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.
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