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)

Over the last 10 years or so in Europe, there has been a development of the "ecstasy" phenomenon, which is the symbol of "recreational" drugs in general. Users, either alone or in private parties, are on the increase. The phenomenon is most frequent in England and in the Netherlands, with an estimated incidence of 13-18% amongst the 18-25 years old, which may reach 52% in "exposed populations", such as individuals who go to "techno" night clubs. In France, the prevalence is uncertain, but estimated at least 5% of males between 18 and 23 years old. Several substance, with more or less the same effects, are grouped together by the term "ecstasy", the best-known one being 3,4-methylenedioxymethamphetamine (MDMA), but there are also an N-demethylated derivative (MDA), methylenedioxyethylamphetamine (MDEA), N-methyl-benzodioxazolylbutanamine (MBDB) and 4-bromo-2,5-dimethoxyphenylethylamine (2-CB or Nexus). The psychopathological consequences of MDMA in man are relatively poorly understood. On the basis of series of cases reported in the literature, acute psychosis, chronic psychosis similar to paranoid delusions, flash-back phenomena similar to with LSD, anxiety/panic states and depressive mood disorders may occur. The case which we report is therefore that of an acute psychotic episode, with residual symptomatology 6 months later, which occurred suddenly following absorption of toxic substances (alcohol and ecstasy), at least 12 hours after taking the ecstasy tablet without his knowing it, in an individual without any previous psychopathology, other than moderate social phobia. Twelve cases of acute psychotic episodes after ecstasy have been reported in the literature. Two of them occurred after a single dose and one after 2 doses. No author was able to examined the previous history of the individuals accurately, nor any possible psychopathological history. Our patient did not have any previous history of psychosis, using a standardized validated interview, which his peers and family confirmed. He did however fulfil the criteria of "social phobia". Retrospectively, we noted the extent of his psychomotor disinhibition with ecstasy, which seemed to be proportional to the intensity of his previous social inhibition. This point does not explain the psychotic episode. From a neurobiologic point of view, acute psychotic disorders are often related to dysfunction of the mesolimbic dopaminergic system. During the first 3 hours, the effect of absorption of MDMA is a massive release of the serotonin, dopamine and noradrenaline stocks. Later, an acute hyposerotoninergic state is present. In our observation, the psychotic disorder appeared at least 12 hours after taking ecstasy, during the reduction phase of the intoxication. Toxicological analysis of the blood was negative (this detection is only positive for 24 hours). Like other authors, our hypothesis is that serotoninergic dysregulation affects the dopaminergic system. Sudden disappearance of serotoninergic feedback on the dopaminergic pathways, may contribute to an increase in the mesolimbic hyperdopaminergic state. In animals, it has been shown that serotonin depletion induced by MDMA, unmasks the effects of a hyperdopaminergic state. In addition, although it has not been mentioned much in the literature, MDMA disturbs dopaminergic function either directly, or through the peptidergic systems (neurotensin, substance P, dynorphines). A consistent series of arguments therefore suggest that there is a sudden central hyperdopaminergic state, which may be related to the appearance, sometimes de novo, of an acute psychotic disorder. From the published cases, psychotic disorders following absorption of ecstasy, appear to become chronic. Most of the cases occurred in individuals, who either abused multiple substances or were chronic ecstasy users. In a case like the one we report, in an individual with good general health, who is not a drug user and who has an acute episode following a single dose, the prognosis should be good. Similarly, a team from Milan has described the experience of 3 friends who had a brief psychotic episode, following ingestion of substances containing ecstasy. These episodes resolved completely, after rehydration and anxiolytic treatment. However, after 6 months' follow-up, our patient still has psychotic symptoms, albeit mild, but which were not present before the intoxication. The patient and his psychiatrist do not envisage changing or stopping his antipsychotic treatment. Other authors have described a lesion in the serotoninergic neurons, by making a parallel with toxic effects described in animals, in particular in primates, with MDMA. Degradation of the serotoninergic cell bodies and nerve endings has been suggested to occur with high doses and/or repeated doses of MDMA. Other authors show the large variations in MDMA and MDA metabolism. (ABSTRACT TRUNCATED)
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PMID:[A case of acute psychotic episode after a single dose of ecstasy]. 1140 74

Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase--immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)-- and beta-synuclein--LI, as well as by Timm staining, all of which revealed relatively normal patterns of excitatory terminal distribution. Control injections produced minor damage at the injection site, but no apparent specific loss of SPR-LI. One to 12 weeks after injection of SSP-saporin, extracellular electrophysiological field responses recorded in the CA1 pyramidal and dentate granule cell layers in response to afferent stimulation were blindly evaluated simultaneously in two sites 1-2 mm apart along the longitudinal hippocampal axis. SSP-saporin-treated rats exhibited relatively normal responses in some sites, whereas disinhibition and hyperexcitability indistinguishable from the pathophysiology produced by experimental status epilepticus were simultaneously recorded at adjacent sites. Anatomic analysis of the recording sites in each animal revealed that epileptiform pathophysiology was consistently observed only within areas of SPR ablation, whereas relatively normal evoked responses were recorded from immediately adjacent and relatively unaffected regions. These data establish the efficacy of [Sar(9), Met(O(2))(11)] Substance P-saporin for producing a selective and spatially extensive ablation of hippocampal inhibitory interneurons in vivo and a highly focal disinhibition that was restricted to the site of interneuron loss. These results also demonstrate that the "epileptic" pathophysiology produced by experimental status epilepticus or head trauma can be replicated by focal interneuron loss per se, without involving principal cell loss and other interpretive confounds inherent in the use of global neurologic injury models.
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PMID:Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P. 1143 20

Cultured spinal cord networks grown on microelectrode arrays display complex patterns of spontaneous burst and spike activity. During disinhibition with bicuculline and strychnine, synchronized burst patterns routinely emerge. However, the variability of both intra- and interculture burst periods and durations are typically large under these conditions. As a further step in simplification of synaptic interactions, we blocked excitatory AMPA synapses with 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulphonamide (NBQX), resulting in network activity mediated through the N-methyl-D-aspartate (NMDA) receptor (NMDA(ONLY)). This activity was APV sensitive. The oscillation under NMDA(ONLY) conditions at 37 degrees C was characterized by a period of 2.9 +/- 0.3 s (16 separate cultures). More than 98% of all neurons recorded participated in this highly rhythmic activity. The temporal coefficients of variation, reflecting the rhythmic nature of the oscillation, were 3.7, 4.7, and 4.9% for burst rate, burst duration, and interburst interval, respectively [mean coefficients of variation (CVs) for 16 cultures]. The oscillation persisted for at least 12 h without change (maximum observation time). Once established, it was not perturbed by agents that block mGlu receptors, GABA(B) receptors, cholinergic receptors, purinergic receptors, tachykinin receptors, serotonin (5-HT) receptors, dopamine receptors, electrical synapses, burst afterhyperpolarization, NMDA receptor desensitization, or the hyperpolarization-activated current. However, the oscillation was destroyed by bath application of NMDA (20-50 microM). These results suggest a presynaptic mechanism underlying this periodic rhythm that is solely dependent on the NMDA synapse. When the AMPA/kainate synapse was the sole driving force (n = 6), the resulting burst patterns showed much higher variability and did not develop the highly periodic, synchronized nature of the NMDA(ONLY) activity. Network size or age did not appear to influence the reliability of expression of the NMDA(ONLY) activity pattern. For this reason, we suggest that the NMDA(ONLY) condition unmasks a fundamental rhythmogenic mechanism of possible functional importance during periods of NMDA receptor-dominated activity, such as embryonic and early postnatal development.
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PMID:NMDA receptor-dependent periodic oscillations in cultured spinal cord networks. 1173 58

Substance P receptor [neurokinin 1 (NK1] antagonists (SPAs) represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficacy to selective serotonin reuptake inhibitors (SSRIs). Because SSRIs are thought to exert their therapeutic effects by enhancing central serotonergic function, we have examined whether SPAs regulate neuronal activity in the dorsal raphe nucleus (DRN), the main source of serotonergic projections to the forebrain. Using in vivo electrophysiological techniques in the guinea pig, we found that administration of the highly selective NK1 receptor antagonist 1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-phenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine (L-760735) caused an increase in DRN neuronal firing rate. However, unlike chronic treatment with fluoxetine, there was no detectable 5-HT1A autoreceptor desensitization. In vitro electrophysiological investigation showed that these effects were not mediated by a direct action in the DRN, an observation supported by immunocytochemical analysis that identified the lateral habenula (LHb) as a more likely site of action. Subsequently, we found that local application of L-760735 into the LHb increased firing in the DRN, which, together with our data showing that L-760735 increased metabolic activity in the cingulate cortex, amygdala, LHb, and DRN, indicates that the effects of L-760735 may be mediated by disinhibition of forebrain structures acting via a habenulo raphe projection. These findings support other evidence for an antidepressant profile of SPAs and suggest that regulation of DRN neuronal activity may contribute to their antidepressant mechanism of action but in a manner that is distinct from monoamine reuptake inhibitors.
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PMID:Substance P (neurokinin 1) receptor antagonists enhance dorsal raphe neuronal activity. 1219 96

