An Intra-brainstem Circuit for Pain-induced Inhibition of Itch

Pain and itch are unpleasant and distinct sensations that give rise to behaviors such as reflexive withdrawal and scratching in humans and mice. Interestingly, it has been observed that pain modulate itch through the neural circuits housed in the brain and spinal cord. However, we are yet to fully understand the identities of and mechanisms by which specific neural circuits mediate pain-induced modulation of itch. Independent studies indicate that brainstem nuclei such as the lateral parabrachial nucleus (LPBN) and rostral ventromedial medulla (RVM) are important for the suppression of itch by painful stimuli. Here, using mouse and viral genetics, rabies tracing, chemogenetics, and calcium imaging, we show that the synaptic connections between LPBN and RVM plays an instrumental role in the interactions between pain and itch. Notably, we found that the LPBN neurons that express the gene encoding the substance P receptor, Tacr1 (LPBN^Tacr1), synapse onto Tacr1-expressing RVM neurons (RVM^Tacr1). The RVM^Tacr1neurons were found to be nociceptive, sufficient for inhibiting itch, and necessary for pain-induced itch suppression. Moreover, through brain-wide anterograde and retrograde viral tracing studies, we found that the RVM^Tacr1neurons are bidirectionally connected with LPBN, periaqueductal gray (PAG), and lateral hypothalamic area (LHA). Thus, together, our data indicate that the RVM^Tacr1neurons integrate nociceptive information to mediate itch-induced scratching and can mediate the physiological effects of itch through their downstream targets.