Direct and Indirect Nociceptive Inputs to Brainstem Pain-Modulating Neurons

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PROJECT SUMMARY The brain regulates nociceptive processing through descending projections from the brainstem to the spinal and trigeminal dorsal horns. This is accomplished through endogenous pain-modulating circuits that can amplify or suppress pain-related signals, and normally maintain a balance between facilitation and inhibition of pain. In chronic pain conditions, the system is dysregulated, contributing to a facilitated pain state. The output of this pain-modulating system, via the rostral ventromedial medulla (RVM) has been extensively studied. Bidirectional pain control from this region is mediated by two physiologically defined cell classes, “ON-cells” and “OFF-cells,” that respectively facilitate and inhibit nociceptive transmission. However, sensory inputs to RVM are only now receiving significant attention. Indirect inputs from the dorsal horn via the parabrachial complex convey nociceptive information to RVM and contribute to the sensitization of RVM neurons in persistent inflammatory pain. However, there also is evidence from anatomical studies for a direct input from the dorsal horn to RVM. The hypothesis of this proposal is that RVM receives both indirect and direct functional inputs from the trigeminal dorsal horn that contribute to pain-modulation, and that the direct input is altered in a persistent pain state. This project will focus on the trigeminal system, which mediates sensory input from the face and head, regions associated with a heavy burden of chronic pain, including migraine headache, temporomandibular disorder, and trigeminal neuralgia. I will use a combination of single-cell recording in RVM combined with optogenetic manipulation of the direct (trigeminal-to-RVM) and indirect (trigeminal relay through parabrachial complex) projections to test the role of each connection to RVM and determine whether and how the function of the direct pathway changes in persistent pain. Collectively, these studies will enhance our understanding of the contribution of trigeminal sensory inputs to the intrinsic pain-modulatory circuit and define how nociceptive inputs gain access to the RVM. By identifying the drivers of pro-nociceptive brainstem outputs, we can gain new insights into how pain-modulating systems are recruited and modulated in acute and chronic pain, providing us with novel targets for therapies. This project will complement a comprehensive and structured training plan that I have developed in collaboration with my mentor, Dr. Mary Heinricher. In addition to advanced training in optogenetics and in vivo electrophysiology, I will enhance my skills in programming, experimental design, and quantitative analysis. I will also gain increased depth of understanding of pain and pain research, in part by exposure to the clinical challenges of chronic pain management. Finally, I expect to engage in activities that will support increased skills in scientific communication. As a whole, the proposed training will position me to succeed as an independent researcher and leader in academic pain research.