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)

Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Neuroprotective therapy could be achieved with the knowledge of the specific trophic requirements of these neuronal populations. Thus, the induction of endogenous trophic response or the exogenous administration of neurotrophic factors may help to prevent or stop the progression of the illness. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults. Transplantation of cells genetically engineered to release neurotrophic factors in the striatum has been used to study the neuroprotective effects of neurotrophin and GDNF family members in the excitotoxic model of Huntington's disease. Neurotrophins (brain-derived neurotrophic factor [BDNF], neurotrophin-3, and neurotrophin-4) protected striatal projection neurons against quinolinic or kainic acid treatment. However, GDNF family members showed a more specific action. Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus. In conclusion, the trophic requirements of each population of striatal projection neurons are due to a complex interaction between several neurotrophic factors, such as neurotrophins and GDNF family members, which can be modified, in different pathological conditions. Moreover, these neurotrophic factors may be able to provide selective protection for basal ganglia circuits, which are affected in striatonigral degenerative disorders, such as Huntington's disease or multisystem atrophy.
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PMID:Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease. 1203 Dec 78

It has been proposed that antidepressant effects of neurokinin NK(1) receptor blockade may result from an increase in serotonin (5-HT) transmission. However, the mechanism by which neurokinins influence 5-HT neurons is not known. In this study, local NK(1) and NK(3) receptor-mediated responses in 5-HT neurons of the dorsal raphe nucleus (DRN) were studied using intracellular recording in rat brain slices. Bath application of the NK(1) receptor agonist substance P (SP) or the NK(3) receptor agonists senktide and NKB induced a robust increase in "spontaneous" excitatory postsynaptic currents (EPSCs) in 5-HT neurons. The EPSCs were blocked by the AMPA/kainate glutamate receptor antagonist CNQX and the fast Na(+) channel blocker tetrodotoxin (TTX), indicating that the increase in EPSCs resulted from an increase in impulse flow in local glutamatergic neuronal afferents. The neurokinins agonists had no direct excitatory effects on 5-HT neurons and no NK(1) or NK(3) receptor immunolabeling was found in 5-HT-labeled neurones. However, neurokinins, by increasing excitatory postsynaptic potentials (EPSPs), did increase the spiking of 5-HT neurons. The SP- and NKB-induced EPSCs were preferentially blocked by NK(1) and NK(3) antagonists, and there was minimal cross-desensitization between agonists at the two receptors. We conclude that neurokinins, via distinct NK(1) and NK(3) receptors, could promote 5-HT transmission, at least in part, by exciting a local population of glutamatergic inputs to 5-HT neurons in the DRN. However, these local excitatory effects, viewed within the context of the global effects of neurokinins on 5-HT neurons, reveal important differences between the functional role of NK(1) and NK(3) receptors.
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PMID:Neurokinins activate local glutamatergic inputs to serotonergic neurons of the dorsal raphe nucleus. 1222 91

Intrathecal (i.t.) administration of big dynorphin (1-10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5-15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1-30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-2 mg/kg) and also dose-dependently, by i.t. co-administration of D(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe(7),D-His(9)]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.
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PMID:Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism. 1236 99

Previously, we reported that the injection of capsaicin into the lateral cerebroventricle (i.c.v.) stimulated gastric acid secretion via vanilloid VR1 receptors and the vagal cholinergic pathways in anesthetized rats. In the present study, we investigated the involvement of receptor systems for neurokinin A, calcitonin gene-related peptide (CGRP) and glutamate in the vanilloid VR1 receptor-mediated response. The i.c.v. injection of neurokinin A (30 nmol) stimulated gastric acid secretion in the presence of cis-2-(diphenylmethyl)-N-[(2-iodophenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine oxalate (L-703606, a tachykinin NK1 receptor antagonist, 30 nmol) and the effect was inhibited by cyclo[Gln-Trp-Phe-Gly-Leu-Met] (L-659877, a tachykinin NK2 receptor antagonist, 30 nmol); the values were 145.9 +/- 32.3 and 21.1 +/- 16.6 microEq HCl per 120 min, respectively. The value in the control group was 14.3 +/- 3.8 microEq HCl. The tachykinin NK2 receptor-mediated secretion was inhibited by i.c.v. injections of antagonists of the CGRP1 receptor (human CGRP fragment 8-37, 15 nmol) and non-N-methyl-D-aspartate (non-NMDA)-type glutamate receptor (6-cyano-7-nitroquinoxaline-2,3-dione, 10.9 nmol); the values were 30.8+/-29.8 and 5.7+/-16.9 microEq HCl, respectively. Gastric acid secretion induced by the i.c.v. injection of 30 nmol capsaicin (178.4 +/- 34.0 microEq HCl) was inhibited by antagonists of tachykinin NK2 (23.7 +/- 6.2) and CGRP1 (21.2 +/- 8.5), but not tachykinin NK1 (181.4 +/- 37.0), receptors. The gastric acid secretion induced by capsaicin was decreased by the i.c.v. pre-injection of low doses of neurokinin A or CGRP, which alone had no effect on the secretion. These findings suggest the involvement of tachykinin NK2, CGRP and non-NMDA receptor systems in the vanilloid VR1 receptor-mediated regulation of gastric acid secretion in the rat brain regions close to the lateral cerebroventricle.
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PMID:Role of neuropeptide receptor systems in vanilloid VR1 receptor-mediated gastric acid secretion in rat brain. 1498 54

