An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice.

Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LH) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LH neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LH neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LH projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LH activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LH neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.