Neurotensin-expressing lateral hypothalamic neurons alleviate neuropathic and inflammatory pain via neurotensin receptor signaling

Persistent, severe pain negatively impacts health and wellbeing, but half of patients do not receive adequate relief from current treatments. Understanding signals that modulate central pain processing could point to new strategies to manage severe pain. Administering Neurotensin (Nts) or Nts receptor (NtsR) agonists into the brain provides analgesia comparable to pharmacologic opioids. However, the endogenous sources of Nts that modify pain processing and might be leveraged for pain relief remained unknown. We previously characterized a large population of Nts-expressing neurons in the lateral hypothalamic area (LHA^Nts neurons) that project to brain regions that participate in descending control of pain processing. We hypothesized that LHA^Nts neurons are an endogenous source of Nts and activating them would alleviate pain dependent on Nts signaling via NtsRs. To test this, we injected Nts^Cre mice in the LHA with AAVs to cre-dependently express either mCherry (Control) or the excitatory hM3Dq in LHA^Nts neurons, permitting their stimulation after treatment with the hM3Dq ligand clozapine N-oxide (CNO). Activating LHA^Nts neurons had no effect on thermal pain and mechanical responses in naïve mice. By contrast, both spared nerve injury- (SNI) and complete Freund’s adjuvant (CFA)-induced mechanical hypersensitivity was completely reversed by CNO-stimulation of LHA^Nts neurons. Pretreatment with the Nts receptor antagonist SR142948 reduced CNO-mediated analgesia, indicating that LHA^Nts neurons alleviate chronic pain in an Nts receptor-dependent manner. Taken together these data identify LHA^Nts neurons as an endogenous source of Nts that modulates central pain processing and may inform future development of Nts-based targets to treat severe pain.