Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Managing patients with treatment-resistant depression (TRD) remains a major challenge for the practicing physician. Depression is considered treatment-resistant when at least two adequate monotherapy trials with drugs from different pharmacologic classes fail to elicit a therapeutic response. Although determining the stage of TRD may allow concise description of a patient's antidepressant history, management of TRD is better served by recent attempts to create a treatment algorithm that encompasses definitive diagnosis of true TRD and strategies for optimizing available therapies, including consideration of novel treatment options. Present strategies for managing TRD include optimization of the initial drug, substitution of another drug from the same or a different antidepressant class, combination of two antidepressants with different mechanisms of action, and adding an antidepressant drug from another class. Potential nonpharmacologic treatments include vagus nerve stimulation, repetitive transcranial magnetic stimulation, and magnetic seizure therapy as an alternative to electroconvulsive therapy. Several neuropeptides and their receptors have also been identified as potential targets for pharmacologic intervention, including corticotropin-releasing factor and substance P. Other treatments currently under investigation include augmentation of antidepressant therapy with an atypical antipsychotic agent such as olanzapine or risperidone. This kind of therapeutic intervention may prove to be especially useful in treating patients with TRD.
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PMID:Treatment-resistant depression: new therapies on the horizon. 1283 33

Both endothelins and corticotropin releasing factor (CRF) appear in capsaicin-sensitive neurons. We have investigated the effects of human endothelin-1 (ET-1) and CRF in the guinea-pig ileum longitudinal and circular preparations and sought for ways of specific antagonism. With the aid of tachyphylaxis to capsaicin (i.e., rendering capsaicin-sensitive neurons functionally impaired) it was tested if these neurons played a mediating role in the effects of ET-1 or CRF. We also tried to find out whether endogenous endothelin or CRF plays a role in the excitatory and inhibitory effects of capsaicin in the ileum. In preparations at basal tone, both exogenous ET-1 (1-100 nM) and CRF (3-100 nM) caused contraction. These responses were not influenced by capsaicin tachyphylaxis. The contractile effect of ET-1 was not affected by tetrodotoxin (1 microM), atropine (1 microM), methysergide (100 nM), chloropyramine (100 nM) or SR140333 (100 nM) but was significantly inhibited or even abolished by the receptor antagonist BQ123 (3 microM) or BQ788 (3 microM). CRF caused contraction that was fully sensitive to tetrodotoxin (1 microM), tachyphylaxis to CRF or to atropine (1 microM) plus the tachykinin NK1 receptor antagonist SR140333 (200 nM). Atropine alone had a weak inhibitory effect on the contractile action of CRF. Neither the antagonist BQ123 (3 microM) nor CRF tachyphylaxis inhibited the contractile action of capsaicin (2 microM), even in the presence of a mixture of GR82334 (3 microM) and SR142801 (100 nM), for blocking tachykinin NK1 and NK3 receptors, respectively--a treatment that by itself significantly reduced the effect of capsaicin. Exogenous ET-1 (0.3-5 nM), but not CRF (30-100 nM), caused relaxation of the atropine-treated, histamine-precontracted ileum. This effect of ET-1 was significantly inhibited or abolished by BQ123 (10 microM), or BQ788 (3 microM), but was not influenced by capsaicin tachyphylaxis. Likewise, relaxation of the atropine-treated, histamine-precontracted ileum in response to capsaicin was not influenced by the endothelin receptor antagonist BQ788 (3 microM) or BQ788 (3 microM) plus BQ123 (3 microM). Apamin (300 nM) was also without effect on the capsaicin-induced relaxation. In circular muscle strips ET-1 inhibited the indomethacin-induced spontaneous activity. This effect was abolished by BQ123 (3 microM) or BQ788 (3 microM). CRF caused a stimulation of the circular muscle. This stimulatory effect was not influenced by atropine (1 microM) alone, but was inhibited by atropine plus tachykinin NK1 and NK2 receptor antagonists (SR140333 (200 nM) and SR48968 (200 nM)) and also by tetrodotoxin (1 microM). It is concluded that capsaicin-sensitive neurons do not play a role in the effects of exogenous ET-1 or CRF in the guinea-pig ileum. ET-1 can both contract and relax the ileal longitudinal smooth muscle directly, probably via both ETA and ETB receptors. CRF acts by specifically stimulating excitatory (but not inhibitory) neurons of the myenteric plexus. Neither endogenous ET-1 nor CRF seems to play a role in the excitatory or inhibitory effects of capsaicin.
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PMID:Actions of endothelin and corticotropin releasing factor in the guinea-pig ileum: no evidence for an interaction with capsaicin-sensitive neurons. 1290 40

