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)

In vivo and in vitro perfusion techniques have been used to study the release of neurokinin A-like immunoreactivity from the rat substantia nigra. Potassium depolarization and electrical field stimulation evoked calcium-dependent release from nigral slices. Potassium depolarization was also effective in vivo. Tetrodotoxin (1 microM) completely blocked electrically stimulated release but only diminished release in response to depolarizing potassium. Neurokinin A-like immunoreactivity release showed frequency dependence and a clear facilitation phenomenon between 5 and 25 Hz. High-performance liquid chromatography analysis of the immunoreactivity released in vitro revealed the presence of neurokinin A, neuropeptide K and neurokinin B, along with their sulphoxide forms. A marked depletion of neuropeptide K and neurokinin B content was observed when the tachykinin content of the nigral slices was examined before and after stimulation. However, the neurokinin A content of the slices was unchanged or even increased, suggesting an accelerated processing of neurokinin A precursors during the stimulation. The tachykinin peptides were degraded at different rates by substantia nigra homogenates; degradation was fastest for neuropeptide K and slowest for neurokinin A. The addition of a mixture of peptidases inhibitors (thiorphan, phosphoramidon, bestatin and captopril) substantially reduced the degradation of all three tachykinins, but did not completely block degradation. GABA-A receptor antagonists such as bicuculline and, particularly, picrotoxin potentiated the stimulated neurokinin A-like immunoreactivity release in vitro, but the GABA-agonist muscimol had no effect. Picrotoxin was even more potent in vivo. The results presented in this study demonstrate that neurokinin A, neuropeptide K and neurokinin B can be released by depolarizing stimuli from rat substantia nigra. Furthermore, the features exhibited by this release suggest that these peptides may have a neurotransmitter/neuromodulator role in the rat substantia nigra.
 ...
PMID:In vitro and in vivo release of neurokinin A-like immunoreactivity from rat substantia nigra. 290 88

The long-term administration of neuroleptics causes tardive dyskinesia, which closely resembles levodopa-induced dyskinesias, and is brought about through complex mechanisms which are ill-defined. It is generally believed that the pathogenesis of tardive dyskinesia relates closely to the chronic blockade of dopamine receptor sites and that its pathophysiology results from a hypersensitivity of dopamine receptor sites. In the therapeutic management of neuroleptic-induced tardive dyskinesia, in addition to reserpine and lithium, diazepam, baclofen, or gamma-vinyl-gamma-aminobutyric acid have also been advocated. However, the reported beneficial effects of diazepam and GABA-mimetic agents in ameliorating the symptoms of tardive dyskinesia may occur through a mechanism which does not necessarily link transmission involving both dopamine and GABA. The presence of high concentrations of both cholecystokinin and opioids in the striatum also suggests that these peptides not only may influence dopaminergic transmission, but that they may also be relevant to the psychopathology of schizophrenia and to the therapeutic effects of neuroleptics. Indeed, the acute and chronic administration of neuroleptics alters the levels of cholecystokinin and opioids and their receptors in several brain regions including the striatum. However, neuroleptics also alter the biochemical integrity of neurotensin, neuropeptide Y, substance P and somatostatin, which may also play a role in the overall expression of the neuroleptic-induced extrapyramidal reactions.
 ...
PMID:Dopamine, GABA, cholecystokinin and opioids in neuroleptic-induced tardive dyskinesia. 290 20

