Review
Neurotensin and neurotensin receptors: Characteristic, structure–activity relationship and pain modulation—A review

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Abstract

Neurotensin (NT) is a tridecapeptide, which – since its discovery in 1973 – has been demonstrated to be involved in the control of various physiological activities in both the central nervous system and in the periphery. Its biological effects are mediated by four receptor types. Exogenously administered NT exerts different behavioral effects, including antinociception. Structure–activity relationship studies performed in recent years resulted in development of several peptidomimetic receptor agonists and non-peptidic receptor antagonists that are useful tools for studies of NT mechanisms in tissue and on cellular level. This may result in design of new generation of analgesics based on neurotensin. NT antinociceptive effects are distinct from opioid analgesia. This creates opportunity of development of hybride analgesics that may simultaneously activate both opioid and NT antinociceptive pathways.

Introduction

Almost 40 years ago Carraway and Leeman (1973) isolated new endogenous tridecapeptide from bovine hypothalamic extracts. Vasodilation in rats after intravenous injection was the first observed property of neurotensin, authors named it neurotensin (NT). The amino acid sequence has been established as tridecapeptide pGlu–Leu–Tyr–Glu–Asn–Lys–Pro–Arg–Arg–Pro–Tyr–Ile–Leu–OH (Carraway and Leeman, 1975). Subsequent studies revealed neurotensin precursor protein. Precursor protein (Scheme 1) contains two similar sequences, neurotensin (NT) and neuromedin (NMN) that could be diversely liberated in different tissues and physiological conditions (Kislauskis et al., 1988). NT and its precursor have been identified in peripheral as well as in central nervous system. Studies showed that NT is involved in broad spectrum of neuromediatory and neuromedulatory effects in both peripheral and central nervous systems. Discovery of strong interaction between neurotensin system (receptors) and dopamine receptors (mainly D2) resulted in claiming of NT to be endogenous neuroleptic (Fuxe et al., 1992) involved in several brain diseases like Huntington's, Parkinson's diseases and schizophrenia (Nemeroff et al., 1992, Rostene et al., 1992). NT is also involved in control of anterior pituitary hormone secretion (McCann and Vijayan, 1992), gut motility (Tyler-McMahon et al., 2000, Vincent, 1995), hypothermia (Bissette et al., 1976) and muscle relaxation.

Involvement of neurotensin in pain inhibition was first reported 2 years after identification of neurotensin (Clineschmidt and McGuffin, 1977). Although, the analgesic effect of NT has been immediately confirmed by other group (Furuta et al., 1984), these direction of studies for years was under shadows of NT neuroleptic properties. Fortunately, during recent years growing knowledge on a role of neurotensin and its receptors in neuronal function as well as searching for new analgesics, alternative to opioid, reopened interest in pharmacological studies of neurotensin and its analogs in pain modulation and treatment.

Section snippets

The neurotensin receptors

Most of the effects observed after administration of neurotensin result from the specific interaction between the peptide and cell surface neurotensin receptors. There are currently three well characterized receptors for NT in the CNS (Table 1):

  • a receptor with high affinity for NT (named NTRH or NTS1), which is insensitive to levocabastine (Tanaka et al., 1990, Vita et al., 1993);

  • a low-affinity NT receptor (NTRL or NTS2), that also binds the histamine H1 receptor antagonist—levocabastine (

Neurotensin structure–activity relationship studies

Structure–activity relationship seems to be one of the most important subject which need to be considered while designing neurotensin analogs with great binding affinities and high activity.

Initially, Carraway and Leeman (1975) proposed a model in which whole neurotensin tridecapeptide interacts with its receptor. Additionally, Leeman and Carraway, due to many structure–activity studies, confirm the importance of COOH-terminal structures as determinants of specific binding and biological

Neurotensin and pain

As it was published recently, NT exerts potent CNS effects like profound analgesia or can enhance pain responses, depending on the circumstances (Tyler-McMahon et al., 2000, Clineschmidt and McGuffin, 1977). Microinjection experiments have provided evidence that NT can modulate pain transmission in several brain regions and pathways that are involved in the central integration of pain responses, including the central amygdale, the hypothalamic medial preoptic nucleus (MPO), certain thalamic