The health burden of stress-related diseases, including depression and anxiety disorders, is rapidly increasing, whereas the range of available pharmacotherapies to treat these disorders is limited and suboptimal with regard to efficacy and tolerability. Recent findings support a major role for neuropeptides in mediating the response to stress and thereby identify neuropeptide systems as potential novel therapeutic targets for the treatment of depression and anxiety disorders. In preclinical models, pharmacological and/or genetic manipulation of substance P, corticotropin-releasing factor (CRF), vasopressin, neuropeptide Y and galanin function alters anxiety- and depression-related responses. Recently, specific and highly potent small-molecule neuropeptide receptor agonists and antagonists have been developed that can readily cross the blood-brain barrier. Clinical assessment of several compounds is currently underway, with antidepressant efficacy confirmed in double-blind, placebo-controlled trials of tachykinin NK(1) (substance P) receptor antagonists, and preliminary evidence of antidepressant activity in an open-label trial of a CRF(1) receptor antagonist.
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PMID:Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. 1512 Apr 87

The mechanism(s) underlying stress-induced colonic hypersensitivity (SICH) are incompletely understood. Our aims were to assess the acute and delayed (24 h) effect of water avoidance (WA) stress on visceral nociception in awake male Wistar rats and to evaluate the role of two stress-related modulation systems: the substance P/neurokinin-1 receptor (SP/NK(1)R) and the corticotropin-releasing factor (CRF)/CRF(1) receptor (CRF/CRF(1)R) systems, as well as the possible involvement of the sympathetic nervous system. Visceral pain responses were measured as the visceromotor response to colorectal distension (CRD) at baseline, immediately after WA and again 24 h later. The NK(1)R antagonists RP-67580 and SR-140333 and the CRF(1)R antagonist CP-154526 were injected 15 min before WA or 1 h before the CRD on day 2. Chemical sympathectomy was performed by repeated injection of 6-hydroxydopamine. WA stress resulted in a significant increase in the visceromotor response on day 2, but no change immediately after WA. Injection of CP-154526 abolished delayed SICH when applied either before WA stress or before the CRD on day 2. Both NK(1)R antagonists only decreased SICH when injected before the CRD on day 2. Chemical sympathectomy did not affect delayed SICH. Our results indicate that in male Wistar rats, both NK(1)R and CRF(1)R activation, but not sympathetic nervous system activation, play a role in the development of SICH.
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PMID:Delayed stress-induced colonic hypersensitivity in male Wistar rats: role of neurokinin-1 and corticotropin-releasing factor-1 receptors. 1461 83

Available data demonstrate that the avian septal region shares a number of social behavior functions and neurochemical features in common with mammals. However, the structural and functional subdivisions of the avian septum remain largely unexplored. In order to delineate chemoarchitectural zones of the avian septum, we prepared a large dataset of double-, triple-, and quadruple-labeled material in a variety of songbird species (finches and waxbills of the family Estrildidae and a limited number of emberizid sparrows) using antibodies against 10 neuropeptides and enzymes. Ten septal zones were identified that were placed into lateral, medial, caudocentral, and septohippocampal divisions, with the lateral and medial divisions each containing multiple zones. The distributions of numerous immunoreactive substances in the lateral septum closely match those of mammals (i.e., distributions of met-enkephalin, vasotocin, galanin, calcitonin gene-related peptide, tyrosine hydroxylase, vasoactive intestinal polypeptide, substance P, corticotropin-releasing factor, and neuropeptide Y), enabling detailed comparisons with numerous chemoarchitectonic zones of the mammalian lateral septum. Our septohippocampal and caudocentral divisions are topographically comparable to the mammalian septohippocampal and septofimbrial nuclei, respectively, although additional data will be required to establish homology. The present data also demonstrate the presence of a medial septal nucleus that is histochemically comparable to the medial septum of mammals. The avian medial septum is clearly defined by peptidergic markers and choline acetyltransferase immunoreactivity. These findings should provide a useful framework for functional and comparative studies, as they suggest that many features of the septum are highly conserved across vertebrate taxa.
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PMID:Chemoarchitectonic subdivisions of the songbird septum and a comparative overview of septum chemical anatomy in jawed vertebrates. 1511 93

