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An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice.

ABSTRACT: 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^PV) 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^PV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LH^PV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LH^PV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LH^PV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LH^PV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

SUBMITTER: Siemian JN

PROVIDER: S-EPMC8159376 | biostudies-literature |

REPOSITORIES: biostudies-literature

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