Targeting spinal orexins to treat chronic pain

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Chronic pain is a highly prevalent and debilitating condition in which the underlying neural circuits that transmit pain information are altered. The brain sends projections to the spinal cord that can modulate incoming sensory information by either turning up or turning down the function of local spinal networks. This process has been well characterized for pain inhibition, but less is known about projections that can facilitate pain transmission. Recent reports, as well as my preliminary investigations, have revealed that treatment with an orexin antagonist, suvorexant, reduces mechanical hypersensitivity in preclinical models of chronic neuropathic pain. This outcome raises the possibility that orexin neurons, which exist solely in the hypothalamus and have prominent projections to the spinal cord, might be targeted to alleviate chronic pain. However, little is known about the role of orexinergic neurons in the context of population level network function in the spinal cord or how these projections could influence pain facilitation. To address this fundamental gap in our knowledge, this proposal will characterize orexinergic projections from the hypothalamus to the spinal cord using physiological and behavioral approaches. This proposal will test the hypothesis that orexinergic neurons in the lateral hypothalamus contribute to chronic pain through descending projections that facilitate net excitatory output from neurons of the superficial dorsal horn. Aim 1 will apply two-photon calcium imaging in an ex vivo somatosensory preparation to probe the functional consequences of treatment with orexin peptides on the population level activity of excitatory and inhibitory neurons in the spinal dorsal horn. Aim 2 will examine the behavioral consequences resulting from chemogenetic activation of descending orexinergic projections using operant and reflexive pain assays. Collectively, these experiments will provide a foundation for our understanding of orexin dependent modulation of spinal nociceptive output and will generate a framework for future work on the treatment of chronic pain by targeting spinal orexin receptors. This fellowship proposal at the Pittsburgh Center for Pain Research (PCPR) includes advanced training in basic science techniques uniquely found in the Ross/Koerber lab and provides career development through coursework, a mentorship committee, and direct training by experts in the field that will facilitate transition to the next stage of my career as a pain focused academic research scientist.