UNIPROT:P20366 - FACTA Search

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)

NMDA receptors are composed of proteins from two families: NMDAR1, which are required for channel activity, and NMDAR2, which modulate properties of the channels. The mRNA encoding the NMDAR2D subunit has a highly restricted pattern of expression: in the forebrain, it is found in only a small subset of cortical, neostriatal and hippocampal neurons. We have used a quantitative double-label in situ hybridization method to examine the expression of NMDAR2D mRNA in neurochemically defined populations of neurons. In the neostriatum, NMDAR2D was expressed by the interneuron populations marked by preprosomatostatin (SOM), the 67-kDa form of glutamic acid decarboxylase (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) mRNAs but not by the projection neurons expressing beta-preprotachykinin (SP) or preproenkephalin (ENK) mRNAs. In the neocortex, NMDAR2D expression was observed in only a small number of neurons, but these included almost all of the SOM-, GAD67-, and PARV-expressing interneurons. In the hippocampus, NMDAR2D was not present in pyramidal or granule cells, but was abundant in SOM-, GAD67-, and PARV-positive interneurons. NMDAR2D expression appears to be a property shared by interneurons in several regions of the brain. The unique electrophysiological characteristics conveyed by this subunit, which include resistance to blockade by magnesium ion and long channel offset latencies, may be important for the integrative functions of these neurons. NMDAR2D-containing receptor complexes may prove to be important therapeutic targets in human disorders of movement. In addition, the presence of NMDAR2D subunits may contribute to the differential vulnerability of interneurons to excitotoxic injury.
...
PMID:Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus. 891 84

The superior colliculus is a midbrain structure serving visual, multisensory and sensorimotor processing. Throughout various collicular layers, visual afferents are linked together with afferents related to other sensory modalities as well as with afferents from sources not easily subsumed under the term 'sensory'. These inputs are orchestrated in a topographic fashion and led to premotor neurons that are important elements in generating saccadic eye movements and orientation movements of other kinds. Using immunocytochemical techniques to chart the distribution of various substances serving neurotransmission and neuromodulation, it was found that many of them, e.g. acetylcholinesterase (AChE), choline acetyltransferase, the enkephalins, substance P, and parvalbumin, relate to repetitive structural islands, or modules, in the superior colliculus. From studies on the distribution of three further neuroactive substances in rat superior collicular tissue: the calcium binding protein calretinin, the growth and plasticity related protein neuromodulin (GAP-43), and a glutamate receptor of the NMDA-type, we were led to conclude (1) that the intermediate layers of the superior colliculus are composed not of two, but of at least three disjunct types of modules, (2) that not just the intermediate layers but more or less the whole superior colliculus is an assemblage of modules, and (3) that, besides topographic connectivity and laminar structuring, the modules constituting an iterative partitioning represent a third major feature of superior collicular architecture. The origin of the collicular mosaic is considered under an evolutionary perspective, and a hypothesis is presented stating that the pattern of AChE-rich modules on the level of the multimodal collicular layers can be predicted from retinal ganglion cell topography.
...
PMID:The mosaic architecture of the superior colliculus. 897 18

Severe or prolonged tissue or nerve injury can induce hyperexcitability of dorsal horn neurons of the spinal cord, resulting in persistent pain, an exacerbated response to noxious stimuli (hyperalgesia), and a lowered pain threshold (allodynia). These changes are mediated by NMDA (N-methyl-D-aspartate)-type glutamate receptors in the spinal cord. Here we report that activation of the NMDA receptor causes release of substance P, a peptide neurotransmitter made by small-diameter, primary, sensory 'pain' fibres. Injection of NMDA in the cerebrospinal fluid of the rat spinal cord mimicked the changes that occur with persistent injury, and produced not only pain, but also a large-scale internalization of the substance P receptor into dorsal horn neurons, as well as structural changes in their dendrites. Both the pain and the morphological changes produced by NMDA were significantly reduced by substance P-receptor antagonists or by elimination of substance P-containing primary afferent fibres with the neurotoxin capsaicin. We suggest that presynaptic NMDA receptors located on the terminals of small-diameter pain fibres facilitate and prolong the transmission of nociceptive messages, through the release of substance P and glutamate. Therapies directed at the presynaptic NMDA receptor could therefore ameliorate injury-evoked persistent pain states.
...
PMID:NMDA-receptor regulation of substance P release from primary afferent nociceptors. 910 89

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.
...
PMID:Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone. 912 15

