Distinct Lateral Hypothalamus GABAergic Projections Regulate Sensory and Affective Dimensions of Pain

Pain is a complex experience with sensory and emotional aspects. The behavioral role and neurobiological mechanisms of this well-conserved phenomenon are still not fully understood. Although the lateral hypothalamus (LHA) is involved in modulating sensory function and pain, its underlying circuitry and causal mechanism remain elusive. Here, we show that formalin-induced pain-like behaviors in mice coincide with decreased responses in LHAGAD2 positive neurons, as well as during acute restraint stress in adult transgenetic male mice. Activating LHAGAD2 neurons ameliorates formalin-induced pain-like and suppresses aversion behaviors. Additionally, we identified a GABAergic connection from the LHA to the lateral habenula that specifically suppresses negative reactions and behaviors in neuropathic pain. Conversely, LHAGAD2 neurons connect with specific cell populations in the ventral lateral periaqueductal gray to suppress neuropathic pain. Thus, LHAGAD2 neural-specific pathways modulate the sensory and affective dimensions of pain-like behavior, which can be exploited for pain relief. Collectively, our results provide new insights into pain processing within specific LHA GABAergic subpopulations, potentially informing cell type- or subregion-targeted therapies for pain management.