ACTIONS OF PROINFLAMMATORY CYTOKINES ON SENSORY NEURONS

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DESCRIPTION (applicant's abstract): Increasing evidence suggests that activation of various components of the immune system contribute to chronic pain and inflammation. A number of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL-1beta), and interleukin-6 (IL-6) are synthesized and released at sites of trauma and produce hyperalgesia in animal models of pain. One mechanism for cytokine-induced augmentation of pain perception could involve their direct actions on nociceptive sensory neurons to enhance excitability and/or sensitize them to physical or chemical stimuli. Despite abundant evidence that TNF-alpha, IL-1beta, and IL-6 produce hyperalgesia and inflammation, there is little information regarding their capacity to modulate intracellular signaling pathways that regulate sensory neuron function. The hypothesis of this proposal is that pro-inflammatory cytokines act directly on sensory neurons to enhance their excitability and sensitize these cells to noxious mechanical and chemical stimuli and, in turn, augment the release of neuroactive substances from these neurons. The proposed studies will utilize two approaches: patch-clamp electrophysiology to assess cytokine-induced alterations in membrane excitability in rat sensory neurons grown in culture and biochemical measurements of neuropeptide release in isolated sensory neurons grown in culture and an in vitro preparation of rat spinal cord slices. The aims of this proposal are: 1) to determine whether acute or chronic exposure to TNF-alpha, IL-1beta, or 1L-6 alters membrane excitability and/or sensitizes isolated sensory neurons to electrical or chemical stimuli, 2) to determine whether these pro-inflammatory cytokines stimulate and/or sensitize the release of SP and CGRP from rat sensory neurons grown in culture or from rat spinal cord slices; and 3) to determine the effects of pro-inflammatory cytokines on sphingolipid second messengers and diacylglycerol in sensory neurons and to establish causal relationships between changes in second messenger systems and cytokine-induced alterations in excitability and peptide release. Overall, the knowledge gained from these studies is critical for understanding the etiology of chronic pain and could eventually aid in designing interventions to alleviate the pain. The results of this work can increase the understanding of the cellular mechanisms mediating the interaction between the nervous system and the immune system and thus be applicable to other areas of neurobiology.