We have previously shown that spermine, a basic polyamine, and big dynorphin, a basic polypeptide, induce nociceptive behavior if injected intrathecally (i.t.) in mice (see [Pain 86 (2000) 55-61] and [Brain Res. 952 (2002) 7-14]). This suggests that other basic molecules might have the same effects. Here, i.t. administration of poly-L-lysine (12 and 36 pg) to mice was found to produce the same characteristic behavioral response, biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 0-10 min after injection. The behavior induced by poly-L-lysine (12 pg) was dose-dependently inhibited by intraperitoneal injection of morphine (0.25-4 mg/kg) and also dose-dependently, by i.t. co-administration of D-(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine hydrogen maleate (MK-801) (0.0156-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 nmol), an antagonist of the polyamine recognition site and the NR2B-containing NMDA receptor subtype. On the other hand, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe7, d-His9]-substance P (6-11), a specific antagonist for substance P (NK1) receptors, or MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit.
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PMID:Nociceptive behavior induced by poly-L-lysine and other basic compounds involves the spinal NMDA receptors. 1508 81

The major objective of this study was to gain insight into whether under physiological conditions medullary raphe area neurons influence breathing through CO(2)/H(+) chemoreceptors and/or through a postulated, nonchemoreceptor modulatory influence. Microtubules were chronically implanted into the raphe of adult goats (n = 13), and breathing at rest (awake and asleep), breathing during exercise, as well as CO(2) sensitivity were assessed repeatedly before and after sequential injections of the neurotoxins saporin conjugated to substance P [SP-SAP; neurokinin-1 receptor (NK1R) specific] and ibotenic acid (IA; nonspecific glutamate receptor excitotoxin). In all goats, microtubule implantation alone resulted in altered breathing periods, manifested as central or obstructive apneas, and fractionated breathing. The frequency and characteristics of the altered breathing periods were not subsequently affected by injections of the neurotoxins (P > 0.05). Three to seven days after SP-SAP or subsequent IA injection, CO(2) sensitivity was reduced (P < 0.05) by 23.8 and 26.8%, respectively, but CO(2) sensitivity returned to preinjection control values >7 days postinjection. However, there was no hypoventilation at rest (awake, non-rapid eye movement sleep, or rapid eye movement sleep) or during exercise after these injections (P > 0.05). The neurotoxin injections resulted in neuronal death greater than three times that with microtubule implantation alone and reduced (P < 0.05) both tryptophan hydroxylase-expressing (36%) and NK1R-expressing (35%) neurons at the site of injection. We conclude that both NK1R- and glutamate receptor-expressing neurons in the medullary raphe nuclei influence CO(2) sensitivity apparently through CO(2)/H-expressing chemoreception, but the altered breathing periods appear unrelated to CO(2) chemoreception and thus are likely due to non-chemoreceptor-related neuromodulation of ventilatory control mechanisms.
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PMID:Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats. 1532 66

The major local symptom of Phoneutria nigriventer envenomation is an intense pain, which can be controlled by infiltration with local anesthetics or by systemic treatment with opioid analgesics. Previous work showed that intraplantar (i.pl) injection of Phoneutria nigriventer venom in rats induces hyperalgesia, mediated peripherally by tachykinin and glutamate receptors. The present study examined the spinal mechanisms involved in pain-enhancing effect of this venom. Intraplantar injection of venom into rat hind paw induced hyperalgesia. This phenomenon was inhibited by intrathecal (i.t.) injection of tachykinin NK1 (GR 82334) or NK2 (GR 94800) receptor antagonists, a calcitonin gene-related peptide (CGRP) receptor antagonist (CGRP8-37) and N-methyl-D-aspartate (NMDA; MK 801 and AP-5), non-NMDA ionotropic (CNQX), or metabotropic (AIDA and MPEP) glutamate receptor antagonists, suggesting the involvement of spinal neurokinins and excitatory amino acids. The role of proinflammatory cytokines, nitric oxide (NO), and prostanoids in spinally mediated pain facilitation was also investigated. Pharmacological blockade of tumour necrosis factor-alpha (TNFalpha) or interleukin-1beta (IL-1beta) reduced the hyperalgesic response to venom. Intrathecal injection of L-N6-(1-iminoethyl)lysine (L-NIL), but not of 7-nitroindazole (7-NI), inhibited hyperalgesia induced by the venom, indicating that NO, generated by the activity of the inducible form of nitric oxide synthase, also mediates this phenomenon. Furthermore, indomethacin, an inhibitor of cyclooxigenases (COX), or celecoxib, a selective inhibitor of COX-2, abolished venom-induced hyperalgesia, suggesting the involvement of spinal prostanoids in this effect. These data indicate that the spinal mechanisms of pain facilitation induced by Phoneutria nigriventer venom involves a plethora of mediators that may cooperate in the genesis of venom-induced central sensitization.
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PMID:Involvement of spinal neurokinins, excitatory amino acids, proinflammatory cytokines, nitric oxide and prostanoids in pain facilitation induced by Phoneutria nigriventer spider venom. 1532 37

