Novel Inhibitory Brainstem Neurons with Selective Projections to Spinal Lamina I Reduce Both Pain and Itch

Abstract

Chronic pain and itch afflict millions of patients, and current treatments are largely ineffective. We do not fully understand the neural control of pain and itch, and are thus limited in developing therapies targeting the underlying circuitry in the brain or spinal cord. Current models show that lamina I of the spinal cord contains the neurons that transmit pain and itch information from the skin up to the brain. However, it is not well understood how the brain modulates pain and itch sensations in a top-down fashion. The simplest and most direct way for the brain to suppress pain and itch would be a direct, inhibitory projection to lamina I sensory neurons, but prior investigations have focused on brainstem regions that project axons nonspecifically across many laminae of the spinal cord. In addition to top-down inhibition of pain, pharmacological studies suggest the possibility of top-down itch control, but this has no known neural substrate. Therefore, the specific neural pathway the brain uses to modulate pain remains incompletely understood, and whether the brain can inhibit itch in a top-down fashion is unknown. Here we identify a novel population of GABAergic neurons in the ventral brainstem, distinguished by prodynorphin expression, which we named LJA5. LJA5 neurons provide the only known inhibitory projection specifically to lamina I of the spinal cord, which contains sensory neurons that transmit pain and itch information up to the brain. Chemogenetically activating LJA5 neurons reduces pain and itch. Identifying this new top-down pathway opens new treatment opportunities for chronic, refractory pain and pruritis.