The relationship between cerebral GABA content and susceptibility to seizures is addressed from the point of view of specific brain loci at which GABA synapses may control convulsive activity. The substantia nigra (SN) has been identified as a critical site at which GABA-agonist drugs act to reduce susceptibility to a number of types of experimentally induced generalized seizures. Moreover, the ability of GABA-elevating agents to protect against seizures in the maximal electroshock model is directly correlated with increases in GABA specifically in the nerve-terminal compartment of SN. Studies with 2-deoxyglucose indicate that a marked increase in metabolic activity in SN is a common feature of several types of generalized seizures; it is possible that some of this increased activity is associated with GABAergic nerve terminals that become activated in an attempt to suppress seizure spread. Because GABA has been shown to inhibit nigral efferents, it is likely that GABA terminals inhibit nigral projections that are permissive or facilitative to seizure propagation. In support of this, bilateral destruction of SN attenuated clonic and tonic chemoconvulsant and electroshock seizures. Other treatments capable of reducing nigral output, namely opiate agonists (morphine and D-Ala-Met-enkephalin), and substance P antagonist analogs, were also found to have anticonvulsant effects when applied bilaterally into SN. Thus, the seizure-facilitating nigral efferents may be subject to inhibition by both GABA and opiates and may normally be driven by substance P. Of the various outputs from SN, the GABAergic projections to thalamus, reticular formation and/or superior colliculus are most likely responsible for influencing seizure propagation. Experimental evidence does not indicate a significant role of pars compacta nigrostriatal dopamine neurons for controlling the various types of seizures subject to nigral influence. We propose that the inhibition of the GABAergic outputs from SN pars reticulata can suppress the progression of seizure discharge through circuits involving the target areas of these outputs. Because chemical or electrical stimulation of SN does not initiate convulsions, it appears that seizure activity generated elsewhere in the brain may be amplified or sustained by activity in these nigral outputs.
 ...
PMID:Role of the substantia nigra in GABA-mediated anticonvulsant actions. 301 Jun 76

Both directly acting (GABAA and GABAB agonists) and indirectly acting GABAergic agents (GABA uptake inhibitors and GABA-transaminase inhibitors) produce analgesia in a variety of animal test systems. Analgesia produced by GABAA agonists is probably due to a supraspinal action, although spinal sites may also play a role. GABAA agonist analgesia is insensitive to naloxone, bicuculline, picrotoxin and haloperidol, but is blocked by atropine, scopolamine and yohimbine suggesting a critical role for central cholinergic and noradrenergic pathways in this action. The lack of blockade by the GABAA antagonist bicuculline is difficult to explain. Both bicuculline and picrotoxin have intrinsic analgesia actions which may not necessarily be mediated by GABA receptors. The GABAB agonist baclofen produces analgesia by actions at both spinal and supraspinal sites. Baclofen analgesia is insensitive to naloxone, bicuculline and picrotoxin, and blockade by cholinergic antagonists occurs only under limited conditions. Catecholamines are important mediators of baclofen analgesia because analgesia is potentiated by reserpine, alpha-methyl-p-tyrosine, phentolamine, ergotamine, haloperidol and chlorpromazine. A role for serotonergic mechanisms is less well defined. Methylxanthines, which produce a clonidine-sensitive increase in noradrenaline (NA) turnover, increase baclofen analgesia by a clonidine-sensitive mechanism. Both ascending and descending NA pathways are implicated in the action of baclofen because dorsal bundle lesions, intrathecal 6-hydroxydopamine and medullary A1 lesions markedly decrease baclofen analgesia. However, simultaneous depletion of NA in ascending and descending pathways by locus coeruleus lesions potentiates baclofen analgesia suggesting a functionally important interaction between the two aspects. Baclofen analgesia within the spinal cord may be mediated by a distinct baclofen receptor because GABA does not mimic the effect of baclofen and the rank order of potency both of close structural analogs of baclofen as well as antagonists differs for analgesia and GABAB systems. The spinal mechanism may involve an interaction with substance P (SP) because SP blocks baclofen analgesia, and desensitization to SP alters the spinal analgesic effect of baclofen. GABA uptake inhibitors produce analgesia which is similar to that produced by GABAA agonists because it is blocked by atropine, scopolamine and yohimbine. Analgesia produced by GABA-transaminase inhibitors is similar to that produced by GABAA agonists because it can be blocked by atropine, but it is potentiated by haloperidol while THIP analgesia is not.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:GABAergic mechanisms of analgesia: an update. 303 1

Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A9 DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade.
 ...
PMID:Electrophysiological studies on the specificity of the cholecystokinin antagonist proglumide. 303 8

