| Summary: | Thesis (Ph.D)--Memorial University of Newfoundland, 2009. Medicine Includes bibliographical references (leaves 213-264). Allodynia is an abnormal state in which pain is triggered by innocuous sensory stimuli. Previous work in our laboratory has shown that L5/L6 spinal nerve ligation (SNL) induces robust mechanical allodynia in the rat which consists of two distinct phases: (a) an early spinal prostaglandin (PG)-dependent phase lasting approximately seven to ten days; and (b) a delayed PG-independent phase lasting at least seventy days. Importantly, the former is a prerequisite to and a trigger for the more complex and time-dependent changes underlying long-term, irreversible allodynia. Interfering with critical signaling events early after nerve injury is a logical strategy by which chronic neuropathic pain might be prevented. Such an approach requires a clear understanding of the sequence, time-course and pharmacology of these early signals. -- In light of the apparent pathogenic role of spinal PG early after nerve injury, the present research investigated the SNL-induced changes in spinal PG synthesis and signaling, their relevance to the development of spinal hyperexcitability and allodynia, and the mechanisms underlying the changes in PG synthesis and signaling in the spinal PG-dependent phase. The specific objectives were: -- (1) To characterize the effect of SNL on A- and C-fiber mediated reflex responses (AFRR and CFRR, respectively) in the affected hind limb, and to determine the temporal and spatial relationship of these changes to SNL-induced allodynia. -- (2) To determine if the SNL-induced changes in the AFRR and CFRR (i.e. spinal hyperexcitability) are spinal PG-dependent, and if so, to determine the relevant cyclooxygenase (COX) isoform(s). -- (3) To determine if SNL triggers the activation of nuclear factor kappa-B (NFκB) in the affected spinal cord which initiate the delayed induction of spinal COX-2. -- (4) To determine if the sensitivity to PG E type (PGE 2 ) is exaggerated during spinal PG-dependent allodynia, and if this abnormal state is limited to the affected spinal cord three days after SNL. -- (5) To determine if PG-dependent spinal hyperexcitability and mechanical allodynia are mediated by E-type prostaglandin (EP) receptors, and to investigate the changes in the expression of spinal EP 1-3 receptor subtypes and the glycine-α3 receptor subunit (GLY-α3R) three days after SNL. -- (6) To determine if disrupting spinal PG synthesis/signaling immediately after SNL (i.e. pre-emptive treatment) prevents the development of PG-dependent spinal hyperexcitability and mechanical allodynia. -- (7) To determine if spinal PG-dependent hyperexcitability is affected by the SNL-induced generation of spinal nitric oxide (NO), and if so, to investigate relevant NO synthase (NOS) isoform(s).
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