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)

Esophageal pain is transmitted via the sympathetic nervous system to the spinal cord, in which pain from visceral and somatic sources ascends to higher centers in the brain. Primary afferent neurons are bipolar, with the peripheral end specialized to be a sensory receptor. Nociceptors of somatosensory afferents are free nerve endings that can be activated by mechanical, thermal, or chemical stimuli. Esophageal nociceptive neurons have not been specifically identified but probably are also free nerve endings. Most esophageal spinal mechanoreceptors have been shown to be nociceptive. Some esophageal mechanonociceptors have a wide dynamic range and respond to physiologic and painful stimuli, while others have a high threshold of stimulation and are solely nociceptive. Esophageal spinal afferents have their cell bodies in the dorsal root ganglia and contain substance P and calcitonin gene-related peptide. These putative neurotransmitters are transported in both the peripheral and central directions of bipolar afferent neurons. Primary afferent neurons are likely to also contain an excitatory amino acid neurotransmitter such as glutamate. Centrally, nociceptive primary afferents terminate on neurons in specific layers of the dorsal horn of the spinal cord. Convergence of multiple visceral afferents with somatic afferents onto the same dorsal horn neurons may explain referred pain. A patient's inability to distinguish esophageal from cardiac pain may be due to convergence of pain pathways. Second-order neurons in the dorsal horn project in the anterolateral system to the brain. Within the anterolateral system, nociception ascends in the spinothalamic, spinoreticular, and spinomesencephalic tracts. The thalamus relays fast pain to the postcentral areas of the parietal lobe of the cortex. Pathways to the reticular formation are slow and may mediate the increased arousal that occurs in response to pain. The spinomesencephalic tract projects to midbrain sites including the periaqueductal gray. Organ-specific pathways in the brain have yet to be defined, but neuroanatomic tracing techniques employing neurotropic viruses are being developed. The perception of pain can be influenced at multiple levels, such as the receptor in the esophagus, the synapses in the dorsal horn of the spinal cord or thalamus, or the cortex. A fundamental mechanism of modulating nociception is descending inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of esophageal pain. 159 55

Glutamate and several neuropeptides are synthesized and released by subpopulations of primary afferent neurons. These sensory neurons play a role in regulating the inflammatory and immune responses in peripheral tissues. We have explored what changes occur in the location and concentration of receptor binding sites for sensory neurotransmitters in two human inflammatory diseases, ulcerative colitis and Crohn's disease, using quantitative receptor autoradiography. The sensory neurotransmitter receptors included bombesin, calcitonin gene-related peptide-alpha, cholecystokinin, galanin, glutamate, somatostatin, neurokinin A (substance K), substance P, and vasoactive intestinal polypeptide. Of the nine receptor binding sites examined only binding sites for substance P and vasoactive intestinal peptide were significantly altered in the inflamed tissue. These data suggest that substance P is involved in regulating the inflammatory and immune responses in human inflammatory diseases and indicate a specificity of efferent action for each sensory neurotransmitter in peripheral tissues.
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PMID:Alterations in receptors for sensory neuropeptides in human inflammatory bowel disease. 165 49

Neuronal degeneration that occurs in both ischemia and degenerative neurologic illnesses may involve excitotoxic mechanisms. In the present study, we examined whether cortical lesions with agonists acting at subtypes of glutamate receptors result in selective patterns of neuronal death. Injections of quinolinic acid, NMDA, homocysteic acid, kainic acid (KA), and alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) were made at 2 sites in the dorsolateral frontoparietal cortex in rats. After 1 week, the cerebral cortex was either dissected for neurochemical studies, or animals were perfused for histologic evaluation. Concentrations of somatostatin (SS), neuropeptide Y (NPY), substance P (SP), cholecystokinin (CCK), and vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay, while amino acids and catecholamines were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. NMDA agonists (quinolinic acid, homocysteic acid, and NMDA itself) resulted in dose-dependent reductions in glutamate and GABA, while SS, NPY, SP, CCK, and VIP were either unchanged or significantly increased in concentration. KA and AMPA at doses that resulted in comparable GABA depletions caused significant reductions in SS concentrations. Markers of cortical afferents were spared. All excitotoxins resulted in dose-dependent marked increases in uric acid concentrations. Histologic examination verified that lesions with NMDA agonists produced relative sparing of NADPH-diaphorase, SS, VIP, and CCK neurons. These results show that NMDA excitotoxin lesions result in a pattern of selective neuronal damage in the cerebral cortex that is similar to that which occurs in both ischemia and Huntington's disease.
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PMID:Neurochemical characterization of excitotoxin lesions in the cerebral cortex. 167 Jul 82

