The overall goal of our research is to better understand the etiology and mechanisms of low back pain and sciatica. Clinical studies indicate that degenerative changes and traumatic injuries of the spine are often associated with mechanical compression and chemical irritation of dorsal root ganglia (DRG). DRG neurons can be exposed to inflammatory cytokines that are released from a herniated nucleus pulposus (HNP) or synthesized inside the ganglion in response to injury. However, the specific role of cytokines and cytokine-induced inflammation in the generation of spontaneous activity and enhancement of neuronal excitability is still unknown. We hypothesize that DRG neurons may develop hyperexcitability in response to peripheral nerve or ganglion injury such that the release of inflammatory cytokines from the injured neurons, the macrophages, the glial cells or the HNP activate hyperexcitable DRG neurons and lead to pain. Using a new animal model of neuropathic pain, involving compression of the L5 lumbar ganglion with a hollow stainless steel rod, we will test our hypothesis via 3 Specific Aims. SA1. Determine whether elevated release/synthesis of cytokines enhances the excitability of normal DRG neurons. SA2. Determine if endogenous inflammatory cytokines contribute to the generation and maintenance of spontaneous activity in compressed DRG neurons and if exogenous cytokines enhance this activity. SA3. Determine whether cytokines contribute to the development and maintenance of cutaneous hypersensitivity in CCD rats. A novel feature of our animal model is that the inserted rod allows local delivery of cytokines to the compressed ganglion in vivo. With this model, we will study how cytokines affect the excitability of DRG neurons and correlate these effects to behavioral measures of hyperalgesia and allodynia. If a relationship between specific cytokines and the sensory hyperexcitability responsible for neuropathic pain is identified, then new therapeutic approaches involving pharmacological modulation of cytokine release or synthesis could be developed to control pain in individuals with an acutely herniated lumbar disc, spinal stenosis, tumor, or other injury or disease of the spine.
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