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1.
Pharmacology ; 105(11-12): 723-728, 2020.
Article in English | MEDLINE | ID: mdl-32694256

ABSTRACT

This study aimed to investigate whether the consecutive administration of methotrexate affects 5-hydroxytryptamine (5-HT) synthesis in the rat small intestine. Rats received methotrexate at a dose of 12.5 mg/kg intraperitoneally on 4 consecutive days. NG-nitro-L-arginine methyl ester (L-NAME) was given subcutaneously to inhibit nitric oxide (NO) synthase. Methotrexate moderately altered 5-HT synthesis, whereas the combined administration of methotrexate and L-NAME significantly changed 5-HT synthesis in the rat ileal tissue. These results suggest that endogenous NO has an antagonistic role in the induction of 5-HT synthesis in rats following the consecutive administration of methotrexate.


Subject(s)
Enzyme Inhibitors/pharmacology , Intestine, Small/drug effects , Intestine, Small/metabolism , Methotrexate/pharmacology , Nitric Oxide/metabolism , Serotonin/biosynthesis , Animals , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Injections, Intraperitoneal , Intestinal Diseases/chemically induced , Intestine, Small/pathology , Male , Methotrexate/administration & dosage , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , RNA, Messenger/metabolism , Rats , Rats, Wistar , Substance P/drug effects , Substance P/metabolism , Tachykinins/drug effects , Tachykinins/genetics , Tachykinins/metabolism , Tryptophan Hydroxylase/drug effects , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolism
2.
Peptides ; 64: 1-7, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25541043

ABSTRACT

OBJECTIVE: Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. METHODS: Acute pneumonitis was induced in Tac4 gene-deleted (Tac4(-/-)) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. RESULTS: All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4(-/-) mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4(-/-) mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. CONCLUSIONS: We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions.


Subject(s)
Pneumonia/physiopathology , Protein Precursors/physiology , Tachykinins/physiology , Acute Disease , Animals , Cytokines/metabolism , Female , Lipopolysaccharides , Lung/drug effects , Lung/immunology , Lung/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Stress , Pneumonia/chemically induced , Pneumonia/immunology , Protein Precursors/drug effects , Protein Precursors/immunology , Tachykinins/drug effects , Tachykinins/immunology
3.
Article in English | MEDLINE | ID: mdl-20383340

ABSTRACT

The purpose of this study was to investigate the effects of capsaicin (CAP) and resiniferatoxin (RTX) on substance P (SP) release and transient receptor potential vanilloid type 1 (TRPV1) expression of cultured rat dorsal root ganglion (DRG) neurons. Dissociated DRG cells of embryonic 15-day-old Wistar rat were cultured for 3 days and then exposed to CAP (1 micromol/L, 10 micromol/L) or RTX (10 nmol/L, 100 nmol/L) for 10 min. At 3 days of culture growth, SP release increased significantly after 10 min of stimulation with CAP or RTX as compared with controls. Six days after acute exposure to CAP or RTX, SP release and SP expression of cultured rat DRG neurons decreased significantly in both CAP- and RTX-treated cultures as compared with controls. Preprotachykinin (PPT) mRNA, TRPV1 mRNA and TRPV1 protein expression decreased in CAP-treated cultures and RTX cultures treated with the higher concentration, whereas RTX cultures treated with the lower concentration were not affected. The results indicate that CAP and high concentrations of RTX are more neurotoxic to cultured rat DRG neurons while the inability of the neurons to express SP or TRPV1 after acute exposure to the lower concentration of RTX could be partially reversed after a period of incubation. The efficacy and therapeutic potential of the reversible action of RTX are more applicable as strategies for pain or neurogenic inflammation therapy.


Subject(s)
Capsaicin/pharmacology , Diterpenes/pharmacology , Substance P/drug effects , TRPV Cation Channels/drug effects , Animals , Capsaicin/administration & dosage , Capsaicin/toxicity , Cells, Cultured , Diterpenes/administration & dosage , Diterpenes/toxicity , Dose-Response Relationship, Drug , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Gene Expression Regulation/drug effects , Neurons/drug effects , Neurons/metabolism , Protein Precursors/drug effects , Protein Precursors/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Sensory System Agents/administration & dosage , Sensory System Agents/pharmacology , Sensory System Agents/toxicity , Substance P/metabolism , TRPV Cation Channels/genetics , Tachykinins/drug effects , Tachykinins/genetics , Time Factors
4.
Curr Opin Pharmacol ; 8(2): 114-9, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18296119

ABSTRACT

The important role of platelets in the development of arterial thrombosis and cardiovascular disease is well established. Current treatments for arterial thrombosis include anti-platelet agents such as aspirin, thienopyridines and glycoprotein IIb-IIIa inhibitors. Despite these drugs being effective there remains a substantial unmet clinical demand for more effective therapeutic approaches, which may reflect the existence of alternative underlying regulatory mechanisms to those already targeted. Recent publications have demonstrated a key role for tachykinins in the positive feedback regulation of platelet aggregation and thrombus formation. The pro-thrombotic effects of tachykinins on platelets are mediated through the neurokinin 1 receptor, which may therefore offer a novel therapeutic drug target in the prevention and the treatment of arterial thrombosis.


Subject(s)
Platelet Aggregation Inhibitors/pharmacology , Receptors, Neurokinin-1/drug effects , Thrombosis/drug therapy , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Drug Delivery Systems , Humans , Receptors, Neurokinin-1/metabolism , Tachykinins/drug effects , Tachykinins/metabolism , Thrombosis/physiopathology
5.
Mol Psychiatry ; 9(11): 1007-29, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15314610

ABSTRACT

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant--methamphetamine, and a mood stabilizer--valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.


Subject(s)
Bipolar Disorder/genetics , Gene Expression Profiling , Genetic Testing/methods , Genomics/methods , Nerve Tissue Proteins/metabolism , Animals , Antimanic Agents/therapeutic use , Bayes Theorem , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Bipolar Disorder/metabolism , Brain/metabolism , Central Nervous System Stimulants , Disease Models, Animal , Dopamine and cAMP-Regulated Phosphoprotein 32 , Enkephalins/drug effects , Enkephalins/genetics , Enkephalins/metabolism , Genetic Linkage/genetics , Genetic Predisposition to Disease , Humans , Male , Methamphetamine , Mice , Mice, Inbred C57BL , Microarray Analysis , Nerve Tissue Proteins/drug effects , Nerve Tissue Proteins/genetics , Pharmacogenetics/methods , Phosphoproteins/drug effects , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Precursors/drug effects , Protein Precursors/genetics , Protein Precursors/metabolism , Substance P/drug effects , Substance P/genetics , Substance P/metabolism , Tachykinins/drug effects , Tachykinins/genetics , Tachykinins/metabolism , Valproic Acid/therapeutic use
6.
Toxicology ; 201(1-3): 39-50, 2004 Sep 01.
Article in English | MEDLINE | ID: mdl-15297018

ABSTRACT

To evaluate the role of substance P (SP)-containing C-fiber nerves in the development of the inflammatory responses to sidestream cigarette smoke (SSCS), female Fischer 344 rats were randomly assigned into vehicle and capsaicin groups, respectively. Then, half the number in each group (N = 24) was nose-only exposed to air or 0.4 mg/m3 total particulate matter of SSCS for 4 h/day for 7 days. Exposure of the vehicle rats to SSCS induced obvious pulmonary neurogenic inflammation as indicated by elevations in plasma extravasation and proinflammatory cytokine secretions [interieukin (IL)-1beta and IL-12]. In addition, except for SP release, SSCS exposure significantly induced the tachykininergic toxicities at the gene level: upregulation of beta-preprotachykinin-I (beta-PPT-I) mRNA. However, neither SSCS exposure nor capsaicin pretreatment affects the immunolabeling density of neurokinin-1 receptor (NK-1R) in airway epithelium. SSCS also significantly inactivated pulmonary neutral endopeptidase (NEP) in lung tissue. Moreover, pretreatment with capsaicin significantly exacerbated the SSCS-induced inflammatory responses mentioned above as well as the release of plasma protein. Considering that capsaicin did not affect the normal control baselines of these parameters except for a decrease in NK-1R mRNA, we conclude that the degree of SSCS-induced inflammatory response was exacerbated because of the depletion of stored SP and/or inactivation of capsaicin-sensitive C-fiber nerves. Our data suggest the loss of afferent tachykinin SP signaling may lead to dysfunction of the sensory C-fiber nerve reflexes during exposure to SSCS, suggesting that SP serves a protective role.


