Targeting pain where it CouNts: the role of neurotensin signaling in pain and analgesia

Abstract

Chronic pain affects more than one-fifth of adults in the United States and represents a major public health burden due to its impact on quality of life, productivity, and healthcare costs. Current pharmacological treatments remain limited in efficacy and are often associated with significant adverse effects, highlighting the need for safer and more effective therapeutic strategies. Neurotensin (Nts), a neuropeptide widely expressed in the central and peripheral nervous systems, has emerged as an important modulator of nociceptive processing. Nts signals through the G protein-coupled receptors neurotensin receptor 1 (NTSR1) and neurotensin receptor 2 (NTSR2), which are expressed in key neuroanatomical components of pain pathways. In this review, we summarize current knowledge of the neuronal and molecular mechanisms underlying pain processing and discuss how Nts signaling modulates nociceptive transmission at peripheral, spinal, and supraspinal levels. In addition to regulating nociceptor excitability and spinal excitatory neurotransmission, Nts critically regulates neural circuits involved in descending pain modulation, including the periaqueductal gray and rostral ventromedial medulla, and contributes to pain processing within limbic and hypothalamic networks that integrate sensory and affective components of pain. Finally, we discuss recent advances in pharmacological modulation of Nts receptors, including biased allosteric modulators and receptor-selective agonists that show promising analgesic efficacy in preclinical models. Together, these findings position the neurotensin system as a promising target for the development of novel non-opioid therapies for pain.