The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.

/pdf/neuropeptide-receptor-ligands-as-drugs-for-psychiatric-4l9efive79.pdf

Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

The role of the periaqueductal gray-rostral ventromedial medulla (RVM) system in descending inhibition of nociception has been studied for over 30 years. The neural basis for this antinociceptive action is reasonably well understood, with strong evidence that activation of a class of RVM neurons termed 'off-cells' exerts a net inhibitory effect on nociception. However, it has recently become clear that this system can facilitate, as well as inhibit pain. Although the mechanisms underlying the facilitation of nociception have not been conclusively identified, indirect evidence points to activation of a class of neurons termed 'on-cells' as mediating descending facilitation. Here we used focal infusion of the tridecapeptide neurotensin within the RVM in lightly anesthetized rats to activate on-cells selectively. Neurotensin has been shown in awake animals to produce a dose-related, bi-directional effect on nociception when applied within the RVM, with hyperalgesia at low doses, and analgesia at higher doses. Using a combination of single cell recording and behavioral testing, we now show that on-cells are activated selectively by low-dose neurotensin, and that the activation of on-cells by neurotensin results in enhanced nociceptive responding, as measured by the paw withdrawal reflex. Furthermore, higher neurotensin doses recruit off-cells in addition to on-cells, producing behavioral antinociception. Selective activation of on-cells is thus sufficient to produce hyperalgesia, confirming the role of these neurons in facilitating nociception. Activation of on-cells likely contributes to enhanced sensitivity to noxious stimulation or reduced sensitivity to analgesic drugs in a variety of conditions.

Nociceptive facilitating neurons in the rostral ventromedial medulla.

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.

/pdf/diverse-roles-of-neurotensin-agonists-in-the-central-nervous-384gcy97aj.pdf

Diverse roles of neurotensin agonists in the central nervous system.

In the present study, we localized the levocabastine-sensitive neurotensin receptor (NTS2) protein in adult rat brain by using an N-terminally-directed antibody. NTS2-like immunoreactivity was broadly distributed throughout the rat brain. At the cellular level, the reaction product was exclusively associated with neurons and predominantly, although not exclusively, with their dendritic arbors. No NTS2 signal was observed over astrocytes, as confirmed by dual confocal microscopic immunofluorescence studies using the astrocytic marker S100beta. High densities of NTS2-like immunoreactive nerve cell bodies and/or processes were detected in many regions documented to receive a dense neurotensinergic innervation, such as the olfactory bulb, bed nucleus of the stria terminalis, magnocellular preoptic nucleus, amygdaloid complex, anterodorsal thalamic nucleus, substantia nigra, ventral tegmental area, and several brainstem nuclei. Most conspicuous among the latter were structures implicated in the descending control of nociceptive inputs (e.g., the periaqueductal gray, dorsal raphe, gigantocellular reticular nucleus, pars alpha, lateral paragigantocellular, and raphe magnus), in keeping with the postulated role of NTS2 receptors in the mediation of neurotensin's supraspinal antinociceptive actions. However, the distribution of NTS2-like immunoreactivity largely exceeded that of neurotensin terminal fields, and some of the highest concentrations of the receptor were found in areas devoid of neurotensinergic inputs such as the cerebral cortex, the hippocampus, and the cerebellum, suggesting that neurotensin may not be the exclusive endogenous ligand for this receptor subtype.

Immunohistochemical distribution of NTS2 neurotensin receptors in the rat central nervous system.

Cancer is a worldwide health problem. Personalized treatment represents a future advancement for cancer treatment, in part due to the development of targeted therapeutic drugs. These molecules are expected to be more effective than current treatments and less harmful to normal cells. The discovery and validation of new targets are the foundation and the source of these new therapies. The neurotensinergic system has been shown to enhance cancer progression in various cancers such as pancreatic, prostate, lung, breast, and colon cancer. It also triggers multiple oncogenic signaling pathways, such as the PKC/ERK and AKT pathways. In this review, we discuss the contribution of the neurotensinergic system to cancer progression, as well as the regulation and mechanisms of the system in order to highlight its potential as a therapeutic target, and its prospect for its use as a treatment in certain cancers.

/pdf/neurotensin-and-its-high-affinity-receptor-1-as-a-potential-4z41a1atrl.pdf

Neurotensin and its high affinity receptor 1 as a potential pharmacological target in cancer therapy.

Mice deficient in the neurotensin (NT)-1 receptor (NTR1) were developed to characterize the NT receptor subtypes that mediate various in vivo responses to NT. F2 generation (C57BL6/Sv129J) NTR1 knockout (−/−) mice were viable, and showed normal growth and overt behavior. The −/− mice lacked detectable NTR1 radioligand binding in brain, whereas NTR2 receptor binding density appeared normal compared with wild-type (+/+) mice. The gene deletion also resulted in the loss of NTR1 expression as determined by reverse transcription-polymerase chain reaction and in situ hybridization. Intracerebroventricular injection of NT (1 μg) to +/+ mice caused a robust hypothermic response (5–6°C) and a significant increase in hot-plate latency. These effects were absent in the −/− mice. Similar results were obtained with i.p. injections of the brain-penetrant NT analog NMe-Arg-Lys-Pro-Trp-Tle-Leu (NT-2, 1 mg/kg i.p.). NT-2 administration also impaired rotarod performance in wild-type mice, but had no effect on motor coordination in knockout mice. In vitro, NT and NT-2 at 30 nM caused predominantly contraction and relaxation in isolated distal colon and proximal ileum, respectively, from +/+ mice, but no responses were observed with tissues from −/− mice. A similar loss of the contractile effects of NT was observed in the isolated stomach fundus from the knockout mice. In vivo, NT-2 administration reduced colonic propulsion substantially in wild-type mice. In contrast, NT-2 had no effect in NTR1 null mice, whereas the hypomotility effect of clonidine was intact. These data indicate that NTR1 mediates several of the central and peripheral effects of NT.

The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin

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The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin