The role of spinal disinhibition in cancer induced bone pain

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Cancer-induced bone pain is described as moderate to severe ongoing pain, often with transient episodes of severe pain that "breaks through" (BT cancer pain) medication controlling ongoing pain. Cancer bone pain is primarily treated with extended release opioids, with addition of rapid onset opioids for BT cancer pain. These drugs are associated with severe side effects that diminish patients' quality of life, and that may limit "dosing to effect" to achieve desired pain control. New non-opioid therapies would represent an advance for the treatment of cancer pain. We will use a variety of behavioral measures of cancer-induced bone pain to examine multiple aspects of tumor-induced bone pain in a mouse model of cancer bone pain. Flinching and conditioned place preference (CPP) to pain relief will be used as measures of ongoing pain. Tactile hypersensitivity and conditioned place aversion (CPA) to movement-triggered breakthrough pain will be used for analysis of components of cancer bone pain that are likely mechanistically distinct from ongoing pain. In this application, we will test the hypothesis that signaling by GABAergic inhibitory interneurons becomes excitatory in the context of cancer-induced bone pain. Aim 1 will determine the effects of stimulation of spinal GABAergic inhibitory interneurons on behavioral measures of ongoing pain tactile hypersensitivity and movement-evoked breakthrough pain. Aim 2 will determine the effects of inhibition of spinal GABAergic inhibitory interneurons on behavioral measures of ongoing pain, tactile hypersensitivity and movement-evoked breakthrough pain. These questions will be examined using new optogenetic and chemogenetic tools that can be used for selective inhibition of GABAergic expressing inhibitory interneurons that signal using the neurotransmitters GABA and glycine within the spinal cord. The proposed studies will fill the following gaps in our knowledge. We will determine the relative role of spinal disinhibition across multiple clinically relevant aspects of cancer bone pain; ongoing pain, mechanical allodynia, and breakthrough pain. We will also delineate whether the normally inhibitory GABAergic signaling undergoes disinhibition through loss of function, loss of contact/signaling, or abnormal excitatory signaling in the setting of cancer bone pain. Such gains in understanding the role of disinhibition in cancer-induced bone pain will allow for future studies using cutting edge techniques (e.g. single cell RNAseq, proteomics) to reveal potential novel targets for development of alternative non-opioid therapies for BT pain.