The proposed experiments will examine the role of inflammatory responses in the dorsal root ganglion (DRG) in the development and persistence of pathologic pain. Inflammatory responses have been observed in the DRG following various clinical conditions that are often associated with acute or chronic pain: lumbar disc herniation/rupture, mechanical compression, viral infection (e.g., shingles, HIV infection), and peripheral nerve injury. Most studies of inflammation in chronic pain have focused on spinal cord, brain, and peripheral nerve. However, it is not known how prolonged inflammation affects the functional or electrophysiological properties of the primary sensory neurons, how the cytokine profile changes in the DRG following inflammatory irritation, and which cytokines are most important in the initiation and persistence of pathological pain states. We have developed a new rat model of localized inflammation of the DRG. This model shows prolonged pain behaviors, spontaneous activity, and changes in a number of different cytokines that are similar to those induced by mechanical compression. The new model allows us to examine the effects of inflammation per se, in the absence of other types of nerve damage. We hypothesize that altered functional properties of the sensory neurons in the inflamed DRGs and the subsequent pathologic pain can be at least partially accounted for by altered activity of the hyperpolarization-activated current (HCN or IH), resulting from imbalanced cytokine expression within the DRG. Using both the mechanical compression and the DRG inflammation models, we will test our hypothesis via 3 Specific Aims (SA). SA1: Identify significantly altered cytokines/chemokines in the locally inflamed DRGs. SA2. Assess changes in the electrophysiological properties of DRG neurons after direct and prolonged inflammatory irritation, and determine if the IH plays an important role in increased excitability and spontaneous activity. SA3. Manipulate the levels of key cytokines (identified in SA1) in vivo to determine their contribution to pain behaviors and the underlying changes in neuronal electrical properties. Using our previously developed methods for long term in vivo perfusion of DRG, we will study the effects of selected cytokines and cytokine antagonists on the functional properties of DRG neurons including IH activity, and correlate these effects to behavioral measures of hyperalgesia and allodynia. By balancing the cytokine profiles in the DRG, we hope to prevent the development of hyperexcitability of DRG neurons and reduce the pain and hyperalgesia in animal models. Results will provide new insights into the mechanism of intractable pathologic pain, and suggest new therapeutic targets. Chronic pain conditions are common, long-lasting, and debilitating. We propose to study the newly recognized role of inflammation in chronic pain. Using a rat model, we will determine how inflammation directly affects the neurons that sense pain. ? ? ?
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