Lateral Hypothalamic Area Neurons Expressing Neurotensin Support Weight Loss and Alleviate Pain

Chronic pain and obesity frequently occur together. An ideal therapy would alleviate pain without weight gain, and most optimally, could promote weight loss. The neuropeptide neurotensin (Nts) is implicated in reducing weight and pain, but the endogenous mechanisms underlying this physiology were unknown. We previously showed that activating lateral hypothalamic area neurons expressing Nts (LHANts neurons) suppresses feeding and promotes weight loss. Here we hypothesized that activating LHANts neurons can also alleviate pain. To test this, we injected NtsCre mice in the LHA with AAVs to cre-dependently express either mCherry (Control) or excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in LHANts neurons, permitting their activation after treatment with the DREADD ligand clozapine N-oxide (CNO, 0.3 mg/kg, i.p.). Activating LHANts neurons had no effect on thermal pain responses in naïve mice. By contrast, spared nerve injury-induced pain hypersensitivity was completely reversed by CNO-mediated activation of LHANts neurons compared to VEH control, both acutely and after chronic injury. In mice treated with complete Freund’s adjuvant (which induces inflammatory pain), activating LHANts neurons also relieved pain hypersensitivity. However, pretreatment with the brain permeable Nts receptor pan-antagonist SR142948 (1mg/kg, i.p, 30 min before VEH/CNO) blocked CNO-mediated analgesia, indicating that LHANts neurons alleviate chronic pain in an Nts-dependent manner. Excitingly, activating LHANts neurons in diet-induced obese mice alleviated their baseline and CFA-induced pain. Taken together these data suggest that augmenting signaling via LHANts neurons may be a common actionable target for both pain and obesity.