Subject(s)
Capsaicin/pharmacology , Lung/drug effects , Smoke/adverse effects , Substance P/physiology , Tachykinins/drug effects , Animals , Cytokines/metabolism , Female , Lung/enzymology , Lung/metabolism , Neprilysin/metabolism , Rats , Rats, Inbred F344 , Receptors, Neurokinin-1/drug effects , Receptors, Neurokinin-1/genetics , Substance P/deficiency , Tachykinins/metabolism
7.
Am J Respir Cell Mol Biol ; 29(5): 606-12, 2003 Nov.
Article in English | MEDLINE | ID: mdl-12738685

ABSTRACT

This study was performed to test whether biosynthesis of tachykinins plays a pivotal role in lipopolysaccharide (LPS)-induced airway alteration by analyzing preprotachykinin-I (PPT-I, a precursor of tachykinins) gene expression. Brown-Norway rats (11-12 wk old) were divided into four groups: control; LPS; dimethylthiourea (DMTU, an effective hydroxyl radical scavenger); and DMTU+LPS. Each animal in the control group received saline treatment. Forty-nine animals in the LPS group were further divided into seven subgroups to test effects of doses and length of the LPS treatment. Total RNA extracted from nodose ganglia and lungs was used to assay relative amount of PPT-I mRNA using the real-time quantitative reverse transcriptase-polymerase chain reaction. In addition, LPS-induced alterations in airway responses to bronchial constrictors, neutral endopeptidase (NEP) gene expression, leukocyte counts, and SP and calcitonin gene-related peptide (CGRP) levels were determined. LPS (4 mg/kg, intraperitoneal) raised significantly PPT-I mRNA level after 4 h in nodose ganglia and 12 h in the lung, and this elevation sustained for 5 d. Also, LPS caused significant increases in NEP mRNA, SP and CGRP levels, airway reactivity to capsaicin and SP, and neutrophil counts, but a significant decrease in macrophage count. Our data support that LPS-induced bronchial hyperreactivity to capsaicin is related closely to the upregulation of tachykinin gene expression, but not the upregulation of NEP.


Subject(s)
Gene Expression Regulation , Lipopolysaccharides/metabolism , Protein Precursors/genetics , Tachykinins/genetics , Thiourea/analogs & derivatives , Animals , Bronchi/drug effects , Free Radical Scavengers/pharmacology , Lung/metabolism , Nodose Ganglion/metabolism , Protein Precursors/biosynthesis , Protein Precursors/drug effects , Rats , Rats, Inbred BN , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tachykinins/biosynthesis , Tachykinins/drug effects , Thiourea/pharmacology
8.
Br J Pharmacol ; 134(7): 1447-54, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11724750

ABSTRACT

1. In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. 2. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. 3. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30 Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK(2) receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the beta-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT - PCR), prior to and 30-40 min following ET-1 challenge. 4. The selective tachykinin NK(2) receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, beta-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. 5. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production.


Subject(s)
Bronchi/drug effects , Cholinergic Fibers/physiology , Endothelin-1/pharmacology , Muscle Contraction/drug effects , Tachykinins/drug effects , Acetylcholine/pharmacology , Aged , Benzamides/pharmacology , Bronchi/metabolism , Bronchi/physiology , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Electric Stimulation , Female , Humans , In Vitro Techniques , Male , Middle Aged , Neurokinin A/metabolism , Piperidines/pharmacology , Protein Precursors/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Radioimmunoassay , Receptors, Neurokinin-2/antagonists & inhibitors , Reverse Transcriptase Polymerase Chain Reaction , Substance P/metabolism , Tachykinins/biosynthesis , Tachykinins/genetics , Vasodilator Agents/pharmacology
9.
Neuroscience ; 105(3): 671-80, 2001.
Article in English | MEDLINE | ID: mdl-11516832

ABSTRACT

It has been hypothesized that dopamine(D1) and serotonin(2) receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine(D1) and serotonin(2) receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine(D1) and serotonin(2) receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine(D1) partial agonist) or (+/-)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, serotonin(2) agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine(D1) and serotonin(2) receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine(D1) antagonist) or ritanserin (1 mg/kg, serotonin(2) antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine(D1) receptor stimulation, but was slightly elevated by DOI or both agonists together (42-58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone. Dopamine depletion appears to promote a synergistic interaction between dopamine(D1) and serotonin(2) receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.


Subject(s)
Dopamine/metabolism , Neostriatum/metabolism , Neurons/metabolism , RNA, Messenger/metabolism , Receptors, Dopamine D1/metabolism , Receptors, Serotonin/metabolism , Tachykinins/biosynthesis , 3,4-Dihydroxyphenylacetic Acid/metabolism , Aging/physiology , Animals , Animals, Newborn/metabolism , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Drug Synergism , Enkephalins/genetics , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/physiology , Male , Movement Disorders/drug therapy , Movement Disorders/metabolism , Movement Disorders/physiopathology , Neostriatum/drug effects , Neostriatum/growth & development , Neurons/drug effects , Oxidopamine/pharmacology , Protein Precursors/genetics , RNA, Messenger/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/drug effects , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Tachykinins/drug effects , Tachykinins/genetics
10.
Neuropsychopharmacology ; 24(2): 183-91, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11120400

