Neurotensin Signaling in Analgesia: Receptor Mechanisms, Targeted Drug Development, and Therapeutic Prospects for Pain and Comorbid Depression.

Abstract

Opioids are effective for severe pain but are limited by adverse effects and the risk of opioid use disorder (OUD), while non-opioid analgesics may provide insufficient relief. Neurotensin (NT), an endogenous neuropeptide, has attracted interest as a potential analgesic, with encouraging findings mainly from preclinical studies. This review summarizes advances in NT-based analgesic development, focusing on the pain-modulatory mechanisms of NTSR1 and NTSR2, the two principal neurotensin G protein-coupled receptors recognized by IUPHAR/BPS, and receptor-directed drug-design strategies. Sortilin, historically termed NTSR3 in some literature, is discussed separately because it is structurally distinct from these GPCRs. We examine NT-derived ligands, opioid-NT bifunctional compounds such as BNT-12, and combination approaches involving NT and opioid therapies. Their potential benefits are considered alongside safety concerns and translational limitations, including opioid-related adverse effects and pruritus. Although preclinical studies suggest promising analgesic effects, the comparative safety advantages of these strategies remain unestablished. NT may also influence mood regulation, making it relevant to the frequent co-occurrence of chronic pain with depression and anxiety. Overall, receptor-selective, multitarget, and combination approaches based on NT may offer complementary strategies for treating pain and associated affective symptoms. Further research is needed to establish their efficacy, safety, and clinical applicability, including whether they can reduce adverse effects and abuse liability.