted by iberiotoxin. These data show that both cAMP and activation of Kca+2 channels contribute to opioid-induced pial artery dilation. Further, these data suggest that opioids elicit dilation, at least in part, via the sequential release of cAMP and subsequent activation of Kca+2 channels by this second messenger.
本研究旨在探讨Kca+2通道激活和环磷酸腺苷（cAMP）在配备闭合式颅窗的新生猪阿片类药物诱导的软脑膜动脉扩张中的作用。内源性μ激动剂甲硫氨酸脑啡肽引起的扩张，被Kca+2通道拮抗剂iberiotoxin（10^(-7)M）适度减弱（甲硫氨酸脑啡肽10^(-10)、10^(-8)、10^(-6)M时，在不存在和存在iberiotoxin的情况下，分别为7±1、11±1和16±1对4±1、7±1和11±1%）。对亮氨酸脑啡肽和强啡肽（内源性δ和κ激动剂）以及合成类似物DAMGO、DPDPE、deltorphin和U50488H的扩张反应，均同样被iberiotoxin减弱。对甲硫氨酸脑啡肽的扩张反应伴随着脑脊液cAMP浓度升高（对照组、10^(-10)、10^(-8)、10^(-6)M甲硫氨酸脑啡肽时，分别为1170±21、1358±22、1473±26和1575±24fmol/ml）。甲硫氨酸脑啡肽诱导的扩张被cAMP拮抗剂Rp 8-溴cAMPs（10^(-5)M）减弱（甲硫氨酸脑啡肽10^(-10)、10^(-8)和10^(-6)M时，在不存在和存在Rp 8-溴cAMPs的情况下，分别为7±1、11±1和17±1对2±1、4±1和7±1%）。其他内源性和合成阿片类类似物引起的扩张也伴随着脑脊液cAMP升高，并被Rp 8-溴cAMPs减弱。此外，cAMP类似物8-溴cAMP产生的扩张被iberiotoxin减弱。这些数据表明，cAMP和Kca+2通道激活均有助于阿片类药物诱导的软脑膜动脉扩张。此外，这些数据表明，阿片类药物至少部分通过依次释放cAMP以及随后由该第二信使激活Kca+2通道来引起扩张。