ABSTRACT

Lithium's therapeutic mechanism of action is unknown. In lithium-treated normal rats, increased striatal concentrations of neurokinin A (NKA)-like immunoreactivity (LI), substance P (SP-LI) and neuropeptide Y (NPY-LI) have been reported. To investigate whether these effects might be of therapeutic relevance, Flinders Sensitive Line rats (FSL), an animal model of depression, and control Flinders Resistant Line (FRL) rats were during a 6-week period fed chow to which either lithium or vehicle was admixed. Following sacrifice, the peptides were extracted from dissected brain regions and measured by radioimmunoassay. NKA-LI and SP-LI were markedly decreased in striatum and increased in frontal cortex in FSL compared to control FRL animals. Lithium treatment abolished these differences. Basal concentrations of NPY-LI were decreased in hippocampus of FSL rats, but unaffected by lithium. The present study suggests that changed tachykinins and NPY may underlie the characterized depressive-like phenotype of the FSL rats. It is hypothesized that altering tachykinin peptidergic neurotransmission in striatum and frontal cortex constitutes a mechanism of action of lithium and that such a mechanism might be of therapeutic relevance.


Subject(s)
Brain/metabolism , Depression/metabolism , Disease Models, Animal , Neuropeptide Y/metabolism , Tachykinins/metabolism , Animals , Brain/drug effects , Depression/drug therapy , Lithium Chloride/pharmacology , Lithium Chloride/therapeutic use , Male , Neuropeptide Y/drug effects , Rats , Species Specificity , Tachykinins/drug effects
11.
Synapse ; 38(2): 216-25, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11018795

ABSTRACT

The present study was designed to determine if there are region-specific differences in serotonin (5-HT) neurotransmission and 5-HT receptor expression that may limit the stimulatory effects of the 5-HT releaser p-chloroamphetamine (pCA) on striatal neuropeptide gene expression to the posterior striatum (P-STR) during postnatal maturation. Sprague-Dawley rat brains from postnatal days (PND) 1-35 were processed for 5-HT(2A) and 5-HT(2C) receptor mRNA expression by in situ hybridization and monoamine analysis by HPLC. Within the P-STR, 5-HT(2A) receptor mRNA expression reached young adult (PND 35) levels by PND 3, while levels in the A-STR were significantly less (range: 1.43 +/- 0.219-6. 36 +/- 0.478) than P-STR (5.36 +/- 0.854-12.11 +/- 1.08) at each respective age throughout the time course. 5-HT(2C) receptor mRNA expression reached young adult levels at PND 7 in the A-STR and by PND 3 in the P-STR. At each PND age 5-HT(2C) receptor mRNA levels within the P-STR were significantly less (6.23 +/- 1.02-12.32 +/- 0.427) than the A-STR (7.31 +/- 1.65-26.84 +/- 2.24). 5-HT content increased across the developmental time course within the P-STR (5.01 +/- 0.327-15.7 +/- 1.03 ng/mg protein) and A-STR (2.97 +/- 0. 223-11.2 +/- 0.701 ng/mg protein). Four hours following injection (i. p.) of pCA (10 mg/kg), preprotachykinin (PPT) mRNA levels increased 89% in the P-STR but not the anterior (A-STR) striatum of the 3-week-old rat, which were prevented by preinjection (30 min, i.p.) of the 5-HT(2) receptor antagonist ritanserin (1 mg/kg). Together, these data suggest that faster maturity of 5-HT(2A) receptor expression in the P-STR may be sufficient to convey the region-specific acute stimulatory effects of pCA on PPT mRNA transcription in the developing rodent striatum. These results provide further evidence that the influence of 5-HT on neuropeptide gene expression is far stronger in caudal vs. rostral striatal regions during postnatal development.


Subject(s)
Corpus Striatum/metabolism , Gene Expression Regulation, Developmental/physiology , Protein Precursors/metabolism , Receptors, Serotonin/metabolism , Tachykinins/metabolism , Animals , Animals, Newborn , Corpus Striatum/drug effects , Corpus Striatum/growth & development , Gene Expression Regulation, Developmental/drug effects , Protein Precursors/drug effects , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/drug effects , Serotonin Agents/pharmacology , Tachykinins/drug effects , p-Chloroamphetamine/pharmacology
12.
Lung ; 178(4): 213-23, 2000.
Article in English | MEDLINE | ID: mdl-10960556

