Persistent small afferent input generated by tissue injury yields a facilitated state of nociceptive processing. The associated pain behavior is blocked by spinal delivery of agonists for Gi/o protein coupled receptors, such as 5 opiates. Analgesic efficacy occurs in part by a presynaptic inhibition of small afferent (e.g. substance P, sP). Continued intrathecal (IT) infusion of 5 opiates results in a loss of analgesic potency and a concurrent loss of suppression of sP. Enabling data suggest that with tissue injury and chronic opiate exposure the evolution of the hyperalgesic state and loss of efficacy reflects upon activation of links which involve the spinal Akt signaling cascade. These studies will undertake the following: 1. Determine expression and phosphorylation of Akt and its downstream substrates, specifically, GSK32, mTOR in spinal dorsal horn and DRG in control and in evocative pain states over time in rat after local tissue injury (Intraplantar formalin, intraplantar carrageenan) and in mice with KBxN serum-induced arthritis. 2. Define cellular localization of pAkt, pGSK3 and pmTOR in spinal DRG and dorsal horn in control animals and after peripheral inflammation. 3. Determine change in phosphorylation state of dorsal horn Akt, GSK/2 and mTOR after intraplantar formalin with the acute spinal delivery of: i) 5 agonist;ii) blockers of NK1, glutamatergic ionotropic or metabotrophic excitatory receptors. 4. Define role of the spinal Akt cascade in pain processing by examining the effects of IT inhibitors of Akt, GSK32 or mTOR in models of hyperalgesia in rat: i) acute flinching and chronic tactile allodynia after intraplantar formalin, ii) tactile allodynia and thermal hyperalgesia after intraplantar carrageenan and iii) the centrally initiated thermal hyperalgesia after IT delivery of agonists for NK1 and group I mGlu receptors;and with IP drug delivery in the mouse model of KBxN arthritis. 5. Examine role of the spinal Akt cascade in spinal opioid tolerance and dependence produced by chronic IT morphine infusion and during the withdrawal produced by antagonism of the respective receptor (e.g. naloxone), wherein the respective enzyme inhibitor is co-infused with opiate agonist. These studies will accordingly define the role of this Akt cascade in pain and opiate tolerance.
Hyperalgesia after injury or inflammation involves spinal signaling links, one of which we hypothesize is the Akt cascade. Akt may also mediate opioid tolerance. Our work thus targets this link for these two critical issues in pain.
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