Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 13-amino acid peptide neurotensin (NT) was discovered over 30 years ago and has been implicated in a wide variety of neurotransmitter and endocrine functions. This review focuses on four areas where there has been substantial recent progress in understanding NT signaling and several functions of the endogenous peptide. The first area concerns the functional activation of the high-affinity NT receptor, NTR-1, including the delineation of the NT binding pocket and receptor domains involved in functional coupling to intracellular signaling pathways. The development of NT receptor antagonists and the application of genetic and molecular genetic approaches have accelerated progress in understanding NT function in several areas, including the involvement of NT in antipsychotic drug actions, psychostimulant sensitization and the modulation of pain, and these are reviewed in that order. There is now substantial evidence indicating that NT is required for certain antipsychotic drug actions and that the peptide plays a key role in stress-induced analgesia.
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PMID:Multitasking with neurotensin in the central nervous system. 1600 89

Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyrpsi(CH2NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.(3.7))-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.
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PMID:Potent spinal analgesia elicited through stimulation of NTS2 neurotensin receptors. 1614 26

Neonatal noxious insult produces a long-term effect on pain processing in adults. Rats subjected to carrageenan (CAR) injection in one hindpaw within the sensitive period develop bilateral hypoalgesia as adults. In the same rats, inflammation of the hindpaw, which was the site of the neonatal injury, induces a localized enhanced hyperalgesia limited to this paw. To gain an insight into the long-term molecular changes involved in the above-described long-term nociceptive effects of neonatal noxious insult at the spinal level, we performed DNA microarray analysis (using microarrays containing oligo-probes for 205 genes encoding receptors and transporters for glutamate, GABA, and amine neurotransmitters, precursors and receptors for neuropeptides, and neurotrophins, cytokines and their receptors) to compare gene expression profiles in the lumbar spinal dorsal horn (LDH) of adult (P60) male rats that received neonatal CAR treatment within (at postnatal day 3; P3) and outside (at postnatal 12; P12) of the sensitive period. The data were obtained both without inflammation (at baseline) and during complete Freund's adjuvant induced inflammation of the neonatally injured paw. The observed changes were verified by real-time RT-PCR. This study revealed significant basal and inflammation-associated aberrations in the expression of multiple genes in the LDH of adult animals receiving CAR injection at P3 as compared to their expression levels in the LDH of animals receiving either no injections or CAR injection at P12. In particular, at baseline, twelve genes (representing GABA, serotonin, adenosine, neuropeptide Y, cholecystokinin, opioid, tachykinin and interleukin systems) were up-regulated in the bilateral LDH of the former animals. The baseline condition in these animals was also characterized by up-regulation of seven genes (encoding members of GABA, cholecystokinin, histamine, serotonin, and neurotensin systems) in the LDH ipsilateral to the neonatally-injured paw. The largest aberration in gene expression, however, was observed during inflammation of the neonatally injured hindpaws in the ipsilateral LDH, which included thirty-six genes (encoding numerous members of glutamate, serotonin, GABA, calcitonin gene-related peptide, neurotrophin, and interleukin systems). These findings suggest that changes in gene expression may be involved in the long-term nociceptive effects of neonatal noxious insult at the spinal level.
Mol Pain 2005 Sep 22
PMID:Neonatal local noxious insult affects gene expression in the spinal dorsal horn of adult rats. 1617 88

The peptide neurotensin has been studied for more than 30 years. Although it is widely distributed in the central and peripheral nervous systems, neurotensin has been more intensely studied with regard to its interactions with the central dopamine system. A number of claims have been made regarding its possible implication in many diseases of the central nervous system, including schizophrenia. In this review, we describe briefly the basic biology of this neuropeptide, and then we consider the strengths and the weaknesses of the data that suggest a role for neurotensin in schizophrenia, drug abuse, Parkinson's disease, pain, central control of blood pressure, eating disorders, cancer, neurodegenerative disorders and inflammation.
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PMID:The role of neurotensin in central nervous system pathophysiology: what is the evidence? 1686 41

Neurotensin (NT) can produce a profound analgesia or enhance pain responses, depending on the circumstances. Recent evidence suggests that this may be due to a dose-dependent recruitment of distinct populations of pain modulatory neurons. NT knockout mice display defects in both basal nociceptive responses and stress-induced analgesia. Stress-induced antinociception is absent in these mice and instead stress induces a hyperalgesic response, suggesting that NT plays a key role in the stress-induced suppression of pain. Cold water swim stress results in increased NT mRNA expression in hypothalamic regions known to project to periaqueductal gray, a key region involved in pain modulation. Thus, stress-induced increases in NT signaling in pain modulatory regions may be responsible for the transition from pain facilitation to analgesia. This review focuses on recent advances that have provided insights into the role of NT in pain modulation.
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PMID:Neurotensin and pain modulation. 1687 Mar 6