ABSTRACT

Leukotrienes (LTs), tachykinins (TKs), and oxygen radicals have been suggested to be important modulating factors for the hyperpnea-induced bronchoconstriction (HIB) of guinea pigs. In this study, we tested the hypothesis that LTs and oxygen radicals modulate HIB by triggering TK release. Eighty-five Hartley guinea pigs were divided into four groups: control, dimethylthiourea (DMTU), FPL 55712, and A63162. DMTU is the scavenger for hydroxyl radical. FPL 55712 is an antagonist of LT receptor, whereas A63162 is an inhibitor of lipoxygenase. Each group was further divided into three subgroups: baseline, hyperpnea, and recovery. Each animal was anesthetized, cannulated, paralyzed, and artificially ventilated. We measured dynamic respiratory compliance (Crs), maximal expiratory flow at 50% total lung capacity (V(max(50))), and forced expiratory volume in 0.1 s (FEV(0.1)) during the baseline and recovery periods. Hyperpnea caused significant decreases in Crs, V(max(50)), and FEV(0. 1), indicating HIB in the control group. Pretreatment with DMTU, FPL 5712, or A63162 attenuated HIB. Plasma substance P (SP) levels increased progressively during the experiment in all groups. However, both FPL 55712 and A63162, but not DMTU, significantly decreased SP levels. Similarly, lung malondialdehyde (MDA) contents increased progressively during the experiment in the control group. Neither FPL 55712 nor A63162 significantly affected the increase. On the contrary, DMTU significantly attenuated the increase in MDA during the recovery period. These results suggest that inhibition of LTs leads to suppression at SP levels and HIB, whereas DMTU attenuates HIB by means of other mechanisms.


Subject(s)
Bronchoconstriction/physiology , Hyperventilation/physiopathology , Leukotrienes/physiology , Reactive Oxygen Species/physiology , Tachykinins/physiology , Acetamides/pharmacology , Animals , Bronchoconstriction/drug effects , Chromones/pharmacology , Female , Free Radical Scavengers/pharmacology , Guinea Pigs , Hyperventilation/complications , Leukotriene Antagonists/pharmacology , Lipoxygenase Inhibitors/pharmacology , Lung/drug effects , Lung/metabolism , Male , Malondialdehyde/metabolism , Phenyl Ethers , Substance P/blood , Substance P/drug effects , Tachykinins/drug effects , Thiourea/analogs & derivatives , Thiourea/pharmacology
14.
J Toxicol Environ Health A ; 53(8): 593-605, 1998 Apr 24.
Article in English | MEDLINE | ID: mdl-9572158

ABSTRACT

Trigeminal sensory neurons innervate the nasal cavity and may release substance P (SP) upon exposure to inhaled irritants. The purpose of this study was to determine if silica dust, an occupational irritant causing inflammation, activates sensory neurons supplying the nasal cavity. Male Fischer 344 rats were placed in inhalation chambers and exposed daily to 2 mg/m3 of fresh silica (average diameter 1 microm) for 6 mo. Following exposure, the trigeminal ganglia (TG) were removed and prepared for SP immunocytochemistry and for preprotachykinin (PPT) autoradiographic in situ hybridization. The SP-like immunofluorescence in TG neurons was subjectively categorized as high, moderate, or low (background) intensity. In situ hybridization autoradiographs were quantified on the basis of grain density using digital imaging analysis. The SP immunoreactivity and PPT mRNA expression in the TG neurons were significantly increased after silica inhalation. The proportion of highly positive SP-immunoreactive neurons shifted from 1.30 +/- 0.58% in controls to 11.30 +/- 1.15% after silica treatment. The neurons exhibiting high grain density for PPT mRNA increased from 1.50 +/- 0.87% in controls to 11.67 +/- 0.58% in the silica group. Thus, inhalation of silica causes upper airway irritation resulting in increased levels of immunoreactive neuronal SP and PPT mRNA. These findings suggest that silica activates sensory pathways that may be involved in nasal inflammation.


Subject(s)
Inflammation/chemically induced , Protein Precursors/drug effects , Silicon Dioxide/adverse effects , Substance P/immunology , Tachykinins/drug effects , Trigeminal Nerve/drug effects , Air Pollutants/adverse effects , Air Pollutants/immunology , Animals , Dust , Immunohistochemistry , In Situ Hybridization , Inflammation/immunology , Inhalation Exposure , Male , Protein Precursors/immunology , RNA, Messenger/biosynthesis , RNA, Messenger/drug effects , Rats , Rats, Inbred F344 , Silicon Dioxide/pharmacology , Substance P/drug effects , Tachykinins/immunology , Trigeminal Nerve/immunology
15.
Brain Res Mol Brain Res ; 54(1): 141-51, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9526067

