Novel Circuits and Mechanisms of Descending Pain Modulation

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Project Summary/Abstract Chronic pain afflicts millions of patients, yet treatments are largely ineffective, and development of new, targeted therapies is limited by knowledge gaps in the neurobiology of pain. Despite recent progress, key questions remain about the incredibly complex cellular and functional organization of ascending and descending neural circuits that control pain processing. Answering these questions is essential for developing new, more efficacious, and better targeted therapeutics for acute and chronic pain. The main objective of this proposal is to identify the circuit connections and synaptic mechanisms of a novel group of neurons that we recently discovered in the lateral pons. Situated juxta the A5 noradrenergic cell group, these neurons (which we termed LJA5) express prodynorphin and glutamic acid decarboxylase 1 (GAD1). They are distinct from the A5 noradrenergic neurons as they do not express tyrosine hydroxylase. LJA5 neurons project to all spinal levels of lamina I of the dorsal horn (DH), as well as to the parabrachial nucleus (PB) and the periaqueductal gray (PAG). Notably, we showed that these neurons play an important role in pain regulation. Specifically, chemogenetic activation of LJA5 neurons suppressed capsaicin- and inflammation-induced mechanical pain, but not thermal sensitivity, whereas chemogenetic inhibition of LJA5 enhanced mechanical hypersensitivity during inflammation. Our preliminary data also showed that chemogenetic activation of LJA5 neurons strongly attenuated neuropathic pain both via systemic and intrathecal administration of a designer drug. Collectively, these findings suggest that LJA5 neurons and their projections represent a novel component of descending pain modulation, and also pose many important questions about this novel circuit: 1) Which types of pain are regulated by LJA5 neurons? 2) What are the key projections/outputs of LJA5 neurons? 3) What synaptic mechanisms are utilized by LJA5 neurons? Our central hypothesis is that LJA5 neurons modulate pain processing by controlling synaptic transmission in lamina I of the dorsal horn of the spinal cord. We will test this hypothesis in 3 specific aims by using a multidisciplinary approach that includes chemogenetic manipulation combined with behavioral testing, patch-clamp recording in innovative intact spinal cord preparation and 2-photon Ca2+ imaging in axonal boutons of primary afferent central terminals. Aim 1 will establish the role of LJA5 neurons in mouse models of inflammatory and neuropathic pain. Aim 2 will examine functional significance of the main LJA5 projections. Aim 3 will determine synaptic mechanisms that mediate the antinociceptive effects of LJA5 neurons in the spinal cord. This proposal will define fundamental characteristics of a novel descending pathway involved in pain modulation, including its functional connectivity, synaptic mechanisms and its role in acute and chronic pain states. This work is transformative because it identifies a novel bulbospinal pain modulatory pathway, a significant advance in our basic understanding of pain that may offer alternative approaches to pain control.