The major hypothesis of this study is that following induction of inflammation, ascending tonic nociceptive inputs induce prolonged functional changes in the neural circuitry at brainstem sites leading ultimately to a net inhibitory modulation of spinal cord activity. This input to the brainstem triggers a cascade of molecular, biochemical and electrophysiological events that result in enhanced excitability and inducible changes in neurotransmitters and receptor populations.
Specific Aim 1 will test the hypothesis that persistent inflammation leads to time-dependent, dynamic changes in the neuronal excitability of medullary brain stem nuclei.
Specific Aim 2 will test the hypothesis that endogenous mechanisms of inflammation-induced changes in the excitability of medullary brain stem neurons involve excitatory and inhibitory amino acids, opioid peptides and their receptors.
Specific Aim 3 will use molecular and immunohistochemical probes to test the hypothesis that alterations in EAA receptor activation play a key role in enkephalinergic transmission and that reduced GABAergic transmission in the RVM is mediated via postsynaptic mu opioid receptors (MORs) after inflammation.
Specific Aim 4 will test the hypothesis that changes in brain stem excitability after inflammation lead to alterations in the response profile of several different classes of neurons in the RVM. These events will be explored in a lightly anesthetized rat preparation in which both behavioral and electrophysiological responses to hindpaw inflammation can be ascertained sequentially over time. Hindpaw inflammation will be induced with complete Freund's adjuvant (CFA) and the studies done over specific, but relatively short, time frames during the development phase of this persistent inflammatory state. Fixed brainstem tissues from other animals with CFA inflamed hindpaws will be compared to control tissues to determine specific inducible neurotransmitter and receptor changes subsequent to inflammation. The screening process will include anatomical studies identifying excitatory amino acid (EAA) and preproenkephalin (PPE) receptor mRNA expression increases, as well as immunocytochemical localization of changes in Fos, GABA, mu opioid receptor, and glutamate receptor subunit NMDA NR1 expression with specific antibodies. The findings of this study will improve understanding of supraspinally initiated descending mechanisms that modulate the pain experience through alteration of the nociceptive information relayed from the spinal cord.
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