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A pivotal role of the lateral hypothalamus (LH) in regulating appetitive and reward-related behaviors has been evident for decades. However, the contributions of LH circuits to other survival behaviors have been less explored. Here we examine how lateral hypothalamic neurons that express the calcium-binding protein parvalbumin (PVALB; LH PV  neurons), a small cluster of neurons within the LH glutamatergic circuitry, modulate nociception in mice. We find that photostimulation of LH PV  neurons suppresses nociception to an acute, noxious thermal stimulus, whereas photoinhibition potentiates thermal nociception. Moreover, we demonstrate that LH PV  axons form functional excitatory synapses on neurons in the ventrolateral periaqueductal gray (vlPAG), and photostimulation of these axons mediates antinociception to both thermal and chemical visceral noxious stimuli. Interestingly, this antinociceptive effect appears to occur independently of opioidergic mechanisms, as antagonism of μ-opioid receptors with systemically-administered naltrexone does not abolish the antinociception evoked by activation of this LH PV →vlPAG pathway. This study directly implicates LH PV  neurons in modulating nociception, thus expanding the repertoire of survival behaviors regulated by LH circuits.

Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area