The striatum, the main component of the basal ganglia, is composed of mainly one type of neuron, the so-called medium spiny neuron. This neuron cell type, which constitutes over 90% of striatal neurons, is the major output neuron of the striatum. Combined ultrastructural neuroanatomical methods have elucidated the organization of afferent connectivity to these neurons. The major physiologic function of striatal efferent activity appears to be inhibition of tonically active GABAergic neurons in the globus pallidus and substantia nigra pars reticulata. Thus, the excitatory input from the cerebral cortex, whose afferents make asymmetric synapses with the spines of medium spiny neurons, appears to drive the efferent activity of the striatum. Other extrinsic and intrinsic afferent synapses are situated in a position to regulate the effect of the corticostriatal excitatory input to the medium spiny neurons. For example, dopaminergic afferents from the midbrain make mainly symmetric synapses with the spine necks and dendritic shafts of the medium spiny neurons. Medium spiny neurons themselves have local axon collaterals, in addition to their efferent axon that exits the striatum, which serve to link together local clusters of medium spiny neurons. These local axon collaterals, which contain either GABA, substance P, or enkephalin, also make mainly symmetric synapses with the necks of spines or dendritic shafts of medium spiny neurons. Other afferents with similar synaptic connections to these neurons arise from cholinergic or somatostatinergic striatal intrinsic neurons. Additionally, the patterns of extrinsic and intrinsic afferents to medium spiny neurons and their extrinsic projections are related to the organization of medium spiny neurons into two mosaically organized macroscopic compartments, the striatal patches and matrix.
 ...
PMID:Synaptic organization of the striatum. 306 70

Immunocytochemical methods were used to localize tachykinin-like immunoreactivity within neurons of the monkey cerebral cortex. Three primary antibodies were used: polyclonal antisera raised against fragments of substance P and substance K that excluded the carboxyl termini of these peptides, and a monoclonal antibody that recognized the carboxyl terminus of the tachykinin family. Each antibody stained 2 populations of cortical nonpyramidal neurons: (1) A small number of large, intensely stained cells that give rise to long, coarsely beaded processes; (2) a relatively large number of small, lightly stained cells that are embedded in dense plexuses of stained punctate profiles. The large, dark cells are present in a superficial band that includes layers II and III, and in a deep band that includes layer VI and the subjacent white matter. The smaller, pale cells are present in the middle layers of cortex (layers IV and/or V). Colocalization studies indicate that virtually all the small tachykinin-immunoreactive neurons also display GABA immunoreactivity. The larger cells are not GABA-positive, but display both somatostatin-like and neuropeptide Y-like immunoreactivity. The immunocytochemically stained beaded processes and punctate profiles from plexuses that vary in density and laminar distribution among different areas of monkey cortex. The coarsely beaded processes form a basic quadrilaminar pattern, with relatively dense plexuses in layers I and VI and in 2 middle layers, usually III and V. However, this pattern varies considerably from area to area. Electron microscopically, the large cells contain a rich collection of cytoplasmic organelles, particularly Golgi complex, while the small cells contain relatively few organelles. Both types of cells, including large neurons in the white matter, receive symmetric and asymmetric synaptic contacts on their somata and proximal dendrites. The numbers of these axosomatic contacts are low. Virtually all synaptic contacts formed by immunoreactive terminals possess symmetric membrane thickenings. In 2 areas examined in detail (areas 2 and 4), pyramidal cell somata and dendrites are the major targets of the immunoreactive synaptic terminals.
 ...
PMID:A study of tachykinin-immunoreactive neurons in monkey cerebral cortex. 316 46