We tested the hypothesis that glutamate, the major excitatory neurotransmitter of the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). Glutamate immunoreactivity was found in cholinergic enteric neurons, many of which were identified as sensory by their co-storage of substance P and/or calbindin. Glutamate immunoreactivity was concentrated in terminal varicosities with a majority of small clear synaptic vesicles. The immunoreactivities of both AMPA and NMDA receptor subunits were also detected on neurons in both submucosal and myenteric plexuses. The immunoreactivity of the EAAC1 neuronal glutamate transporter was widespread in both plexuses. Glutamate evoked depolarizing responses in myenteric neurons that had fast and slow components. The fast component was mimicked by AMPA, and the slow component was mimicked by NMDA. The fast component and the response to AMPA mimicked fast EPSPs evoked in 2/AH neurons; moreover, fast EPSPs as well as fast glutamate and AMPA responses were blocked by selective AMPA antagonists and potentiated by the glutamate uptake inhibitor L-(-)-threo-3-hydroxyaspartic acid. These observations demonstrate, for the first time, the presence of glutamatergic neurons and glutamate-mediated neurotransmission in the ENS.
...
PMID:Glutamatergic enteric neurons. 916 36

The excitability of spinal neurons that transmit pain is modulated by glutamate and substance P (SP). Glutamate is an excitatory neurotransmitter in the dorsal horn, and its effects are enhanced by SP acting on neurokinin 1 receptors (NK1Rs). We assessed activation of NK1Rs by studying their internalization in spinal cord slices. NK1Rs were localized in sections from the slices by using immunohistochemistry combined with fluorescence and confocal microscopy. Incubating the slices with SP induced internalization in most NK1R-positive neurons in laminae I, IIo, and X and in half of NK1R-positive neurons in laminae III-V. SP-induced internalization was abolished by the specific NK1R antagonist L-703,606 (1 microM). Stimulating the dorsal root with long-duration (0.4 msec) pulses evoked EPSPs in dorsal horn neurons with latencies consistent with the conduction speed of A partial differential- and C-fibers. High-frequency (100 Hz) stimulation of the dorsal root with these pulses induced NK1R internalization in neurons in laminae I-IIo of the stimulated side of the slice but not in the contralateral side or in other laminae. Stimulation at lower frequencies (1 and 10 Hz) failed to elicit significant internalization, suggesting that the release of SP is frequency-dependent. Internalization produced by the 100 Hz tetanus was mimicked by NMDA and blocked by an NMDA antagonist, 2-amino-5-phosphonopentanoic acid, but not by the AMPA and kainate antagonist CNQX. The NK1R antagonist L-703,606 abolished the internalization produced by 100 Hz stimulation or NMDA. Therefore, the release of SP in the dorsal horn appears to be controlled by NMDA receptors.
...
PMID:Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. 933 88

This review summarizes recent findings of our laboratory that have been directed at: (1) identifying the neural circuits underlying the expression and modulation of defensive rage behavior in the cat and the neurotransmitters associated with these pathways; and (2) determining which components of the circuitry are affected by alcohol administration and which significantly alter the rage mechanism. The experiments described herein incorporated a number of converging methods, which include brain stimulation, behavioral pharmacology, immunocytochemistry, retrograde tract tracing and receptor binding. For behavioral pharmacological studies, monopolar electrodes and cannula-electrodes were implanted into selected regions along the limbic-midbrain axis for electrical stimulation and local microinfusion of drugs. The findings demonstrated: (1) a direct pathway from the anterior medial hypothalamus to the dorsal periaqueductal gray (PAG) over which this response is mediated. This pathway utilizes excitatory amino acids that act upon NMDA receptors within the midbrain PAG; (2) that the region of the dorsal PAG, from which defensive rage could be elicited, receives other inputs from the basal amygdala that facilitate this response by acting upon NMDA receptors; (3) a pathway from the medial amygdala to the medial hypothalamus that also facilitates defensive rage and whose functions are mediated by substance P receptors within the medial hypothalamus; (4) that the PAG also receives enkephalinergic inputs from the central nucleus of amygdala, which act upon mu receptors, and which powerfully suppress defensive rage; and (5) that recent findings reveal that ethanol administration facilitates defensive rage by virtue of its interactions with the medial hypothalamus, its descending projection to the PAG, and possibly with NMDA receptors within this pathway.
...
PMID:Neurotransmitters regulating defensive rage behavior in the cat. 941 98

