Diverse Roles of Neurotensin Agonists in the Central Nervous System

Abstract

Neurotensin (NT) is a tridecapeptide that is found in the central nervous system (CNS) and the gastrointestinal tract. NT behaves as a neurotransmitter in the brain and as a hormone in the gut. Additionally, NT acts as a neuromodulator to several neurotransmitter systems including dopaminergic, sertonergic, GABAergic, glutamatergic, and cholinergic systems. Due to its association with such a wide variety of neurotransmitters, NT has been implicated in the pathophysiology of several CNS disorders such as schizophrenia, drug abuse, Parkinson’s disease (PD), pain, central control of blood pressure, eating disorders, as well as, cancer and inflammation. The present review will focus on the role that NT and its analogs play in schizophrenia, endocrine function, pain, psychostimulant abuse, and PD.

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

“…administration. In addition, the analgesic activities of systemically administered ANG2002 in models of nociception were very similar to those of centrally administered NT (22)(23)(24)(25). Finally, the hypotensive and hypothermogenic responses, which were previously reported for the NT peptide (46,47), were not observed with the low analgesic dose of ANG2002.…”

“…We also showed that ANG2002 bound to NTS1 and NTS2 receptors in the low nanomolar range, thus exhibiting a similar binding affinity to that of native NT. We further found that ANG2002 and NT were equally effective in inducing β-arrestin2 recruitment, G protein functional coupling, and second effects reported in the use of chronic opioid medications (22)(23)(24)(25). However, the approach described in this work substantially differs from other approaches taken in the past for NT therapeutics, most notably those that explored the utility of chemically modifying NT fragments (typically consisting of the 6 C-terminal amino acids of the peptide) as a means of allowing systemic administration.…”

“…In the current study, we conjugated NT, an endogenous tridecapeptide with recognized analgesic properties (22)(23)(24)(25), to An2, a proprietary 19-amino acid peptide that crosses the BBB by receptor-mediated transcytosis (7,12). The primary goal of this research was to assess whether the An2-based platform, which has proven to be effective with small-molecule anticancer agents in the past (13)(14)(15)(16)(17)(18), could be extended to larger peptide therapeutics.…”

“…management. In recent years, the NT tridecapeptide, which exerts biological effects by interacting with 2 distinct GPCRs (termed NTS1 and NTS2), has emerged as an important modulator of nociceptive transmission (22)(23)(24)(25). Existing data also indicate that the analgesic effects of NT are independent of the endogenous opioid system (26)(27)(28)(29)(30), and may act synergistically with opioids to reduce pain (31)(32)(33).…”

Emerging role of neurotensin in regulation of the cardiovascular system

“…In the brain, NT interacts with different neurotransmitter systems, and is involved in the central control of appetite, endocrine functions, pain modulation, and pathogenesis of mental disorders (Boules et al, 2013). High amounts of NT are also present in endocrine-like cells localized in intestinal mucosa, whereby NT is released upon food intake, and contributes to regulation of gastrointestinal motility and secretion (Kalafatakis and Triantafyllou, 2011).…”