The overall goal of our research is to understand neurochemical mechanisms in the spinal cord that contribute to persistent hyperalgesia. This proposal continues our investigation of neurokinin receptors with respect to nociceptive pathways in the spinal cord and explores how the function of NK1 receptors is enhanced during persistent hyperalgesia.
Specific aim #1 tests the hypothesis that NK3 receptors occur on primary afferent neurons. This hypothesis is based on evidence that tachykinins have excitatory effects on primary afferent neurons and will be tested in biochemical experiments that address the following questions: 1) Are NK3 receptors present on sensory neurons in adult rats? 2) Which second messenger links NK3 receptors to cellular events in sensory neurons? 3) Are NK3 receptors associated with sensory neurons that express SP? 4) Are NK3 binding sites on sensory neurons altered during peripheral inflammation? Specific aim #2 continues our studies of the regulation of spinal NK1 receptors and will test the hypothesis that prostaglandins regulate NK1 receptors on spinal neurons. This hypothesis is based on evidence that prostaglandins generated in the spinal cord contribute to hyperalgesia and will be investigated in biochemical experiments that address the following questions: 1) Which prostaglandin has the greatest potency in altering binding of 125I-Bolton Hunter-SP to NK1 receptors on spinal neurons? 2) Do prostaglandins alter the potency or efficacy of SP activation of phospholipase C? 3) What second messengers mediate the effects of the prostaglandins? 4) Is down regulation of NK1 receptors by SP attenuated by prostaglandins? 5) Does administration of prostaglandins to the spinal cord in vivo alter NK1 receptor binding? An extension of specific aim #2 is to understand how the synthesis of prostaglandins is altered during persistent hyperalgesia. Cox-2, an inducible form of cyclo-oxygenase, may be increased in the spinal cord during persistent hyperalgesia. If this is rue, then inhibition of cox-2 may attenuate the increased excitability of spinal neurons that accompanies hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA).
Specific aim #3 tests the hypothesis that products of cox-2, resulting from increased synthesis of cox-2, contribute to the increased excitability of spinal neurons during CFA-induced hyperalgesia. Answers to the following questions will address this hypothesis: 1) Are levels of mRNA for cox-2 in dorsal root ganglia and the dorsal spinal cord altered following induction of hyperalgesia with CFA? 2) Is the amount of cox-2 protein altered? 3) Where are neurons that express cox-2 located in the spinal cord? 4) For inhibitors of cox, is there a positive correlation between potency in inhibiting cox-2 and potency in attenuating the increased excitability of the nociceptive flexor reflex in animals with CFA-induced inflammation? In total, these specific aims are a logical progression of testable hypotheses that address the participation of tachykinins and prostaglandins in spinal mechanism of hyperalgesia. Data from the proposed experiments will provide information on potential targets for therapeutic intervention of persistent pain.
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