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

The effects of opioids on cigarette smoke-induced plasma exudation were investigated in vivo in the main bronchi of anesthetized guinea pigs, with Evans blue dye as a plasma marker. Acute inhalation of cigarette smoke increased plasma exudation by 216% above air control values. Morphine, 0.1-10 mg/kg but not 30 mg/kg, inhibited the exudation but had no significant effect on substance P-induced exudation. Both 10 and 30 mg/kg of morphine increased exudation in air control animals, an effect inhibited by antihistamines but not by a tachykinin neurokinin type 1-receptor antagonist. Naloxone inhibited all morphine responses. Cigarette smoke-induced plasma exudation was inhibited by a mu-opioid-receptor agonist (DAMGO) but not by agonists at delta (DPDPE)- or kappa (U-50488H)-receptors. None of these agonists affected exudation in air control animals. DPDPE prevented the inhibition by DAMGO of cigarette smoke-induced plasma exudation, and the combination of DAMGO and DPDPE increased exudation in air control animals. Prevention of inhibition and the combination-induced increase were inhibited by antihistamines or the mast cell-stabilizing drug sodium cromoglycate. U-50488H did not alter the response to either DAMGO or DPDPE. We conclude that, in guinea pig main bronchi in vivo, mu-opioid-receptor agonists inhibit cigarette smoke-induced plasma exudation via a prejunctional mechanism. Plasma exudation induced by mu- and delta-receptor interactions is due to endogenous histamine release from mast cells.
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PMID:Effects and interactions of opioids on plasma exudation induced by cigarette smoke in guinea pig bronchi. 1007 Jan 1

The present investigation details the modulation of medullary dorsal horn neuron responses to excitatory amino acids and peripheral cutaneous stimuli by orphanin FQ (nociceptin), an endogenous ligand for the opioid receptor-like, receptor. Effects of orphanin FQ, administered microiontophoretically or given intracerebroventricularly, were tested on the responses of nociceptive-specific, wide dynamic range and low threshold neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (urethane or pentobarbital) male rats. Microiontophoretic application of orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 86% (71/82) of neurons, and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses in 86% (30/35) of neurons. However, orphanin FQ produced a longer lasting inhibitory effect on the N-methyl-D-aspartate-evoked responses relative to the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses. The inhibitory effect of orphanin FQ was not modality-specific, responses evoked by noxious as well as non-noxious stimuli were reduced in 22/23 neurons. However, the inhibitory effect was more pronounced on noxious stimulus-evoked responses. Naloxone applied at currents that antagonized the inhibitory effects of selective agonists at mu and kappa opioid receptors failed to inhibit the effects of orphanin FQ. Microiontophoretic co-application of substance P with N-methyl-D-aspartate facilitated the N-methyl-D-aspartate-evoked responses in 52% (26/50) of nociceptive neurons. Orphanin FQ blocked or reduced the substance P-induced facilitation by 86+/-24.4% (n = 14). In order to compare electrophysiological data with previous behavioral observations, effects of orphanin FQ administered intracerebroventricularly were tested on the excitatory amino acid-evoked responses. Orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 85% (11/13) of neurons whereas the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses were facilitated in 69% (9/13) of neurons. We suggest that orphanin FQ produces a predominantly inhibitory effect on, (i) noxious stimuli evoked responses, (ii) excitatory amino acid receptor-mediated transmission and, (iii) the substance P-induced facilitation of the N-methyl-D-aspartate-evoked responses. We conclude that orphanin FQ primarily produced an antinociceptive action at the level of the dorsal horn of the medulla.
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PMID:Orphanin FQ (nociceptin) modulates responses of trigeminal neurons evoked by excitatory amino acids and somatosensory stimuli, and blocks the substance P-induced facilitation of N-methyl-D-aspartate-evoked responses. 1046 54

Effects of two commonly used tachykinin NK-3 receptor antagonists (SR 142801 and R820) intrathecally (i.t.) administered were assessed in the rat tail-flick test. SR142801 and its (R)-enantiomer SR142806 (1.3, 6.5 and 65 nmol) were found as potent as senktide and [MePhe7]NKB (NK-3 selective agonists) to induce transient antinociceptive effects. Naloxone (10 microg) and R820 (6.5 nmol) blocked reversibly the responses to 6.5 nmol senktide, [MePhe7]NKB, SR142801 and SR142806 when administered i.t. 15 min earlier. However, the antinociceptive responses induced by SR142801 and SR142806 were not affected by i.t. pretreatments with NK-1 (6.5 nmol SR140333) and NK-2 (6.5 nmol SR48968) receptor antagonists. In control experiments, the NK-1 and NK-2 antagonists prevented the hyperalgesic effects to NK-1 ([Sar9,Met(O2)11]SP) and NK-2 ([beta-Ala8] NKA(4-10)) receptor agonists (6.5 nmol i.t.), respectively. R820 had no direct effect on nociceptive threshold and failed to alter angiotensin II-induced antinociception. The data suggest that the antinociceptive effect of SR142801 is due to an agonist effect at NK-3 receptor in the rat spinal cord that involves a local opioid mechanism. These results can be best explained by the existence of inter-species NK-3 receptor subtypes.
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PMID:SR142801 behaves as a tachykinin NK-3 receptor agonist on a spinal nociceptive reflex in the rat. 1065 24