Neurotensin (NT) is a peptide that is widely distributed throughout the brain. NT is involved in locomotion, reward, stress and pain modulation, and in the pathophysiology of drug addiction and depression. In its first part this review brings together relevant literature about the neuroanatomy of NT and its receptors. The second part focuses on functional-anatomical interactions between NT, the mesotelencephalic dopamine system and structures targeted by dopaminergic projections. Finally, recent data about the actions of NT in processes underlying behavioral sensitization to psychostimulant drugs and the involvement of NT in the regulation of the hypothalamo-pituitary-adrenal gland axis are considered.
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PMID:Brain neurotensin, psychostimulants, and stress--emphasis on neuroanatomical substrates. 1693 69

Thimet oligopeptidase (EC 3.4.24.15) and neurolysin (EC 3.4.24.16) are closely related zinc-dependent metallopeptidases that metabolize small bioactive peptides. They cleave many substrates at the same sites, but they recognize different positions on others, including neurotensin, a 13-residue peptide involved in modulation of dopaminergic circuits, pain perception, and thermoregulation. On the basis of crystal structures and previous mapping studies, four sites (Glu-469/Arg-470, Met-490/Arg-491, His-495/Asn-496, and Arg-498/Thr-499; thimet oligopeptidase residues listed first) in their substrate-binding channels appear positioned to account for differences in specificity. Thimet oligopeptidase mutated so that neurolysin residues are at all four positions cleaves neurotensin at the neurolysin site, and the reverse mutations in neurolysin switch hydrolysis to the thimet oligopeptidase site. Using a series of constructs mutated at just three of the sites, it was determined that mutations at only two (Glu-469/Arg-470 and Arg-498/Thr-499) are required to swap specificity, a result that was confirmed by testing the two-mutant constructs. If only either one of the two sites is mutated in thimet oligopeptidase, then the enzyme cleaves almost equally at the two hydrolysis positions. Crystal structures of both two-mutant constructs show that the mutations do not perturb local structure, but side chain conformations at the Arg-498/Thr-499 position differ from those of the mimicked enzyme. A model for differential recognition of neurotensin based on differences in surface charge distribution in the substrate binding sites is proposed. The model is supported by the finding that reducing the positive charge on the peptide results in cleavage at both hydrolysis sites.
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PMID:Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase. 1725 Nov 85

Our previous study has proven that hypothalamic paraventricular nucleus (PVN) stimulation increases pain threshold and PVN cauterization decreases pain threshold. The studied neuropeptides in PVN were investigated to involve to pain modulation in the rat. The results showed that (1) intraventricular injection (icv) of anti-arginine vasopressin (AVP) serum completely reversed pain threshold increase induced by l-glutamate sodium (Glu) injection into the PVN, and local administration (icv) of anti-leucine-enkephalin (L-Ek) serum or anti-beta-endorphin (beta-Ep) serum partly attenuated pain threshold increase induced by Glu injection into the PVN, but pre-treatment of anti-oxytocin (OXT), dynorphinA(1-13) (DynA(1-13)), cholecystokinin-like peptide (CCK), neurotensin (NT), corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), somatostatin (SST), prolactin-releasing hormone (PRH), angiotensinII (AngII), vasoactive intestinal polypeptide (VIP), melanotropin-releasing hormone (MRH), thyrotropin-releasing hormone (TRH), substance P (SP) or growth hormone-releasing hormone (GHRH) serum (icv) did not influence the analgesic effect of PVN administration with Glu; (2) PVN stimulation with Glu elevated the concentrations of AVP, OXT, CCK, NT, CRH, SST, PRH and DynA(1-13) in PVN perfusion liquid, and could not change the concentrations of L-Ek, beta-Ep, AngII, ACTH, VIP, MRH, TRH, SP and GHRH in PVN perfusion liquid; (3) Pain stimulation increased the concentrations of AVP, L-Ek, beta-Ep, DynA(1-13), CRH and ACTH in PVN perfusion liquid, and did not alter the concentrations of OXT, CCK, NT, SST, PRH, AngII, VIP, MRH, TRH, SP and GHRH in PVN perfusion liquid. The data suggested that AVP played a more important role than the other studied peptides (OXT, L-Ek, beta-Ep, DynA(1-13), CCK, NT, CRH, ACTH, SST, PRH, AngII, VIP, MRH, TRH, SP and GHRH) in PVN antinociceptive progress.
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PMID:Arginine vasopressin is an important regulator in antinociceptive modulation of hypothalamic paraventricular nucleus in the rat. 1731 91