To define the effects of antisense oligonucleotides on spinal neurokinin 1 (NK1) receptor function in nociceptive processing, several antisense oligonucleotides directed against the NK1 receptor mRNA were intrathecally injected into rats via an implanted catheter, and their effect on the behavioural response to formalin injected into the paw was assessed. We observed that there was no significant reduction of pain behaviour or immunostaining of spinal NK1 receptors after repeated daily intrathecal treatment with an antisense oligonucleotide. However, spinal application of substance P (SP) in the antisense oligonucleotide-treated animals resulted in a profound and long-lasting reduction in the behavioural response to formalin injection, and a parallel reduction in the NK1 receptor immunoreactivity normally observed in spinal dorsal horn. Intrathecal SP in the control groups, i.e., rats treated with an oligonucleotide containing four mismatched bases, the corresponding sense oligonucleotide, a mixture of the sense and the antisense oligonucleotides, in each case had no effect. The effects of SP were blocked by NK1 receptor antagonists and were not mimicked by NMDA. The mechanism underlying these effects is not clear. It may be due to partial degradation of the internalised receptors, which cannot be replaced by newly synthesised receptors because of the action of the NK1 antisense oligonucleotide.
...
PMID:Spinal neurokinin NK1 receptor down-regulation and antinociception: effects of spinal NK1 receptor antisense oligonucleotides and NK1 receptor occupancy. 945 63

Sensitization is manifested as an increased response of neurones to a variety of inputs following intense or noxious stimuli. It is one of the simplest forms of learning and synaptic plasticity and it represents an important feature of nociception. In the spinal cord, repeated stimulation (at constant strength) of dorsal root afferents including nociceptive C fibres can elicit a progressive increase in the number of action potentials generated by motoneurones and interneurones. This phenomenon is termed "action potential windup" and is used as a cellular model of pain sensitization developing at the level of the central nervous system. Understanding the mechanisms responsible for windup generation might allow clarification of the cellular mechanisms of pain signalling and development of new strategies for pain treatment. Action potential windup is observed in a minority of cells only, indicating that certain cell-specific mechanisms are responsible for its generation. The most reliable index to predict windup generation is the rate at which the membrane potential is depolarized during repetitive stimulation. This phenomenon has been proposed to be due to gradual recruitment of NMDA receptor activity, to summation of slow excitatory potentials mediated by substance P (and related peptides) or to facilitation of slow calcium channels by metabotropic glutamate receptors. Little is known about the role of synaptic inhibition in windup, although it should not be underestimated. Each theory per se is unable to account for all the experimental observations. Since NMDA receptors are involved in many forms of synaptic plasticity, additional mechanisms such as summation of slow peptidergic potentials, facilitation of slow Ca2+ currents and disinhibition are proposed as necessary to impart specificity to pain-induced sensitization. These additional mechanisms might be species specific and change during development or chronic pain states.
...
PMID:Sensitization of pain pathways in the spinal cord: cellular mechanisms. 948 3

Tachykinin immunoreactivity is found in a ventromedial spinal plexus in the lamprey. Neurons in this plexus project bilaterally and are thus in a position to modulate locomotor networks on both sides of the spinal cord. We have examined the effects of the tachykinin substance P on NMDA-evoked locomotor activity. Brief (10 min) application of tachykinin neuropeptides results in a prolonged concentration-dependent (>24 hr) modulation of locomotor activity, shown by the increased burst frequency and more regular burst activity. These effects are blocked by the tachykinin antagonist spantide II. There are at least two phases to the burst frequency modulation. An initial phase (approximately 2 hr) is associated with the protein kinase C-dependent potentiation of cellular responses to NMDA. The long-lasting phase (>2 hr) appears to be protein synthesis-dependent, with protein synthesis inhibitors causing the increased burst frequency to recover after washing for 2-3 hr. The modulation of the burst regularity is caused by a separate effect of tachykinins, because unlike the burst frequency modulation it does not require the modulation of NMDA receptors for its induction and is blocked by H8, an inhibitor of cAMP- and cGMP-dependent protein kinases. The effects of substance P were mimicked by the dopamine D2 receptor antagonist eticlopride. The effects of eticlopride were blocked by the tachykinin antagonist spantide II, suggesting that eticlopride may endogenously release tachykinins. Because locomotor activity in vitro corresponds to that during swimming in intact animals, we suggest that endogenously released tachykinins will result in prolonged modulation of locomotor behavior.
...
PMID:Substance P modulates NMDA responses and causes long-term protein synthesis-dependent modulation of the lamprey locomotor network. 961 53

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