Fellowship for Corder: Prolonged activation of endogenous opioid analgesia after inflammation

Following peripheral tissue or nerve injury, maladaptive neuronal and glial alterations in the spinal cord and brain lead to persistent or recurrent pain. Endogenous inhibitory systems are also augmented. It is thought that the intensity and quality of pain perception is determined by the net balance between the activities of these pronociceptive and antinociceptive systems. Endogenous opioids are recognized to counteract ongoing spinal pain transmission and allodynia associated with injury. But whether this inhibition continues after pain resolves is not clear. My overall hypothesis is that endogenous spinal OR signaling homeostatically reduces the maintenance of persistent pain. Although no pain-associated behaviors are observed, I hypothesize that there is a latent glutamatergic sensitization that is inhibited by endogenous opioid signaling. The following NRSA F-31 proposal will attempt to characterize long lasting opioid signaling by means of opioid receptor antagonist studies after the behavioral manifestations of pain have subsided. Aim 1 will attempt to show the contribution of opioids to the behavioral development of recovery after injury, and will pinpoint specific opioid receptor isotype (ì,ä,ê) inhibition to specific pain modalities (mechanical, heat) over a 15 week time course. Aim 2 will evaluate the extent of opioid expression and function for many weeks after the induction of persistent inflammation. Tonic intracellular signaling will be tested by GTPãS35 binding assay of opioid GPCR:G-protein coupling. Aims 3 and 4 evaluate the hypothesis of latent spinal glutamatergic activity. Aim 3 will test the hypothesis that spinal glutamate receptors remain up-regulated after behavioral signs of chronic pain have subsided and contribute to latent sensitization of pain pathways. Aim 4 will use intrathecal injection of an NMDA-R antagonist, in vivo microdialysis in the dorsal horn, and sequestering antiseurm to glutamate to test the hypothesis that glutamatergic signaling drives allodynia in the absence of opioid inhibitory signaling. Understanding of long-lasting homeostasis between the opioidergic and glutamatergic system will aid in understanding the recurrence of allodynia and hyperalgesia in chronic pain patients. Potential therapeutic strategies designed to enhance endogenous opioid signaling with better efficacy and fewer side-effects than available treatments may reduce the occurrence of persistent pain.