The main purpose of this study was to evaluate the effects of early dexamethasone treatment on pain-related peptides at an early stage in the development of neuropathic pain induced by implantation of a sciatic nerve cuff in Sprague Dawley rats (body weight 250 to 350 g). The rats were tested for touch sensitivity with the use of von Frey filaments before and 3 d after cuff implantation (n = 12) or sham surgery (n = 6). Half of the cuff-implanted rats received dexamethasone, 1 mg/kg intraperitoneally, 1 h after surgery. Spinal cords were collected on the 3rd day after surgery, and the lumbar enlargement was processed for the detection of selected peptides (neurotensin, substance P, cholecystokinin [CCK], vasoactive intestinal peptide, and calcitonin gene-related peptide) by means of liquid chromatography and tandem mass spectrometry. The right sciatic nerve of each rat was collected, fixed, and stained for histopathological evaluation. Except for neurotensin, all the peptides showed an increased concentration with neuropathic pain; however, the differences were significant (P < 0.05) only for substance P and CCK. In the animals treated with dexamethasone, mechanical allodynia was less pronounced (P < 0.01), and only the concentration of substance P was decreased significantly (P < 0.05). Sciatic nerve sections showed a decrease in C (P < 0.01) and Adelta (P < 0.03) fibres with neuropathic pain and a nearly normal percentage of C fibres after dexamethasone treatment. The dexamethasone-treated animals also had less inflammation detectable microscopically at the nerve constriction site compared with cuff-implanted animals that were not treated with dexamethasone. Our results suggest that in the early stages of neuropathic pain induced by an inflammatory process, dexamethasone may be a useful treatment and that substance P plays an important role in pain perception.
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PMID:Early dexamethasone treatment after implantation of a sciatic-nerve cuff decreases the concentration of substance P in the lumbar spinal cord of rats with neuropathic pain. 1747 71

Hepatic fibrolamellar carcinoma (FLC) is an uncommon tumour that differs from hepatocellular carcinoma (HCC) in demographics, condition of the affected liver, tumour markers, and prognosis. FLC characteristically manifests as a large hepatic mass in adolescents or young adults with female predominance (mean age 23 years). Cirrhosis, elevated alpha-fetoprotein levels, and risk factors for HCC such as viral hepatitis are typically absent. FLC is usually associated with serum tumour markers such as vitamin B12 binding protein, and neurotensin. FLC is characterized pathologically by cords of tumour cells surrounded by abundant collagenous fibrous tissue arranged in a parallel or lamellar distribution. FLC usually appears on radiologic images as a lobulated heterogeneous mass with a central scar in an otherwise normal liver. The clinical presentation of patients with FLC is variable. These patients commonly have pain, and palpable right upper quadrant abdominal mass. An uncommon presenting sign is gynaecomastia in men. Use of percutaneous biopsy (FNAB) is beneficial if there is diagnostic uncertainty about the radiologic diagnosis (US, CT MRI). Although FLC is frequently recurrent, patients have a better prognosis than those with HCC, and aggressive surgical liver resection with extended lymphadenectomy or liver transplantation may be indicated. The presence of advanced-stage disease, direct invasion of adjacent organs, lymphadenopathy, or limited metastasis does not preclude attempts at curative resection. In inoperable cases, the patient may benefit from chemotherapy, permitting in up to 50% of these cases a curative resection. The case is reported of a 18-year-old man with bilateral gynecomastia secondary to an unknown hepatic fibrolamellar carcinoma producing oestrogens. Serum alpha-fetoprotein was negative; des-gamma-carboxy prothrombin (DCP) level was elevated. CT scan and MRI showed a solid hepatic tumour (theta 10 cm) without evidence of extrahepatic spreading. By a needle biopsy a fibrolamellar carcinoma was diagnosed. On March 1995 a right hemihepatectomy was performed. The postoperative course was uneventful and the patient recovered. Specimen's histologic examination confirmed the preoperative diagnosis. Intracellular (hepatocytes) oestrogens were found, but oestrogen and androgen receptors were negative. After surgery DCP and oestradiol levels rapidly decreased and gynaecomastia disappeared. A follow-up program was established. On April 2000 a probable recurrence within the caudate lobe was discovered by a liver CT scan without evidence of extrahepatic spreading. Tumour markers, FNAB, and bone scintigraphy were negative. On July 2000 the patient underwent second look laparotomy. Only a coeliac lymphadenopathy was found and a lymphadenectomy performed. Specimen's histologic examination showed a metastatic lymph nodal disease (FLC). The postoperative course was uneventful and the patient recovered. He is currently alive without evidence of recurrence 5 years after the second operation.
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PMID:[Surgical therapy of hepatic fibrolamellar carcinoma]. 1751 32


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