In transgenic mice expressing ectopic substance P fibres in the spinal white matter, a normally innocuous mechanical stimulus induces hyperalgesia and allodynia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists. This period of enhanced excitation is followed by a rebound overshoot in these animals. As previous evidence indicates opioid mechanisms in a similar rebound in normal animals, the present study was done to determine the effects of systemic administration of morphine and the opiate receptor antagonist, naloxone, on the stimulus-induced responses in the tail withdrawal reflex. Once baseline reaction times had been taken, different combinations of saline, naloxone and morphine were administered intraperitoneally to transgenic and control mice of either sex. A mechanical conditioning stimulus of 450g was then applied to the tip of the tail for 2s. This stimulus was innocuous in control mice given saline or naloxone, but provoked a nociceptive response in transgenic mice given these compounds. In control and transgenic mice, following morphine administration there was an antinociceptive effect. In control mice the subsequent mechanical stimulus had no effect. However, in transgenic mice the mechanical stimulus produced a further antinociception. Naloxone blocked the effect of morphine and the subsequent conditioning stimulus in both control and transgenic mice. The results indicate that while morphine is equally effective on the withdrawal reflex in both types of animal, in the transgenic mice morphine reveals an intrinsic, naloxone-sensitive antinociceptive mechanism. The data are interpreted to suggest that over-expression of substance P or some other factor in the spinal cord of transgenic mice is associated with the up-regulation or facilitation of an opiate-mediated intrinsic antinociceptive mechanism. This is a novel observation because the genetic manipulation in this transgenic mouse results in a transient over-expression of nerve growth factor during development that leads to the formation of ectopic primary afferent fibres in the spinal cord containing substance P. These fibres persist indefinitely after the nerve growth factor levels return to normal. Opioid mechanisms, which are likely of dorsal horn origin, do not fall under the direct influence of nerve growth factor mechanisms and therefore the intriguing possibility is raised that opioid mechanisms in the spinal cord are regulated at least in part by substance P-related mechanisms.
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PMID:Upregulation of an opioid-mediated antinociceptive mechanism in transgenic mice over-expressing substance P in the spinal cord. 1072 96

Our recent study demonstrated that ginsenosides had antinociceptive effects by reducing some types of pain-related behavior in mice (Yoon et al., 1998. Ginsenosides induce differential antinociception and inhibit substance P-induced nociceptive response in mice. Life Science 62, PL319-PL325). In the present study we further investigated whether ginsenosides produce antinociceptive effects through an action at central or peripheral site(s) and whether these effects are mediated by the opioid system. Intraperitoneally injected ginsenosides suppressed in a dose-dependent manner the pain-related behavior produced by capsaicin injection into the plantar surface of the hind paw; the ED(50) was 49 mg/kg [26-92 mg/kg, 95% confidence interval (C.I.)]. Intrathecally or intracerebroventricularly administered ginsenosides also suppressed the capsaicin-induced pain-related behavior in a dose-dependent manner; the ED(50)s were 1.72 mg/kg (0.8-3.72 mg/kg, 95% C.I.) and 1. 48 mg/kg (0.8-2.6 mg/kg, 95% C.I.), respectively. On the other hand, subcutaneously injected ginsenosides to the plantar surface prior to the capsaicin injection did not alter the pain-related behavior. Naloxone pretreatment was without effect in blocking the antinociceptive effect of intrathecally administered ginsenosides. Intraperitoneally injected ginsenosides also did not significantly affect the motor response of animals. These results suggest that ginsenosides produce antinociceptive effects through their action at the spinal and/or supraspinal site(s), not at nociceptors in the periphery. In addition, the results suggest that the antinociceptive effects are not mediated by opioid receptors.
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PMID:Effect of ginsenosides, active components of ginseng, on capsaicin-induced pain-related behavior. 1096 61

We investigated and compared the effects of two amphibian tachykinins, the NK1 receptor agonist PG-SPI and the NK3 receptor agonist PG-KII, and the mammalian tachykinins substance P, neurokinin A and neurokinin B on the reaction time to a painful radiant heat stimulus (tail-flick test in rats) after intracerebroventricular injection. PG-SPI (1, 10 and 20 microg) and PG-KII (1, 5 and 10 microg) significantly increased the reaction time. Substance P (10 microg) injected intracerebroventricularly induced antinociception, whereas neurokinin A and neurokinin B did not. Like analgesia evoked by exogenous substance P, PG-SPI-evoked analgesia was blocked by pretreatment with naloxone. Naloxone left PG-KII antinociception unchanged, but the NK3 receptor selective antagonist markedly reduced it. These findings suggest NK1 and NK3 tachykinin receptor system involvement in supraspinal analgesia in rats.
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PMID:Effects of supraspinal administration of PG-SPI and PG-KII, two amphibian tachykinin peptides, on nociception in the rat. 1109 Sep 14

