Understanding mechanisms involved in the CNS associated with persistent pain is important in developing therapeutic strategies. The role of neuron-derived tumor necrosis factor (TNF) as a mediator of hyperalgesia will be examined. We hypothesize that TNF promotes adaptive changes in adrenergic activity that intensifies the perception of persistent pain (hyperalgesia). Since the cognitive perception of hyperalgesia requires higher centers of the brain, neuroplastic changes in the brain are likely to also play an important role in the expression of pain. We will determine the requirement for the generation of TMF and establish the sequence and relative contribution of adrenergic neuroplastic changes. These changes will be compared between select regions of the brain and select regions of the spinal cord in order to establish whether TNF is involved in initiation or maintenance of hyperalgesia. The generation of TNF, adrenergic plasticity and hyperalgesia will be investigated in the Bennett model of neuropathic pain. We will extend in Aim I our studies involving the synthesis of TNF in neurons of the CNS. The kinetic profiles and cellular source will be corTelated to the temporal relationship between TNF expression and hyperalgesia.
In Aim II, using superfused hippocampal brain slices and spinal cord slices from rats with neuropathic pain, we will correlate adrenergic responsiveness with expression of TNF. Neurotransmitter release during field stimulation of slices at different electrical frequencies will be assayed in the presence of specific alpha 2-adrenergic agonists or antagonists, as well as exogenous TNF.
In Aim m, we will examine the role of TMF in the expression of altered adrenergic activity and the requirement of TNF for the development of hyperalgesia. TNF biological activity will be selectively altered in regions of the brain and spinal cord and the impact this has on the intensity of pain symptoms, as well as on the neuroplastic changes will be assessed. Previously we have demonstrated that adrenergic agents can alter the neuroplastic responses to changes in TNF expression. Thus, in Aim IV, we will examine the requirement for the adaptive adrenergic neuroplastic changes in the expression of hyperalgesia in neuropathic pain. Specifically, we will selectively inhibit adrenergic neuroplastic changes pharmacologically in regions of the brain and spinal cord, and determine whether regional TNF profiles are altered and whether there is inhibition of hyperalgesia. These studies will help in the development of therapeutic strategies that will allow us to manage difficult-to-treat, centrally-mediated, and persistent pain.
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