Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception.
Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception.
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发表时间：
1998-12
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通讯作者：
Ying-fu Su;R. Mcnutt;Kwen-Jen Chang
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作者：
Ying-fu Su;R. Mcnutt;Kwen-Jen Chang
有证据表明，阿片样物质μ和δ受体可能在不同的中枢神经系统部位参与呼吸调节。过去，各种阿片类药物的重叠受体特异性使得难以剖析参与呼吸调节的受体亚型特异性活性。新的δ受体选择剂家族，例如环状[D-Pen 2，5]脑啡肽、δ啡肽、（+）-4-（（α-R）-α-（（2S，5 R）-4-烯丙基-2，5-二甲基-1-哌嗪基）-3-羟基苄基）-N，N-二乙基苯甲酰胺、纳曲吲哚和H-Tyr-Tic（psi）[CH 2NH]Phe-Phe-OH，现在已经使得更清楚地定义δ受体在呼吸控制中的作用变得可行。在一系列实验中，我们观察到，大鼠全身输注高度μ受体特异性阿片类药物阿芬太尼诱导抗伤害感受和高碳酸血症，这两种作用都被μ受体拮抗剂D-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH 2拮抗。然而，δ受体拮抗剂纳曲吲哚的外周给药逆转高碳酸血症，但不是阿芬太尼的镇痛活性。纳曲吲哚对抗伤害感受和高碳酸血症的这种不同作用也可以用δ激动剂（+）-4-（（α-R）-α-（（2S，5 R）-4-烯丙基-2，5-二甲基-1-哌嗪基）-3-羟基苄基）-N，N-二乙基苯甲酰胺产生。此外，脑室内递送许多肽δ配体环[D-Pen 2，5]脑啡肽、deltorpnin II和H-Tyr-Tic（psi）[CH 2NH]Phe-Phe-OH也产生高碳酸血症的相同差异逆转而不影响抗伤害感受。因此，传统的δ激动剂和拮抗剂都能够逆转阿芬太尼诱导的高碳酸血症而不影响抗伤害感受。这些δ配体对阿芬太尼诱导的高碳酸血症的逆转作用被一种新的合成δ拮抗剂cis-4-（alpha-（4-（（Z）-2-丁烯基）-3，5-二甲基-1-哌嗪基）-3-羟基苄基）-N，N-二乙基苯甲酰胺拮抗。我们提出，在这个实验性呼吸模型中，δ拮抗剂纳曲吲哚和H-Tyr-Tic（psi）[CH 2NH]Phe-Phe-OH表现得像δ激动剂，具有低但足够的内在活性来逆转大鼠中阿芬太尼诱导的高碳酸血症。结果表明，δ受体的功能是调节或抵消μ受体诱导的呼吸抑制。
Evidence suggests both opioid mu and delta receptors may participate in the regulation of respiration at different central nervous system sites. In the past, the overlapping receptor specificity of various opioid drugs has made it difficult to dissect the receptor subtype-specific activities involved in respiratory regulation. The new family of delta receptor selective agents such as cyclic[D-Pen2, 5]enkephalin, deltorphins, (+)-4-((alpha-R)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide, naltrindole and H-Tyr-Tic(psi)[CH2NH]Phe-Phe-OH have now made it feasible to more clearly define the role of delta receptors in respiratory control. In a series of experiments we observed that systemic infusion of rats with the highly mu receptor-specific opioid alfentanil induced antinociception and hypercapnia, and both of these effects were antagonized by the mu antagonist D-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH2. However, peripheral administration of the delta receptor antagonist naltrindole reverses the hypercapnia but not the antinociceptive activity of alfentanil. This differential effect of naltrindole on antinociception and hypercapnia could also be produced with the delta agonist (+)-4-((alpha-R)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. In addition, intracerebroventricular delivery of a number of peptide delta ligands cyclic[D-Pen2,5]enkephalin, deltorpnin II and H-Tyr-Tic(psi)[CH2NH]Phe-Phe-OH also produced the same differential reversal of hypercapnia without affecting antinociception. Thus, both the traditional delta agonists and antagonists are able to reverse the alfentanil-induced hypercapnia without affecting antinociception. The reversal of alfentanil-induced hypercapnia by these delta ligands was antagonized by a novel synthetic delta antagonist cis-4-(alpha-(4-((Z)-2-butenyl)-3, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. We propose that in this experimental respiration model, the delta antagonists naltrindole and H-Tyr-Tic(psi)[CH2NH]Phe-Phe-OH behave like delta agonists with low but sufficient intrinsic activities to reverse alfentanil-induced hypercapnia in rats. The results suggest that a function of the delta receptor is to modulate or counteract the respiratory depression induced by the mu receptor.