The onset of therapeutic effectiveness of carbamazepine is generally very rapid in the treatment of seizure and paroxysmal pain disorders, shows some lag in the treatment of mania, and exhibits the longest lag in depression. These time course variations may indicate that different mechanisms underlie the efficacy of carbamazepine in the differential neuropsychiatric syndromes. Biochemical and pharmacological data suggest that the anticonvulsant effects of carbamazepine are related to "peripheral-type" benzodiazepine and alpha 2-noradrenergic receptor systems and to its ability to stabilize sodium channels. GABAB (baclofen-like) actions appear to be involved in antinociceptive, but not anticonvulsant, effects. The relatively acute time course of antimanic efficacy may be related to the above-mentioned mechanisms or to other effects related to systems postulated to be altered in the manic syndrome. These effects might include carbamazepine's ability to increase acetylcholine in the striatum, decrease probenecid-induced levels of CSF homovanillic acid (HVA) in man and dopamine turnover in animals, decrease CSF norepinephrine in manic patients, inhibit adenylate cyclase activity (in response to norepinephrine, dopamine, adenosine, or ouabain), decrease GABA turnover, or act as a vasopressin agonist. Efficacy in depression may be related to actions in man that take time or chronic drug administration to develop, such as increases in plasma tryptophan, decreases in CSF somatostatin, decreases in thyroid indices, and increases in urinary free cortisol excretion and, in animals, increases in substance P sensitivity and increases in brain adenosine receptors. The ability of carbamazepine to block the development of lidocaine- and cocaine-induced seizures also requires chronic administration, suggesting that these seizure models may provide a unique perspective for understanding mechanisms of time-dependent effects.
 ...
PMID:Time course of clinical effects of carbamazepine: implications for mechanisms of action. 328 May 60

The effects of various pairs of convulsant and nonconvulsant barbiturates on mono- and polysynaptic activity were studied in the isolated spinal cord of the immature rat, using extracellular recording. The convulsant barbiturates, 5-ethyl-5-(3-methylbut-2'-enyl) barbituric acid (3M2B), 5-ethyl-5-(1,3-dimethylbut-1'-enyl) barbituric acid (1,3M1B) and (+)-5-(1,3-dimethylbutyl)-5-ethyl barbituric acid [(+) DMBB] all increased the monosynaptic reflex at concentrations between 5 and 50 microM with no change in polysynaptic activity. When the concentration was raised to between 100 and 300 microM, however, the convulsants all reduced the monosynaptic reflex, thus producing a biphasic dose-response relationship. The nonconvulsant barbiturates phenobarbital, 5-ethyl-5-(3-methylbut-1'-enyl) barbituric acid (3M1B), amylobarbital (3MB) and (-)-5-(1,3-dimethylbutyl)-5-ethyl barbituric acid [(-)DMBB] produced only a decrease in mono- and polysynaptic reflexes. At concentrations which enhanced the monosynaptic reflex, the responses of motoneurones to glycine and eledoisin-related peptide (an analogue of substance P) were reduced by (+)DMBB, while 1,3M1B and 3M2B had no significant effects upon any of the neurotransmitters tested. At concentrations which depressed the monosynaptic reflex, the convulsants all reduced the response to glycine whereas the nonconvulsant barbiturates all increased the response to GABA. With the exception of phenobarbital, both convulsant and nonconvulsant barbiturates produced a direct depolarisation of the presynaptic terminal membrane, with only the convulsants producing a depolarisation of the membrane of the motoneurone. Using another convulsant barbiturate, 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB), this direct depolarising action was found to be calcium-dependent.
 ...
PMID:Differing actions of convulsant and nonconvulsant barbiturates: an electrophysiological study in the isolated spinal cord of the rat. 339 68

GABAergic mechanisms appear to be involved in antinociceptive processes. Generally, peripheral administration of GABAergic agents increases the antinociceptive effect of morphine, but central administration inhibits this effect, suggesting that multiple interactions may occur. GABAergic agents also can produce antinociception directly. Muscimol and THIP (GABAA agonists) act at supraspinal sites to produce antinociception, but do not appear to interact with bicuculline sensitive receptors. Baclofen (a GABAB agonist) acts at both supraspinal and spinal sites. Supraspinal mechanisms include inhibition of ascending noradrenergic and dopaminergic pathways but activation of descending noradrenergic pathways. The spinal mechanism may involve postsynaptic inhibition of the effect of substance P. D-Baclofen is an antagonist at spinal baclofen receptors. Antinociception produced by inhibitors of GABA-transaminase is not reduced by bicuculline in most studies, while manipulations which increase the antinociceptive effect of baclofen do not alter or block the effect of GABA-transaminase inhibitors. An understanding of the role of GABAA and GABAB receptors in antinociception will require clarification of some curious pharmacological actions of bicuculline and the use of a specific GABAB receptor antagonist.
 ...
PMID:GABAergic mechanisms in antinociception. 608 75


<< Previous 1 2 3 4 5 6 7 8 9 10