Cell Specific Identification of IL-1R Actions in Acute and Chronic Pain

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Abstract Inflammatory and anti-inflammatory cytokines contribute to neuronal hyperexcitability in pain transmission pathways. One of the inflammatory cytokines, Interleukin-1 (IL-1), is involved in many neuroimmune responses. In particular, it has been demonstrated that IL-1 induces acute pain, reduces morphine analgesic activity, is involved in tolerance development, and is necessary for chronic neuropathic and inflammatory pain. This has been studied in many ways, including use of an endogenous IL-1 receptor antagonist, and the use of IL-1 and IL-1R knockout mice. The problem with these experiments from a mechanistic standpoint is that IL-1 receptors are found endogenously on a variety of cell types in the brain, including astrocytes, microglia, endothelial cells, and neurons, and global knockout experiments can't define the cell types that mediate the actions of IL-1. The development of novel genetic models, in which the IL-1 receptor, IL-1R1, can be reciprocally knocked out and restored (IL-1R1r/r) from a global knockout, into individual cell types in the brain, spinal cord, and dorsal root ganglion permits a much more specific identification of the actions of IL-1 with respect to pain. Specific Aim 1 will study morphine analgesia and tolerance development in 5 mouse genotypes, wild type, global IL-1R1 KO, and mice in which the IL-1R1 receptor is restored selectively into neurons, endothelial cells, and astrocytes. We expect to find that the global KO animals and two of the restored mouse genotypes will have more potent and prolonged morphine analgesia and reduced tolerance development, as described in the literature. Furthermore, one of the restored mouse lines will act like the wild type animals with reduced morphine activity and will exhibit tolerance development. Aim 2 will examine two chronic pain models, spinal nerve ligation and Complete Freund's Adjuvant, using the same mouse genotypes, to determine which cell type mediates the development of chronic pain. Aim 3 will develop a new mouse model by crossing the IL-1R1r/r mice with c-Fos-Cre/ERT2 (TRAP2) mice. With this new genetic model, IL-1R1 will be restored only in mice that have been subjected to some pain stimulus. The use of these novel genetic models will pinpoint the actions of IL-1 with respect to opioid analgesia and pain to specific cell types and develop a collaboration that will be able to determine the mechanisms of IL-1 actions, in future R01 applications.