ABSTRACT

It is established that dopamine (DA) controls the expression of preprodynorphin (PPDYN), preprotachykinin A (PPT-A) and preproenkephalin (PPE) mRNAs in striatal structures. Since cocaine, nicotine and ethanol enhance extracellular DA concentration, we have examined whether their repeated administration produced common changes in the expression of these mRNAs. Quantitative in situ hybridization histochemistry was performed in rats 2 h after a final challenge subsequent to repeated subcutaneous injections (3 X a day) of cocaine (12.5 mg/kg), nicotine (0.4 mg/kg) for 14 days and ethanol (160 mg/kg) for 7 days. In the dorsal striatum, cocaine produced simultaneous PPDYN and PPT-A mRNA increases without PPE mRNA change whereas nicotine and ethanol produced no modification. After cocaine, PPDYN mRNA was preferentially increased in striatal patch compartment. In the nucleus accumbens, the effects were more complex. In cocaine-treated rats, we measured concomitant increases of PPDYN and PPE mRNA in the rostral pole, an isolated induction of PPT-A mRNA signals in the core without any change in the two shell subregions: the cone and the ventral shell. In contrast, after nicotine and ethanol, the ventral shell was the only accumbal subregion which showed a neuropeptide mRNA alteration, nicotine leading to decreased PPDYN mRNA and ethanol to increased PPT-A mRNA contents. The neuropeptide regulation after chronic treatment with these psychostimulant drugs does not strictly conform to a general DA control scheme in the dorsal and the ventral striatum. The cocaine effects can be clearly distinguished from those of nicotine and ethanol in terms of neuropeptide regulation and striatal subregions affected.


Subject(s)
Cocaine/administration & dosage , Corpus Striatum/metabolism , Dynorphins/genetics , Enkephalins/genetics , Ethanol/administration & dosage , Nicotine/administration & dosage , Protein Precursors/genetics , RNA, Messenger/biosynthesis , Tachykinins/genetics , Animals , Body Weight/drug effects , Corpus Striatum/drug effects , Drug Administration Schedule , Dynorphins/drug effects , Enkephalins/drug effects , In Situ Hybridization , Injections, Subcutaneous , Male , Nucleus Accumbens/chemistry , Nucleus Accumbens/drug effects , Protein Precursors/drug effects , RNA, Messenger/drug effects , Rats , Rats, Sprague-Dawley , Tachykinins/drug effects
16.
Naunyn Schmiedebergs Arch Pharmacol ; 357(3): 245-51, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9550295

ABSTRACT

The aim of this study was to assess at which extent an even co-release of the tachykinins, substance P (SP) and neurokinin A (NKA), occurs from enteric neurons/nerves of the guinea-pig proximal colon during graded depolarization. In this preparation, a sharply diverging NK1/NK2 receptor pattern of tachykininergic co-transmission has been observed in physiological studies. The experiments were performed in capsaicin-pretreated (10 microM for 15 min) mucosa-free smooth muscle of guinea-pig proximal colon, to exclude the mucosa and the peripheral endings of primary afferent nerves as possible sources of released tachykinins. The content of extractable tachykinins was measured as SP- and NKA-like immunoreactivities (-LI) by radioimmunoassay. Chromatographic characterization of aqueous acetic acid extracts showed one peak of SP-LI corresponding to authentic SP, whereas there were multiple peaks of NKA-LI, the major one co-eluting with authentic NKA. An increased outflow of both SP- and NKA-LI was evenly produced in a concentration-dependent manner when the preparations were superfused with a high potassium (K) medium in which NaCl had been replaced with equimolar amounts (20-100 mM) of KCl. The high K-evoked release of SP- and NKA-LI was dependent upon the presence of extracellular calcium and was inhibited by about 50% in the presence of the N-type voltage-dependent calcium channel blocker, omega-conotoxin GVIA (0.1 microM). Omega-conotoxin MVIIC (1 microM), a non-selective blocker of N-, P- and Q-type voltage-dependent calcium channels, likewise produced about 40% inhibition of evoked release of both peptides. No evidence for a role of L-type channels in tachykinin release was obtained, since the addition of nifedipine (1 microM) or Bay K8644 (1 microM) did not significantly affect the response to high K. Neither NK1 receptor agonist (septide, 0.1 microM) or antagonist (SR 140333, 10 nM) nor NK2 receptor agonists ([betaAla8]NKA(4-10) and GR 64349, 0.1 microM each) or antagonist (SR 48968, 10 nM) did affect the high K-evoked release of tachykinins. We conclude that SP and NKA are evenly co-released in response to graded depolarization of enteric nerves in the guinea-pig colon. Therefore, the specialization of tachykininergic transmission observed in functional studies does not originate at the prejunctional level. The co-release of tachykinins involves the influx of extracellular calcium via N-type but not L-type calcium channels. No evidence for the presence of NK1 or NK2 autoreceptors affecting tachykinin release from enteric neurons was obtained.


