Little is known about the role of descending brain stem modulatory systems in the development of persistent or chronic pain after tissue injury. Descending mechanisms are important because they provide pathways by which cognitive, emotional and attentional aspects of the pain experience influence sensory transmission at spinal and other CNS levels. It has been well-established that descending pathways originating in the brain stem modulate the output of spinal nociceptive neurons in response to phasic stimuli. In contrast, inflammation leads to a tonic, peripheral neural barrage that results in long-term changes in the central nervous system. The major hypothesis of this study is that descending brain stem inputs modulate the cascade of molecular, biochemical and physiological events leading to the prolonged functional changes in the spinal cord associated with persistent pain and hyperalgesia.
Specific aim 1 is to characterize the changes in inflammation-induced hyperalgesia produced by spinal tract lesions and to determine the involvement of NMDA receptors and spinal opioids in these effects. Our working hypothesis is that descending influences enhance endogenous and exogenous opioid effects and counteract NMDA activation at the spinal level.
Specific aims 2 and 3 will utilize chemical stimulation and lesion methods to investigate the modulatory roles of selective brain stem sites on the excitability of spinal nociceptive neurons after inflammation. These experiments will test the hypothesis that specific brain stem sites are differentially activated to dampen or enhance inflammation-induced spinal central hyperexcitability. To accomplish this we will record from single nociceptive neurons in the superficial and deep laminae of the spinal dorsal horn and also examine changes in Fos protein immunocytochemistry. The role of serotonin and norepinephrine in modulating spinal dorsal horn hyperexcitability will be determined by injecting specific neurotoxins into selected brain stem sites.
Specific aim 4 will determine the influence of descending inputs on spinal neuropeptide transmitter gene expression induced by hindpaw inflammation. We will use RNA blots and in situ hybridization histochemistry to assess the changes in prodynorphin, proenkephalin, protachykinin, neuropeptide Y and galanin mRNA levels in the spinal cord produced by selective spinal lesions. These findings will be important to our understanding of the descending mechanisms and pathways that modulate at the spinal level the development of persistent pain after tissue injury.
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