Opioid–neurotensin hybrides

The most interesting aspect of NT-mediated analgesia is its opioid independence. Application of morphine into periaqueductal gray (PAG) produces analgesia that can be blocked by naloxone, whereas injection of NT produces analgesia that cannot be blocked by naloxone (Behbehani, 1992). This creates the chance that development of molecules activating both opioid and NT systems may result in more effective synergic antinociception. Following this idea, peptide that hybridizes opioid and NT

Conclusion

NT is an endogenous peptide with broad spectrum of central and peripheral activities, including modulation of pain signal transmission and perception. The antinociceptive effects of NT are independent from opioid antinociception. The structure–activity studies of NT and its receptors, in relation to analgesia are on quite preliminary stage. Nevertheless, already available results create hope of developing new generation of analgesics exploiting activation of NT receptors that are known to be

References (68)

  • J. Einsiedel et al.

    Peptide backbone modifications on the C-terminal hexapeptide of neurotensin

    Bioorg. Med. Chem. Lett.

    (2008)
  • S. Geisler et al.

    Brain neurotensin, psychostimulants, and stress-emphasis on neuroanatomical substrates

    Peptides

    (2006)
  • X. Gui et al.

    Endogenous neurotensin facilitates visceral nociception and is required for stress-induced antinociception in mice and rats

    Neuroscience

    (2004)
  • H. Heise et al.

    Probing conformational disorder in neurotensin by two-dimensional solid-state NMR and comparison to molecular dynamics simulations

    Biophys. J.

    (2005)
  • E. Hermans et al.

    Mechanism of regulation of neurotensin receptors

    Pharmacol. Ther.

    (1998)
  • G. Horvath et al.

    Interaction of endogenous ligands mediating antinociception

    Br. Res. Rev.

    (2006)
  • L. Jacobsen et al.

    Activation and functional characterization of the mosaic receptor SorLA/LR11

    J. Bio. Chem.

    (2001)
  • E. Kislauskis et al.

    The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences

    J. Biol. Chem.

    (1988)
  • M. Lafrance et al.

    Involvement of NTS2 receptors in stress-induced analgesia

    Neuroscience

    (2010)
  • D. Lugrin et al.

    Reduced peptide bond pseudopeptide analogs of neurotensin: binding and biological activities, and in vitro metabolic stability

    Eur. J. Pharmacol.

    (1991)
  • J. Mazella et al.

    The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor

    J. Biol. Chem.

    (1998)
  • B.M. McMahon et al.

    Neurotensin analogs. Indications for use as potential antipsychotic compounds

    Life. Sci.

    (2002)
  • J.M. Palacios et al.

    The ontogeny of brain neurotensin receptors studied by autoradiography

    Neuroscience

    (1988)
  • C.M. Petersen et al.

    Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography

    J. Biol. Chem.

    (1997)
  • K.E. Smith et al.

    NTS1 and NTS2 mediate analgesia following neurotensin analog treatment in a mouse model for visceral pain

    Behav. Brain Res.

    (2012)
  • F. Sotty et al.

    Comparative effects of neurotensin, neurotensin(8-13) and [d-Tyr(11)] neurotensin applied into the ventral tegmental area on extracellular dopamine in the rat prefrontal cortex and nucleus accumbens

    Neuroscience

    (2000)
  • K. Tanaka et al.

    Structure and functional expression of the cloned rat neurotensin receptor

    Neuron

    (1990)
  • B.M. Tyler et al.

    In vitro binding and CNS effects of novel neurotensin agonists that cross the blood-brain barrier

    Neuropharmacology

    (1999)
  • B.M. Tyler-McMahon et al.

    Neurotensin: peptide for the next millennium

    Regul. Peptides

    (2000)
  • J.P. Vincent et al.

    Neurotensin and neurotensin receptors

    Trends Pharmacol. Sci.

    (1999)
  • N. Vita et al.

    Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor

    FEBS Lett.

    (1993)
  • M.M. Behbehani et al.

    Effect of neurotensin on neurons in the periaqueductal gray: an in vitro study

    J. Neurosci.

    (1987)
  • M.,.M. Behbehani

    Physiological mechanisms of the analgesic effect of neurotensin

    Ann. NY. Acad. Sci.

    (1992)
  • E.B. Binder et al.

    Neurotensin and dopamine interactions

    Pharmacol. Rev.

    (2001)
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