DYNORPHIN-A-(1-17) INDUCES ALTERATIONS IN FREE FATTY-ACIDS, EXCITATORY AMINO-ACIDS, AND MOTOR FUNCTION THROUGH AN OPIATE-RECEPTOR-MEDIATED MECHANISM
DYNORPHIN-A-(1-17) INDUCES ALTERATIONS IN FREE FATTY-ACIDS, EXCITATORY AMINO-ACIDS, AND MOTOR FUNCTION THROUGH AN OPIATE-RECEPTOR-MEDIATED MECHANISM
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DOI：
10.1523/jneurosci.10-12-03793.1990
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发表时间：
1990-12-01
影响因子：
5.3
通讯作者：
FADEN, AI
中科院分区：
文献类型：
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作者：
BAKSHI, R;NEWMAN, AH;FADEN, AI
内源性阿片类强啡肽A-(1-17)(Dyn A)被认为是创伤性脊髓损伤(TSCI)后组织损伤的介质，鞘内给药可导致后肢瘫痪。鞘内注射Dyn A后的运动损伤可通过兴奋性氨基酸拮抗剂(EaaS)来减轻；阿片受体介导这种损伤的情况一直受到质疑。TSCI引起与继发性组织损伤相关的各种生化变化，包括组织氨基酸、磷脂和脂肪酸的变化。这些变化反映了损伤的严重程度，并与运动功能障碍有关。目前的研究考察了强啡肽给药是否引起类似的生化改变，以及是否可以通过阿片受体拮抗剂治疗来改变强啡肽A的作用。鞘内注射dyn A后24小时，谷氨酸、天冬氨酸和甘氨酸的组织水平显著下降。总游离脂肪酸在2小时和24小时时增加，反映了饱和和不饱和成分的变化，这与较早时间点组织胆固醇和磷脂磷的显著下降有关。每一种神经化学变化以及相应的运动障碍，都受到阿片类拮抗剂纳美芬预处理的限制。在单独的实验中，纳美芬和选择性kappa阿片拮抗剂Nor-BNI都限制了强啡肽诱导的运动功能障碍；Nor-BNI的作用与剂量有关，而纳美芬的作用是立体特异性的。因此，Dyn A给药的行为和神经化学后果部分是通过阿片受体，最有可能是kappa受体介导的。这些研究表明，磷脂水解和EaS的释放可能参与强啡肽诱导的组织损伤，首次表明神经创伤后继发性损伤的阿片类药物、兴奋性毒素和膜脂机制之间存在潜在的联系。
The endogenous opioid dynorphin A-(1-17) (Dyn A) has been implicated as a mediator of tissue damage after traumatic spinal cord injury (TSCI) and causes hindlimb paralysis when administered intrathecally. Motor impairment following intrathecal Dyn A is attenuated by antagonists of excitatory amino acids (EAAs); where opioid receptors mediate such injury has been questioned. TSCI causes various biochemical changes associated with secondary tissue damage, including alterations in tissue amino acids, phospholipids, and fatty acids. Such changes reflect injury severity and correlate with motor dysfunction. The present studies examined whether dynorphin administration causes similar biochemical alterations and whether effects of Dyn A can be modified by treatment with opioid-receptor antagonists. At 24 hr after intrathecal Dyn A, there were significant declines in tissue levels of glutamate, aspartate, and glycine. Increase in total free fatty acids were found at 2 and 24 hr, reflecting changes in both saturated and unsaturated components, which were associated with significant decreases in tissue cholesterol and phospholipid phosphorus at the earlier time point. Each of these neurochemical changes, as well as corresponding motor deficits, were limited by pretreatment with the opioid antagonist nalmefene. In separate experiments, both nalmefene and the selective kappa-opioid antagonist nor-binaltorphimine (nor-BNI) limited dynorphin-induced motor dysfunction; effects of nor-BNI were dose related, and those of nalmefene were stereospecific. Therefore, behavioral and neurochemical consequences of Dyn A administration are mediated in part through opiate receptors, most likely kappa-receptors. These studies indicate that phospholipid hydrolysis and release of EAAs may contribute to dynorphin-induced tissue damage, suggesting for the first time a potential linkage among opioid, excitotoxin, and membrane lipid mechanisms of secondary injury after neurotrauma.