Antinociceptive effect of a tachykinin NK1 receptor antagonist ezlopitant [(2S,3S-cis)-2-(diphenylmethyl)-N-{(2-methoxy, 5-isopropylphenyl)methyl}-1-azabicyclo[2.2.2]octan-3-amine] was investigated in the 4beta-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive test in the rat. Intraplantar injection of PMA-induced paw-licking and flinching behaviour lasted up to 120 min and was accompanied by inflammatory reactions, such as swelling and invasion of granulocytes. Pretreatment with resiniferatoxin [200 microg/kg, subcutaneous (s.c.)] blocked the PMA-induced nociceptive behaviour, suggesting that vanilloid VR1 receptor-expressing primary sensory neurons play a major role in this response. Subcutaneous pretreatment with ezlopitant (0.3-30 mg/kg) and morphine (0.3-6 mg/kg) caused a dose-dependent inhibition of the behaviour. Ezlopitant (3-30 mg/kg) given subcutaneously after PMA injection also significantly attenuated the behavioural response. When administered intrathecally, ezlopitant and a nonselective glutamate receptor antagonist MK-801 had an inhibitory effect, whereas CJ-12,191, an inactive isomer of ezlopitant, was unaffected. These results suggest that spinal tachykinin NK1 receptors contribute to processing of ongoing pain associated with peripheral inflammation.
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PMID:A tachykinin NK1 receptor antagonist attenuates the 4 beta-phorbol-12-myristate-13-acetate-induced nociceptive behaviour in the rat. 1565 91

Glutamate participates in the regulation of secretion of several neuropeptides, including substance P (SP). Glutamate acts through ionotropic (iGluR) and metabotropic (mGluR) receptors. We have investigated whether glutamate receptor agonists and antagonists could affect SP release from the arcuate nucleus and the median eminence (ARC/ME). An increase in SP-like immunoreactivity (SP-LI) release from ARC/ME was induced by glutamate and N-methyl-D-aspartate (NMDA). This increase was prevented by D-(-)-2-amino-5-phosphono pentanoic acid (DAP5) (0.1mM), a specific NMDA antagonist and by (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) (0.1 mM), a selective antagonist of group I mGluR. The selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H-4H)-dione (DNQX) (0.1mM) and (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG) (0.1 mM), a group II and III mGluRs antagonist, did not affect the stimulatory effect of glutamate. A group I selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG) induced a significant increase in SP-LI release. Supporting the participation of nitric oxide (NO) in the effect of glutamate on SP-LI release, NAME (0.5 mM), a NO synthase inhibitor, reduced the glutamate-induced increase in SP-LI release from ARC/ME. Similarly, glutamate did not induce an increase in SP-LI release in the presence of meloxicam (0.1 mM) (a cyclooxygenase-2 (COX-2) specific inhibitor) indicating that prostaglandins production may also be involved in the glutamate effect. These data indicate that glutamate increases SP-LI release from the ARC/ME by acting through NMDA and group I mGluRs in the male rat. This stimulatory effect could be mediated by nitric oxide and prostaglandin production.
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PMID:NMDA and group I metabotropic glutamate receptors activation modulates substance P release from the arcuate nucleus and median eminence. 1622 74

Intra-articularly injected complete Freund's adjuvant creates in rats a chronic monoarthritis suitable for studying neuronal plasticity and chronic pain. Using such a model, we report electrophysiological and morphological evidence of alterations in somatosensory synaptic function. In arthritic rats, the baseline activity of dorsal spinal cord wide dynamic range or nociceptive-specific neurons was greater than in control animals. Moreover, neuronal responses elicited by an innocuous stimulation with von Frey filaments applied to the arthritic joint were greater in amplitude and produced the afterdischarge that normally characterizes a nociceptive response. In contrast to the response in control animals, passive movement of the arthritic joint produced an increase in the amplitude of the response of these neurons to iontophoretic application of glutamate receptor agonists over a time frame of 10-30 min. This potentiation was blocked by pretreatment with a neurokinin-1 (NK-1) receptor antagonist, suggesting the involvement of substance P. Ultrastructural analysis of the dorsal horn revealed that movement of the arthritic joint also induced NK-1 receptor internalization, indicative of nociception. Morphological examination revealed significantly increased expression of substance P and its receptor within the superficial dorsal horn of monoarthritic animals. These unique functional and chemical changes reflect alterations in both presynaptic and postsynaptic mechanisms in nociceptive transmission at the spinal level. Thus, although treatment of arthritis should obviously target its peripheral aetiology, targeting its central components is a logical therapeutic complementary objective.
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PMID:Remodelling of spinal nociceptive mechanisms in an animal model of monoarthritis. 1626 39


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