Subject(s)
Colon/innervation , Enteric Nervous System/drug effects , Potassium Chloride/pharmacology , Tachykinins/drug effects , Animals , Calcium/pharmacology , Colon/drug effects , Colon/metabolism , Enteric Nervous System/metabolism , Guinea Pigs , Neurokinin A/analogs & derivatives , Neurokinin A/pharmacology , Peptide Fragments/pharmacology , Piperidines/pharmacology , Pyrrolidonecarboxylic Acid/analogs & derivatives , Quinuclidines/pharmacology , Receptors, Tachykinin/agonists , Receptors, Tachykinin/antagonists & inhibitors , Receptors, Tachykinin/drug effects , Substance P/analogs & derivatives , Substance P/pharmacology , Tachykinins/metabolism
17.
Respirology ; 2(3): 193-200, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9400681

ABSTRACT

Tachykinins, found in sensory nerves, have effects in the airways which suggest that they may contribute to the pathogenesis of asthma. We aimed to find evidence for tachykinin involvement in the immediate airway response to allergen in a sheep model of experimental asthma. Twenty-four sheep were actively sensitized to Ascaris suum, then challenged with nebulized Ascaris extract in a dose-response fashion. Change in lung resistance (RL) in response to challenge was measured. Responder sheep (those with an increase in RL of > or = 100% over baseline) that had reproducible responses over three challenges were identified (n = 4 sheep) and a PC100 (number of breaths of extract required to induce a 100% increase in RL) was determined. The effect of the neutral endopeptidase inhibitor phosphoramidon, the NK-1 receptor-specific antagonist CP 96, 345 and capsaicin desensitization on the RL response to Ascaris challenge was then assessed. Administration of phosphoramidon before Ascaris decreased the PC100 to 31 +/- 7% of the PC100 seen with Ascaris alone (P < 0.05), whereas CP 96,345 and capsaicin desensitization increased the PC100 to 285 +/- 41% and 555 +/- 93% respectively (P < 0.05 for both). These findings suggest that endogenous tachykinins are released in response to allergen challenge and that they contribute to the immediate increase in RL.


Subject(s)
Allergens/administration & dosage , Ascaris suum , Asthma/immunology , Bronchial Hyperreactivity/immunology , Tachykinins/immunology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Biphenyl Compounds/administration & dosage , Bronchial Hyperreactivity/drug therapy , Bronchial Hyperreactivity/metabolism , Bronchoconstriction/drug effects , Capsaicin/administration & dosage , Disease Models, Animal , Drug Interactions , Glycopeptides/administration & dosage , Immunization , Reference Values , Reproducibility of Results , Sheep , Tachykinins/biosynthesis , Tachykinins/drug effects
18.
Brain Res Mol Brain Res ; 47(1-2): 311-21, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9221930

ABSTRACT

The present study examined the effects of prolonged L-DOPA treatment (6 months) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the mesostriatal dopaminergic pathway on substance P and enkephalin mRNA expression in the rat neostriatum. This was done by means of quantitative in situ hybridization histochemistry. As reported previously, the unilateral dopaminergic lesion induced a significant and homogeneous decrease in striatal substance P mRNA expression and a marked increase in enkephalin mRNA expression in the ipsilateral neostriatum which was more pronounced in the dorsolateral than ventromedial part of the structure. Long-term L-DOPA treatment alone had no significant effects on the two striatal peptide mRNA levels. The chronic L-DOPA treatment in 6-hydroxydopamine-lesioned rats was found to partially reverse the lesion-induced down-regulation of substance P mRNA expression, without significantly affect the up-regulation of enkephalin when considering the neostriatum as a whole. Topographical analysis revealed that long-term L-DOPA treatment reversed, in fact, both post-lesional enkephalin and substance P responses to 6-hydroxydopamine lesion, in the ventromedial neostriatum, without significantly modified these peptide responses in the dorsolateral neostriatum. These findings provide new evidence that prolonged L-DOPA treatment differentially affects the post-lesional peptide responses in the ventromedial and dorsolateral parts of the neostriatum, suggesting regional cellular mechanisms in the neostriatum underlying the benefit and/or side-effects of L-DOPA treatment in parkinsonian patients.


