Functional interaction between α2-adrenoceptors, μ- and κ-opioid receptors in the guinea pig myenteric plexus:: Effect of chronic desipramine treatment
Functional interaction between α2-adrenoceptors, μ- and κ-opioid receptors in the guinea pig myenteric plexus:: Effect of chronic desipramine treatment
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DOI：
10.1016/j.ejphar.2006.09.025
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发表时间：
2006-12-28
影响因子：
5
通讯作者：
Frigo, Gianmario
中科院分区：
文献类型：
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作者：
Canciani, Luca;Giaroni, Cristina;Frigo, Gianmario
在肠神经系统中，通过在慢性交感神经去神经后肠胆碱能神经元对α 2肾上腺素受体、μ和κ阿片受体药物的敏感性发生变化，证实了α 2肾上腺素受体和阿片受体抑制通路之间存在调节神经递质释放的功能性相互作用。在本研究中，为了进一步检验这一假设，我们评估了抗抑郁药地昔帕明（10 mg/kg，每天腹腔注射，持续21天）长期治疗对α 2肾上腺素受体通路的操纵是否会引起豚鼠远端结肠肌间神经丛中肠μ和κ阿片受体通路的变化。在该区域，慢性地昔帕明治疗后，对UK 14，304和U69，593（分别为α（2A）-肾上腺素受体和κ-阿片受体激动剂）对蠕动反射的抑制作用不敏感。相反，在这些实验条件下，对μ-阿片受体激动剂[D-Ala，N-Me-Phe 4-Gly-ol 5]-脑啡肽（DAMGO）对推进速度的抑制作用产生超敏感性。慢性地昔帕明治疗后，豚鼠结肠肌间神经丛中α（2A）-肾上腺素受体、μ-和κ-阿片受体的免疫反应性表达水平显著降低。在这些实验条件下，α（2A）-肾上腺素受体，μ-和κ-阿片受体的mRNA水平显着增加，不包括直接参与受体表达的调节转录机制。地昔帕明慢性治疗后，肌间神经丛G蛋白偶联受体激酶2/3和抑制性G（i/o）蛋白的水平显著降低。这种变化可能代表了对UK 14，304和U69，593的不敏感性对细胞增殖效率的影响的可能分子机制。替代的分子机制，包括受体活化和下游细胞内效应系统之间的偶联的更高效率，可能独立于抑制性G（i/o）蛋白，可能是对DAMGO超敏感性发展的原因。对μ-阿片激动剂的敏感性增加可能补偿α（2A）-肾上腺素受体和κ-阿片受体亚敏感性的发展。总的来说，目前的数据进一步加强了这样的概念，即在肠神经系统中操纵α（2）-肾上腺素能抑制性受体通路需要阿片抑制性受体通路的变化，这可能涉及维持体内平衡，如μ-阿片受体所示，但不是κ-阿片受体。(c)2006 Elsevier B.V保留所有权利。
The existence of a functional interplay between alpha(2)-adrenoceptor and opioid receptor inhibitory pathways modulating neurotransmitter release has been demonstrated in the enteric nervous system by development of sensitivity changes to alpha(2)-adrenoceptor, mu- and kappa-opioid receptor agents on enteric cholinergic neurons after chronic sympathetic denervation. In the present study, to further examine this hypothesis we evaluated whether manipulation of alpha(2)-adrenoceptor pathways by chronic treatment with the antidepressant drug, desipramine (10 mg/kg i.p. daily, for 21 days), could entail changes in enteric mu- and kappa-opioid receptor pathways in the myenteric plexus of the guinea pig distal colon. In this region, subsensitivity to the inhibitory effect of both UK14,304 and U69,593, respectively alpha(2A)-adrenoceptor and kappa-opioid receptor agonist, on the peristaltic reflex developed after chronic desipramine treatment. On opposite, in these experimental conditions, supersensitivity developed to the inhibitory effect of [D-Ala, N-Me-Phe4-Gly-ol5]-enkephalin (DAMGO), mu-opioid receptor agonist, on propulsion velocity. Immunoreactive expression levels of alpha(2A)-adrenoceptors, mu- and kappa-opioid receptors significantly decreased in the myenteric plexus of the guinea pig colon after chronic desipramine treatment. In these experimental conditions, mRNA levels of alpha(2A)-adrenoceptors, mu- and kappa-opioid receptors significantly increased, excluding a direct involvement of transcription mechanisms in the regulation of receptor expression. Levels of G protein-coupled receptor kinase 2/3 and of inhibitory G(i/o) proteins were significantly reduced in the myenteric plexus after chronic treatment with desipramine. Such changes might represent possible molecular mechanisms involved in the development of subsensitivity to UK14,304 and U69,593 on the efficiency of peristalsis. Alternative molecular mechanisms, including a higher efficiency in the coupling between receptor activation and downstream intracellular effector systems, possibly independent from inhibitory G(i/o) proteins, may be accounted for the development of supersensitivity to DAMGO. Increased sensitivity to the mu-opioid agonist might compensate for the development of alpha(2A)-adrenoceptor and kappa-opioid receptor subsensitivity. On the whole, the present data further strengthen the concept that, manipulation of alpha(2)-adrenergic inhibitory receptor pathways in the enteric nervous system entails changes in opioid inhibitory receptor pathways, which might be involved in maintaining homeostasis as suggested for mu-opioid, but not for kappa-opioid receptors. (c) 2006 Elsevier B.V All rights reserved.