The long-range goal of this joint application is to identify the spinal circuits that process cutaneous somatic sensory information with a focus on pain and itch pathways. The overall research strategy employs cutting edge intersectional genetic manipulations to mark and ablate more than 10 classes of excitatory and inhibitory interneurons (INs) in the dorsal spinal cord, coupled with behavioral tests to assess the functional contribution that these cell types make to gating and transducing pain, itch and temperature. The experimental approach will utilize three sets of mice. The first is an intersectional DTR mouse in which the diphtheria toxin receptor (DTR) protein is only expressed after FlpO- and Cre- mediated removal of two stop cassettes. The second is the Lbx1FlpO mouse strain, in which the expression of FlpO recombinase is restricted to neurons in the dorsal horn of the medulla and spinal cord and dorsal hindbrain neurons. The third set includes eleven Cre mouse lines that express Cre recombinase in various subsets of excitatory or inhibitory dorsal horn INs. Crosses of these will enable investigators to ablate specific populations of dorsal interneurons so that their specific contributions to pain and itch pathways can be determined. Three issues will be addressed: 1) The molecular identity of neurons that transduce and gate specific pain and itch modalities, 2) a determination of the cellular basis of allodynia, and 3) the anatomical and functional organization of the circuits in the dorsal horn that gate pain and itch. These analyses, which combine rabies virus-based retrograde tracings, molecular neuroanatomy electrophysiological recordings, genetic manipulations and behavioral testing, will provide the first comprehensive picture of how the spinal circuits that process the noxious somatosensory modalities are organized at a cellular level. They will be used to examine in more detail the population-coding hypothesis and the cellular basis for the gate control theory of pain. Finally, they will provide new insights into the antagonistic interactions that occur among different sensory modalities, which when altered are a major factor in the pathogenesis of pain and itch.
The treatment and management of chronic pain and itch are major medical challenges. Studies in this proposal will dissect the functional circuitry in the dorsal horn that process the sensory modalities of pain and itch, in order to better understand how these senses are coded at a cellular level. These studies will define the cellular underpinnings of gate control theory with greater precision, and reveal how changes to the spinal circuitry lead to pain and itch being evoked by innocuous mechanical or thermal stimuli, thereby providing new thinking for strategies to treat chronic pain or itch.
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