Subject(s)
Corpus Striatum/drug effects , Enkephalins/drug effects , Gene Expression/drug effects , Levodopa/pharmacology , Protein Precursors/drug effects , Tachykinins/drug effects , Animals , Corpus Striatum/metabolism , Enkephalins/metabolism , Female , Immunohistochemistry , In Situ Hybridization , Oxidopamine/pharmacology , Protein Precursors/metabolism , Rats , Rats, Wistar , Tachykinins/metabolism , Time Factors
19.
Eur Respir J ; 9(3): 486-92, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8730008

ABSTRACT

Leukotriene D4-(LTD4) has been reported to cause tachykinin release from airway sensory nerves. However, the functional significance of endogenously released tachykinins in LTD4-mediated airway responses has not been fully clarified. The aim of this study was to investigate whether LTD4-induced airway responses are due, in part, to tachykinin release in guinea-pigs. Airway plasma exudation and bronchoconstriction were assessed by measuring extravasation of Evans blue dye and by mean pulmonary resistance (RL) in the presence of atropine (1 mg.kg-1 i.v.) and propranolol (1 mg.kg-1 i.v.), respectively. LTD4 (5 micrograms.mL-1 for 1 min) inhalation caused increase in plasma exudation and RL. Capsaicin pretreatment of animals to deplete sensory neuropeptides significantly inhibited LTD4-induced plasma exudation in the main bronchi, but not in the central (cIPA) and peripheral intrapulmonary airways (pIPA). Pretreatment with specific tachykinin neurokinin-1 (NK1)-receptor antagonists, FK 888 (10 mg.kg-1 i.v.) and CP 96345 (4 mg.kg-1 i.v.), also significantly reduced LTD4-induced plasma exudation in the main bronchi, and in the main bronchi and cIPA, respectively. However, these antagonists did not significantly affect the LTD4-induced increase in RL. In contrast, neurokinin-2 (NK2)-receptor antagonist, SR 48968 (0.3 mg.kg-1 i.v.), significantly inhibited the bronchoconstriction after LTD4-inhalation. These results suggest that leukotriene D4-induced bronchoconstriction and plasma exudation in guinea-pigs are, in part, due to tachykinin release from airway sensory nerves.


Subject(s)
Bronchi/drug effects , Bronchoconstriction/drug effects , Capsaicin/pharmacology , Leukotriene D4/pharmacology , Neurokinin-1 Receptor Antagonists , Tachykinins/metabolism , Administration, Inhalation , Animals , Bronchi/physiology , Capsaicin/administration & dosage , Cell Membrane Permeability/drug effects , Chromones/pharmacology , Dipeptides/pharmacology , Evans Blue , Extravasation of Diagnostic and Therapeutic Materials , Guinea Pigs , Indoles/pharmacology , Leukotriene D4/physiology , Male , Respiratory System/drug effects , Tachykinins/drug effects
20.
J Appl Physiol (1985) ; 79(5): 1411-8, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8593995

ABSTRACT

To investigate whether prostaglandin F2 alpha (PGF2 alpha) stimulates the release of tachykinins and whether the tachykinins play a role in the PGF2 alpha-induced bronchial contraction, we examined the contractile response to PGF2 alpha in the presence or absence of a neutral endopeptidase (NEP) inhibitor phosphoramidon in the guinea pig main bronchus in vitro. Because NEP effectively cleaves tachykinins, we hypothesized that the inhibition of NEP would enhance a PGF2 alpha-induced bronchial contraction if PGF2 alpha stimulates the release of tachykinins. Phosphoramidon significantly enhanced the concentration-response curve to PGF2 alpha. And it also significantly enhanced 10(-5) M PGF2 alpha-induced contraction. The enhancement was significantly attenuated in tissues where the tachykinins had been depleted by treatment with capsaicin. Furthermore, the enhancement of contraction was also significantly attenuated in the presence of tachykinin antagonist FK-224 (10(-5) M). Tetrodotoxin, a sodium-channel blocker that blocks nerve conduction, did not affect the enhancement. From these results we conclude that 1) PGF2 alpha causes the release of tachykinin-like substances, 2) these substances play a role in bronchial contraction in tissues where NEP activity is inhibited, and 3) nerve conduction is not necessary for the release of these substances in the guinea pig bronchus.


Subject(s)
Bronchi/physiology , Bronchoconstriction/physiology , Dinoprost/physiology , Tachykinins/metabolism , Animals , Bronchi/drug effects , Bronchoconstriction/drug effects , Capsaicin/pharmacology , Glycopeptides/pharmacology , Guinea Pigs , In Vitro Techniques , Male , Peptides, Cyclic/pharmacology , Protease Inhibitors/pharmacology , Tachykinins/drug effects , Tetrodotoxin/pharmacology
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