Intrathecal (i.t.) injection of nociceptin elicited a behavioral response mainly consisting of biting and licking, which were eliminated by the i.t. co-administration of opioid receptor-like-1 (ORL-1) receptor antagonists. The behavioral response induced by nociceptin was characteristically similar to that by i.t.-administered histamine, and was attenuated by i.t. co-administration of the H1 receptor antagonists, but not by the H2 receptor antagonists, whereas the H3 receptor antagonist promoted the nociceptin-induced behavior. H1 receptor knockout (H1R-KO) mice did not show the nociceptin-induced nociceptive behavior, which was observed in wild-type mice. Pretreatment with a histamine antiserum or a histidine decarboxylase inhibitor resulted in a significant reduction of the response to nociceptin. The previous studies showed that NK1 receptor antagonists and a novel substance P (SP)-specific antagonist given i.t. could reduce the behavioral response to nociceptin and histamine. On the other hand, the nociceptive response induced by nociceptin, but not histamine, was completely attenuated by the i.t. co-administration of agonists for GABAA and GABAB receptors. In contrast, the antagonists for GABAA and GABAB receptors injected i.t. showed same nociceptive response with nociceptin and histamine, and their nociceptive responses were significantly blocked by the i.t. co-administration of the H1 receptor antagonists, but not H2 receptor antagonists or ORL-1 receptor antagonists. The present results suggest that the activation of the ORL-1 receptor by nociceptin may induce the disinhibition of histaminergic neuron and enhance the release of histamine, which subsequently acts on the H1 receptor located on the SP-containing neurons to produce the spinal cord-mediated nociceptive response.
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PMID:Involvement of the histaminergic system in the nociceptin-induced pain-related behaviors in the mouse spinal cord. 1549 98

Blockade of local spinal cord inhibition mimics the behavioral hypersensitivity that manifests in chronic pain states. This suggests that there is a pathway capable of mediating allodynia/hyperalgesia that exists but is normally under strong inhibitory control. Lamina I and III neurokinin 1 (NK1) receptor expressing (NK1R+) dorsal horn neurons, many of which are projection neurons, are required for the development of this hypersensitivity and are therefore likely to be a component of this proposed pathway. To investigate, whole-cell patch-clamp recordings were made from lamina I and III NK1R+ neurons in the spinal cord slice preparation with attached dorsal root. Excitatory postsynaptic currents were recorded in response to electrical stimulation of the dorsal root. Lamina I NK1R+ neurons were shown to receive high-threshold (Adelta/C fiber) monosynaptic input, whereas lamina III NK1R+ neurons received low-threshold (Abeta fiber) monosynaptic input. In contrast, lamina I neurons lacking NK1 receptor (NK1R-) received polysynaptic A fiber input. Blockade of local GABAergic and glycinergic inhibition with bicuculline (10 microm) and strychnine (300 nm), respectively, revealed significant A fiber input to lamina I NK1R+ neurons that was predominantly Abeta fiber mediated. This novel A fiber input was polysynaptic in nature and required NMDA receptor activity to be functional. In lamina I NK1R- and lamina III NK1R+ neurons, disinhibition enhanced control-evoked responses, and this was also NMDA receptor dependent. These disinhibition-induced changes, in particular the novel polysynaptic low-threshold input onto lamina I NK1R+ neurons, may be an underlying component of the hypersensitivity present in chronic pain states.
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PMID:Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. 1646 32

