OPIOID MECHANISMS OF TRAUMATIC BRAIN INJURY

实验性创伤性脑损伤（TBI）引起弥漫性神经元损伤， 去极化产生大量非特异性释放， 神经传递素 TBI诱导激动剂受体的急性净效应 相互作用是过度的神经元兴奋。 由此产生的兴奋毒性 对TBI的病理生理学有显著贡献。 这个过程 即使抑制性受体（阿片样物质等）也被激活 受伤。 我们的中心假设指出，大脑阿片受体的激活， 损伤的时间可以调节急性TBI诱导的过程， 在最初的损伤后长期存在的功能缺陷。 我们提出 评估单次给予选择性阿片类药物的效果 受体亚型激动剂或拮抗剂对结局指标的影响 甚至是在给药后数周。 初步数据表明，损伤前给予mu或delta 受体亚型激动剂可减少与 关于TBI 相反，其他初步数据表明， 选择性μ或δ拮抗剂的给药加重了TBI长- 长期功能缺陷。 其他研究表明，kappa的激活 受体加剧TBI病理生理学。 阿片受体对大多数神经元的兴奋性有抑制作用， 大脑区域。 然而，在海马体中某些阿片样物质的激活 受体亚型通过以下过程增加神经元兴奋性： 去抑制 因此，阿片受体激活可以减少或 增加对TBI的病理生理反应，这取决于解剖结构 受影响的阿片受体的位置和亚类。 我们将研究阿片类药物介导TBI的机制， 选择性μ、δ和κ阿片激动剂和拮抗剂对TBI的影响 病理生理学 我们将研究药物对TBI诱导的： 海马兴奋性，增加的脆弱性（神经元死亡）， 继发性缺血，脑血流量减少， 功能缺陷 这项研究将提供有关可能的有毒和 阿片类药物的治疗作用，对于任何潜在的临床 使用这些药物。

Experimental traumatic head injury (TBI) causes diffuse neuronal depolarization which produces a large non-specific release of neurotransmitters. the acute, net effect of TBI-induced agonist-receptor interactions is excessive neuronal excitation. The resulting excitoxicity significantly contributes to the pathophysiology of TBI. this process occurs even though inhibitory receptors (opioid, etc.) are also activated by injury. Our central hypothesis states that activation of brain opioid receptors at the time of injury can modulate acute TBI-induced processes which result in functional deficits persisting long after the initial insult. We propose to assess the effects of a single administration of selective opioid receptor subtype agonists or antagonists on outcome measures assessed days or even weeks after drug administration. Preliminary data suggest that pre-injury administration of mu or delta receptor subtype agonists reduces long-term function deficits associated with TBI. Conversely, other preliminary data suggest that pre-injury administration of selective mu or delta antagonists exacerbate TBI long- term functional deficits. Other studies suggest that activation of kappa receptors exacerbate TBI pathophysiology. Opioid receptors have inhibitory effects on neuronal excitability in most brain regions. However, in the hippocampus activation of certain opioid receptor subtypes increase neuronal excitability through a process of disinhibition. Thus, opioid receptor activation may either reduce or increase pathophysiological responses to TBI depending upon the anatomical location and subclass of opioid receptor affected. We will examine opioid mechanisms mediating TBI by examining the effects of selective mu, delta, and kappa opioid agonists and antagonists on TBI pathophysiology. We will examine drug effects on TBI-induced:increases in hippocampal excitability, increased vulnerability (neuronal death) to an imposed secondary ischemia, decreases in cerebral blood flow, and functional deficits. This research will provide important information on possible toxic and therapeutic effects of opioids necessary for any potential clinical application of such drugs.