OPIOID MECHANISMS OF TRAUMATIC BRAIN INJURY

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date7/1/926/30/11

Funding

  • National Institutes of Health: $227,546.00
  • National Institutes of Health: $372,350.00
  • National Institutes of Health: $241,400.00
  • National Institutes of Health: $362,780.00
  • National Institutes of Health: $50,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $234,372.00
  • National Institutes of Health: $362,369.00
  • National Institutes of Health: $376,049.00
  • National Institutes of Health: $204,749.00
  • National Institutes of Health
  • National Institutes of Health: $216,021.00
  • National Institutes of Health: $12,485.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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