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 LHANts neurons are an endogenous source of Nts that can provide antinociception, and hence, that activating LHANts neurons would alleviate pain dependent on Nts signaling via NtsRs. We first used Designer Receptor Exclusively Activated by Designer Drug (DREADDs) to activate LHANts neurons in normal weight and diet-induced obese (DIO) NtsCre mice. Activating LHANts neurons had no effect on thermal pain and mechanical responses in naïve normal weight mice. By contrast, both spared nerve injury- (SNI) and complete Freund’s Adjuvant (CFA)-induced mechanical hypersensitivity was completely reversed by DREADD ligand clozapine N-oxide (CNO)-mediated stimulation of LHANts neurons compared to control naïve normal weight mice. Similarly, activating LHANts neurons had no effect on thermal pain responses in DIO mice. By contrast, obesity-induced pain hypersensitivity as well as CFA-induced inflammatory pain was completely reversed by CNO-mediated activation of LHANts neurons compared to VEH control. 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. Furthermore, Nts deletion from the LHA by injecting AAV-Cre into the LHA of Ntsflox/flox mice further exacerbated hyperalgesia in DIO mice compare to normal weight mice. Taken together these data suggest that augmenting signaling via LHANts neurons may be a common actionable target to treat comorbid obesity pain.
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