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 microm) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.
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PMID:Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study. 1168 1

Neutral endopeptidase (EC3.4.24.11, NEP, enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like enkephalins, substance P, and bradykinin. In the brain, NEP is a key enzyme in the degradation of enkephalins. Pharmacological inhibition of NEP-activity causes analgesia resulting from enhanced extracellular enkephalin concentrations. Recently, transgenic mice lacking the enzyme NEP have been developed (Lu, 1995). The present study was designed to investigate the nociceptive behavior of these NEP-knockout mice. Interestingly, NEP-deficient mice did not respond with decreased pain perception, but exhibited hyperalgesia in the hot-plate jump, warm-water tail-withdrawal, and mostnotablyin theacetic-acid writhing test. Inhibition of aminopeptidase N by bestatin reduced writhing in both strains, whereas NEP-inhibition by thiorphan reduced writhing selectively in wild-type mice. Naloxone increased writhing in wild-type but not in knockouts, whereas the bradykinin B2-receptor antagonist HOE140 reduced writhing selectively in NEP-knockouts. Similarly, the nitric oxide synthase inhibitor L-NAME reduced writhing in NEP-knockouts. These results indicate that genetic elimination of NEP, in contrast to pharmacological inhibition, leads to bradykinin-induced hyperalgesia instead of enkephalin-mediated analgesia. Nitric oxide (NO) is suggested to be involved in this process.
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PMID:Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide. 1193 42

This study examined the role of spinal calcitonin gene-related peptide (CGRP), substance P, and prostaglandins in the development and expression of opioid physical dependence. Administration of escalating doses (5 - 100 mg kg-1, i.p.) of morphine for 7 days markedly elevated CGRP and substance P- immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg-1, i.p.) challenge decreased both CGRP and substance P immunoreactivity and precipitated a robust withdrawal syndrome. Acute intrathecal pre-treatment with a CGRP receptor antagonist, CGRP(8 - 37) (4, 8 microg), a substance P receptor antagonist, SR 140333 (1.4, 2.8 microg), a cyclo-oxygenase (COX) inhibitor, ketorolac (30, 45 microg), and COX-2 selective inhibitors, DuP 697 (10, 30 microg) and nimesulide (30 microg), 30 min before naloxone challenge, partially attenuated the symptoms of morphine withdrawal. CGRP(8 - 37) (8 microg), but no other agents, inhibited the decrease in CGRP immunoreactivity. Chronic intrathecal treatment with CGRP(8 - 37) (4, 8 microg), SR 140333 (1.4 microg), ketorolac (15, 30 microg), DuP 697 (10, 30micro g), and nimesulide (30 microg), delivered with daily morphine injection significantly attenuated both the symptoms of withdrawal and the decrease in CGRP but not substance P immunoreactivity. The results of this study suggest that activation of CGRP and substance P receptors, at the spinal level, contributes to the induction and expression of opioid physical dependence and that this activity may be partially expressed through the intermediary actions of prostaglandins.
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PMID:The role of spinal neuropeptides and prostaglandins in opioid physical dependence. 1197 66

Opioid receptors are expressed in cells of the immune system, and potent immunomodulatory effects of their natural and synthetic ligands have been reported. In some studies, the opiate receptor antagonist naloxone itself displayed immunomodulatory actions. We investigated effects of naloxone on leukocyte chemotaxis. Cell migration was tested in micropore filter assays using modified Boyden chambers, and receptor expression was investigated using radiolabel binding assays. Naloxone induced peripheral blood nonadherent mononuclear cell and neutrophil chemotaxis at nanomolar concentrations and deactivated their migration toward beta-endorphin, angiotensin II, somatostatin, or interleukin-8 but not toward RANTES, vasoactive intestinal peptide, or substance P. Ligand binding studies showed no alteration in the binding of interleukin-8 to neutrophils by naloxone. Cleavage of heparan sulfate from proteoglycans on the cells' surface completely inhibited chemotactic and deactivating properties of naloxone but not other attractants. Chemotactic properties were abolished by pretreating cells with heparinase, chondroitinase, sodium chlorate, and anti-syndecan-4 antibodies, indicating the involvement of syndecan-4. The extent of migration toward naloxone was diminished by pretreatment with dimethylsphingosine, a specific sphingosine kinase inhibitor. As syndecan-4 signaling in leukocyte chemotaxis involves activation of sphingosine kinase, results indicate that naloxone interacts with syndecan-4 function in cell migration and suggest a role for heparan sulfate proteoglycans as coreceptors to members of the delta-opiate receptor family.
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PMID:Heparan sulfate proteoglycans are involved in opiate receptor-mediated cell migration. 1470 51


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