Dorsal horn circuits for mechanical allodynia

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Pain continues to be a major clinical problem due to its high prevalence and lack of adequate treatment options. The identification of more effective therapies is hampered by a lack of understanding of the neural circuits and mechanisms that underlie pain. Work outlined in this proposal is focused on delineating the dorsal horn circuits for mechanical allodynia, a common condition in which touch or movement become painful after injury. The dorsal horn is a major site for the integration of somatosensory information. It is also where injury- induced changes in the circuitry give rise to mechanical allodynia. In studies to elucidate the dorsal horn mechanical allodynia circuits, we have identified populations of dorsal horn excitatory interneurons that mediate this form of pain. Additionally, we present evidence supporting the concept that the neural circuitry that mediates mechanical allodynia in the dorsal horn differs depending on the nature of the injury. Thus, the overarching goal of this project is to delineate the dorsal horn circuits underlying mechanical allodynia in the context of the type of injury, inflammatory and neuropathic. In Aim 1) we will determine whether the populations of excitatory interneurons are required for mechanical allodynia produced by models of inflammatory and neuropathic pain. In Aim 2) we will expand our understanding of the dorsal horn circuitry related to these excitatory interneuron populations under naïve conditions by identifying the neurons monosynaptically connected to them. This more detailed picture of the basic dorsal horn circuitry will facilitate experiments aimed at identifying key changes that underlie mechanical allodynia caused by different types of injuries. In Aim 3) we will use an in vitro model of mechanical allodynia to test the role of these excitatory interneuron populations in inflammatory and neuropathic pain models. This will allow us to assess on a synaptic level the role of these neurons in mechanical allodynia in the context of injury-type. Classes of afferents and populations of lamina I projection neurons will also be assessed. These novel studies will provide a critical anatomical framework with which to advance molecular- and synaptic-level studies of the neurons and mechanisms that underlie mechanical allodynia as well as generate new therapeutic strategies.