Chromogranin A (CgA) is an acidic protein identified within a large variety of endocrine cells. Colocalized with catecholamines in chromaffin cells, CgA is a prohormone precursor of small biologically active peptides. Vasostatin (CgA 1-76) is the most conserved fragment of CgA and chromogranin A 47-66 peptide (CgA 47-66) possesses potent antimicrobial activities. The aim of this study was to test the hypothesis that CgA 47-66 may be involved in mechanisms modulating nociception. Thus, we used acetic acid (AA) which produces a delayed inflammatory response and episodes of abdominal writhing, a marker of pain, when injected intraperitoneally (i.p.) to rats. Administration (i.p.) of CgA 47-66 induced specific opposite dose-dependent effects depending on concentration. That is, CgA 47-66 below 0.5 mg/kg produced antinociceptive effects, whereas at 2 mg/kg it produced a marked pronociceptive effect. The latter effect was blocked by diltiazem and indomethacin. CgA 47-66-induced antinociceptive effects on AA-induced responses were reversed when the corticotropin-releasing factor (CRF) antagonist alpha-helical CRF 9-41 was i.p. injected to animals prior to AA and CgA 47-66 administration. The administration of i.p. calcitonin gene-related peptide (CGRP) or substance P (SP) evoked dose-dependent abdominal writhing; this effect was abolished when CgA 47-66 was injected. The present data suggest, for the first time, that a fragment of CgA, CgA 47-66, possesses potent antinociceptive effects at low doses. Although the mechanism triggered by this peptide is unknown, CRF receptors are likely to be involved.
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PMID:Effects of a chromogranin-derived peptide (CgA 47-66) in the writhing nociceptive response induced by acetic acid in rats. 1512 Apr 81

The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and alpha-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.
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PMID:Elaborate interactions between the immune and nervous systems. 1528 54

Several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, are exacerbated by stress. Recent evidence suggests that crosstalk between mast cells, neurons and keratinocytes might be involved in such exacerbation. Mast cells are distributed widely in the skin, are present in increased numbers in AD and are located in close proximity to substance P- or neurotensin-containing neurons. Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress. Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcepsilonRI) crosslinking. Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators. Thus, we propose that CRF receptor antagonists could be used together with natural molecules, such as retinol and flavonoids, to inhibit mast cell activation and provide new therapeutic options for chronic inflammatory conditions exacerbated by stress.
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PMID:Mast cells as targets of corticotropin-releasing factor and related peptides. 1549 78

Reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiological recording, and intraneuronal injection of the neuronal tracer biocytin were integrated in a study of the functional expression of corticotropin-releasing factor (CRF) receptors in the guinea pig enteric nervous system. RT-PCR revealed expression of CRF1 receptor mRNA, but not CRF2, in both myenteric and submucosal plexuses. Immunoreactivity for the CRF1 receptor was distributed widely in the myenteric plexus of the stomach and small and large intestine and in the submucosal plexus of the small and large intestine. CRF1 receptor immunoreactivity was coexpressed with calbindin, choline acetyltransferase, and substance P in the myenteric plexus. In the submucosal plexus, CRF1 receptor immunoreactivity was found in neurons that expressed calbindin, substance P, choline acetyltransferase, or neuropeptide Y. Application of CRF evoked slowly activating depolarizing responses associated with elevated excitability in both myenteric and submucosal neurons. Histological analysis of biocytin-filled neurons revealed that both uniaxonal neurons with S-type electrophysiological behavior and neurons with AH-type electrophysiological behavior and Dogiel II morphology responded to CRF. The CRF-evoked depolarizing responses were suppressed by the CRF1/CRF2 receptor antagonist astressin and the selective CRF1 receptor antagonist NBI27914 and were unaffected by the selective CRF2 receptor antagonist antisauvagine-30. The findings support the hypothesis that the CRF1 receptor mediates the excitatory actions of CRF on neurons in the enteric nervous system. Actions on enteric neurons might underlie the neural mechanisms by which stress-related release of CRF in the periphery alters intestinal propulsive motor function, mucosal secretion, and barrier functions.
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PMID:Expression of type 1 corticotropin-releasing factor receptor in the guinea pig enteric nervous system. 1559 76

The dorsal raphe nucleus (DR) contains serotonin (5-HT) neurons that innervate the cortex and limbic system and through these projections is thought to regulate cognition and behavior. Clinical and pharmacological findings implicate dysfunctions in the DR-5-HT system in affective disorders, including anxiety, depression and suicide. Although the DR is often considered in light of its 5-HT neurons, recent studies underscore the complexity of this nucleus and its heterogeneous nature. Of particular interest, are peptides that are either present within neurons in the DR, innervate DR-5-HT neurons or act upon local circuitry within the DR to indirectly impact on this 5-HT system. These peptides are positioned to fine-tune the activity of selective groups of serotonergic neurons within the DR and thereby 5-HT release in different terminal fields. This review will focus on substance P and corticotropin-releasing factor as two peptides that act independently and interdependently to influence DR-5-HT function. The role of non-serotonergic components of the DR in translating the effect of each of these peptides is discussed. This synthesis refines our views on the regulation of the DR-5-HT system and importantly, gives insight into mechanisms of endogenous control of DR function, the dysregulation of which may contribute to pathophysiology.
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PMID:Peptides that fine-tune the serotonin system. 1562 94


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