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LJA5: A Novel Population of Pain and Itch Suppressing Brainstem Neurons

Agostinelli, LJ;

Chronic pain and itch afflict millions of patients, and current treatments are largely ineffective. The neural control of pain and itch are not fully elucidated, and this limits the development of therapies targeting the underlying neural circuitry. Sensory information is transmitted from peripheral nerves, to the spinal cord, and up to the brain (“bottom up” pathway), but may be modulated by “top-down” projections from the brain to the spinal cord. However, the neurons mediating top-down inhibition of pain are not fully elucidated, nor has any such pathway been identified for itch sensation. Here we identify a novel population of GABAergic neurons in the ventral brainstem, distinguished by prodynorphin expression. We named the neurons LJA5 to describe their location in the lateral pons, juxta the A5 cell group. LJA5 neurons provides the only known inhibitory projection to the spinal cord selectively targeting lamina I, which exclusively transmits pain, temperature, and itch information up to the brain. Through this work, we sought to investigate the role of LJA5 neurons in sensation. The first set up experiments were designed to more fully characterize LJA5 neurons. We first identified the gene expression pattern in mouse, and then we looked to identify these neurons in human brains. We then fully explored the input and output connections of LJA5 neurons in mouse using anterograde and retrograde tracers. These neurons demonstrate the first inhibitory projection specifically targeting lamina I of the spinal cord. This finding, along with projections to other sensory regions in the brainstem, suggested that LJA5 neurons directly inhibit noxious sensory information. Furthermore, we show that LJA5 neurons receive input from forebrain structures implicated in stress and sensory detection. In the second set of experiments, we tested the function of LJA5 neurons through chemogenetic activation during behavioral tests. We knew that LJA5 neurons projected to many known sensory regions including lamina I of the spinal cord, so we hypothesized that LJA5 neurons could modulate itch, pain, or temperature sensations. Chemogenetically activating LJA5 neurons reduced capsaicin-induced pain and histamine-induced itch. Together, our findings identify and characterize a novel nucleus in the brainstem with the first described inhibitory projection specifically targeting lamina I of the spinal cord. Additionally, this is the first identified descending projection that reduces both pain and itch. This new top-down pathway updates current sensory models and opens new treatment opportunities for refractory pain and pruritis.