Modern concepts of pain therapy involve neuronal mechanisms of endogenous analgesia. Recent animal experiments have provided new insights into the anatomy, physiology and neurobiology of endogenous antinociception. We have shown that antinociception can be maximally activated by disinhibition-and not by direct electrical or chemical excitation-in the midbrain periaqueductal grey matter. This disinhibition is a likely mechanism of opioid analgesia. 'Purely analgesic' stimulation produces a very distinct pattern of activated neurons within the periaqueductal grey matter and other areas of the brain stem, as revealed by the expression of the nuclear c-FOS protein as a cellular marker of activated neurons. In addition to the classic segmental and supraspinal, descending inhibition, a third principle of endogenous antinociception exists: the propriospinal, intersegmental inhibition of nociceptive spinal dorsal horn neurons. Propriospinal antinociception partly mediates the descending inhibition from the brain stem and can be activated by conditioning heterosegmental noxious stimuli, thus possibly contributing to analgesia by counterirritation. In addition to the fast synaptic transmission mediated by classic neurotransmitters, the extrasynaptic transmission of chemical signals such as neuropeptides may play an important role for long-term effects following intense noxious stimulation. The controlled superfusion of the dorsal cord with neuropeptides produces a similar distribution in the spinal cord to that of endogenously released neuropeptide. We have shown that extrasynaptic neuropeptides such as substance P may increase the excitability of nociceptive spinal dorsal horn neurons and may induce the expression of 'immediate-early genes' in dorsal horn neurons in vivo. Changes in gene expression following extrasynpatic spread of neuropeptides in the spinal cord may be involved in chronic pain syndromes after massive peripheral trauma. This hypothesis has led to the concept of pre-emptive analgesia. The available evidence suggests that the known systems of endogenous antinociception do not affect the endogenous release of neuropeptides in the spinal cord. All previous concepts of endogenous antinociception are based on changes in dischargerates of nociceptive neurons. Background activity in the absence of noxious stimulation was considered to be purely stochastic 'noise'. By the use of modern tools for the analysis of nonlinear dynamics in point processes we have, however, shown that background activity of most nociceptive spinal dorsal horn neurons is highly deterministic with a low degree of freedom. The high order in the discharges of these neurons is maintained, at least in part, by tonically active descending systems. Thus, the spinal shock syndrome seen in some species after acute spinalisation may result from the loss of order in spinal neuronal discharges normally provided by the brain. The use of modern methods in studies of the functional neuroanatomy, neurophysiology and neurobiology of endogenous antinociception may help in the achievement of better application of results from basic sciences to clinically relevant pain problems.
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PMID:[Endogenous analgesic mechanism: new concepts from functional neuroanatomy, neurophysiology, neurobiology and chaos research.]. 1841 89

Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a 'short-loop feedback mechanism'. A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood-brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia.
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PMID:Prolactin and dopamine: what is the connection? A review article. 1847 17

The pars tuberalis is a distinct subdivision of the pituitary gland but its function remains poorly understood. Suprasellar tumors in this pars tuberalis region are frequently accompanied by hyperprolactinemia. As these tumors do not immunoreact for any of the established pituitary hormones, they are classified as nonsecretory. It has been postulated that these suprasellar tumors induce hyperprolactinemia by compressing the pituitary stalk, resulting in impaired dopamine delivery to the pituitary and, consequently, disinhibition of the lactotropes. An alternative hypothesis proposed is that suprasellar tumors secrete a specific pars tuberalis factor that stimulates prolactin secretion. Hypothesized candidates are the preprotachykinin A derived tachykinins, substance P and/or neurokinin A.
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PMID:Rethinking the stalk effect: a new hypothesis explaining suprasellar tumor-induced hyperprolactinemia. 1902 20

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. We recently provided a novel perspective on the mechanisms of this symptom by showing that a simple switch in trigeminal glycine synaptic inhibition can turn touch into pain by unmasking innocuous input to superficial dorsal horn nociceptive specific neurons through a local excitatory, NMDA-dependent neural circuit involving neurons expressing the gamma isoform of protein kinase C. Here, we further investigated the clinical relevance and processing of glycine disinhibition. First, we showed that glycine disinhibition with strychnine selectively induced dynamic but not static mechanical allodynia. The induced allodynia was resistant to morphine. Second, morphine did not prevent the activation of the neural circuit underlying allodynia as shown by study of Fos expression and extracellular-signal regulated kinase phosphorylation in dorsal horn neurons. Third, in contrast to intradermal capsaicin injections, light, dynamic mechanical stimuli applied under disinhibition did not produce neurokinin 1 (NK1) receptor internalization in dorsal horn neurons. Finally, light, dynamic mechanical stimuli applied under disinhibition induced Fos expression only in neurons that did not express NK1 receptor. To summarize, the selectivity and morphine resistance of the glycine-disinhibition paradigm adequately reflect the clinical characteristics of dynamic mechanical allodynia. The present findings thus reveal the involvement of a selective dorsal horn circuit in dynamic mechanical allodynia, which operates through superficial lamina nociceptive-specific neurons that do not bear NK1 receptor and provide an explanation for the differences in the pharmacological sensitivity of neuropathic pain symptoms.
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PMID:Glycine inhibitory dysfunction induces a selectively dynamic, morphine-resistant, and neurokinin 1 receptor- independent mechanical allodynia. 1924 26


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