Pain continues to be a major clinical problem due to its high prevalence (~100 million people in the US) and lack of adequate treatment options. Hampering the identification of more effective therapies is the complexity of pain, which is not one condition, but many that manifest differently within the nervous system. Additionally, the neural networks and mechanisms that underlie pain remain poorly understood. Work in this proposal will delineate the dorsal horn network for mechanical allodynia, a common condition in which touch or movement become painful after injury. The work is focused on the dorsal horn because it is a major site for the integration of somatosensory information and importantly where early, fundamental alterations in circuit dynamics give rise to mechanical allodynia. Our studies to elucidate the dorsal horn mechanical allodynia network point to the involvement of three previously unappreciated excitatory interneuron populations. The studies also indicate that the dorsal horn neurons that transmit mechanical allodynia differ depending on the nature of the injury. Thus, the goal of this grant proposal is to expand on these findings to elucidate the dorsal horn network for mechanical allodynia in the context of injury-type.
In Aim 1) we will determine the role of dorsal horn excitatory interneuron populations in the transmission of mechanical allodynia using both inflammatory and neuropathic pain models.
In Aim 2) we will map the monosynaptic connections to and by the required excitatory dorsal horn populations, including to other dorsal horn neurons, primary afferents and descending supraspinal inputs.
In Aim 3) we will use an in vitro model of mechanical allodynia to assess on a synaptic level the requirement for the dorsal horn excitatory populations in the transmission of mechanical allodynia induced by inflammatory and neuropathic pain models. Results from these studies will provide a fundamental anatomical framework with which to further investigate synaptic and molecular mechanisms underlying mechanical allodynia and identify new treatment options.
The neural circuits that induce and maintain mechanical allodynia, a persistent pain condition brought on by nerve and tissue damage, are poorly understood and treatment options remain limited. Efforts outlined in this grant application will take advantage of our recent progress investigating the dorsal horn circuits for mechanical allodynia. A clearer understanding of how the dorsal horn circuits encode mechanical allodynia will increase our understanding of underlying mechanisms and provide new opportunities for therapeutic intervention.
