ReviewNeurotensin and neurotensin receptors: Characteristic, structure–activity relationship and pain modulation—A review
Graphical abstract
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):
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a receptor with high affinity for NT (named NTRH or NTS1), which is insensitive to levocabastine (Tanaka et al., 1990, Vita et al., 1993);
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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
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