The cytosolic calcium concentration [( Ca2+]i) of the isolated outer hair cell of the guinea pig was measured using fluorescence imaging microscopy and the effects of efferent neuroregulators such as acetylcholine, ATP, GABA, substance P, enkephalin, calcitonin gene-related peptide, serotonin, dopamine, norepinephrine, and glutamate were investigated. Among the drugs tested only ATP induced an elevation of the [Ca2+]i of the outer hair cell. In the resting condition, [Ca2+]i averaged 104.5 +/- 31.1 nM (n = 27), while 100 microM ATP significantly increased [Ca2+]i to 146.3 +/- 43.5 nM (n = 19). Superfusion with Ca2(+)-free solution (pCa = 7.5) abolished the increase in [Ca2+]i induced by ATP, suggesting that ATP causes an entry of external Ca2+. The relevance of [Ca2+]i to the inhibitory actions of efferent neuroregulators is discussed.
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PMID:Effect of neuroregulators on the intracellular calcium level in the outer hair cell isolated from the guinea pig. 167 35

Sharp pain is conducted rapidly by myelinated delta A fibers and diffused pain slowly by nonmyelinated C fibers to pseudobipolar neurons in the posterior ganglion and from there to neurons located in the posterolateral horn of the spinal cord. From here on nociferous impulses are transmitted by excitatory peptides (e.g. substance P) or amino acids (e.g. glutamate, aspartate) through interconnecting neurons of the pain pathways, primarily on the contralateral side, to the brain stem and from there to the sensory cortex, where they are appreciated and acted upon. There are specific inhibitory receptors located on axon terminals, near to the release sites of the excitatory amino acids and peptides. Stimulation of these receptors by their appropriate ligands such as endogenous (e.g. enkephalis, endorphins) or exogenous opioids, clonidine, serotonin, somatostatin inhibits the release of excitatory neurotransmitters and relieves pain. There are at least 3 different opioid receptors, called mu-, kappa- and delta-receptors in the spinal cord. These can be differentiated from one another by their specific affinity toward different endogenous or exogenous opioids and the pure narcotic antagonist, naloxone. It appears that the nociferous impulses transmitted by parallel pathways equipped with different inhibitory receptors have to be integrated to produce pain sensation and partial inhibition of transmission in different pathways or complete inhibition in one of the pathways may relieve pain. In recent years the concept of "selective spinal analgesia" has been applied clinically for the relief of postoperative, obstetrical and chronic pain. At first it was expected that the intrathecal or peridural administration of morphine will produce analgesia without the side effects of systemically administered morphine. It soon became evident, however, that intrathecally and peridurally administered morphine after several hours of delay reaches the fourth ventricle and by stimulating mu-receptors may cause respiratory depression and other undesired effects (e.g. nausea, vomiting, pruritus). Several different approaches are being investigated for the production of selective spinal analgesia without side effects. They include: a. the use of more lipophilic, long-lasting opioids (e.g. lofentanil) which would be almost completely absorbed by the spinal cord and therefore would not reach the medullary centers; b. the development of opioids with specific affinity to kappa- and for delta- and little or no affinity to mu-receptors, primarily responsible for side effects; and c. combining lower doses of opioid agonists with alpha 2-adrenergic agonists (e.g. clonidine) or with somatostatin. It is conceivable that in the not-too-distant future, it will be possible to achieve through these measures, selective spinal analgesia without side effects.
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PMID:Pain control with intrathecally and peridurally administered opioids and other drugs. 168 73

As many putative transmitter substances have been shown to be co-localized in areas of the central nervous system involved in cardiovascular control, we have investigated the possibility that some of these substances may interact in eliciting changes in heart rate and arterial pressure in anesthetized rats. In a first set of experiments, interactions between atrial natriuretic factor and glutamate were investigated by microinjection into the nucleus of the tractus solitarius, the site of termination of baroreceptor fibers of the aortic depressor nerve. In addition, interactions between the transmitter released in the nucleus tractus solitarius by electrical stimulation of the aortic depressor nerve and atrial natriuretic factor microinjected into the nucleus tractus solitarius were investigated. Combined microinjection of atrial natriuretic factor and glutamate into the nucleus tractus solitarius, or stimulation of the aortic depressor nerve combined with atrial natriuretic factor in the nucleus tractus solitarius, elicited decreases in heart rate and arterial pressure which were greater than the responses to either substance or stimulation alone or their algebraic sum. In a second set of experiments, interactions between substance P and acetylcholine were investigated in the intermediolateral nucleus of the spinal cord, the location of sympathetic preganglionic neurons. Furthermore, we investigated the possibility that the cardiovascular responses to microinjection of substance P and acetylcholine into the intermediolateral nucleus could be potentiated by the transmitter released in the intermediolateral nucleus by microinjection of glutamate into the rostral ventrolateral medulla, a region with known sympatho-excitatory function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of putative transmitters in central nervous pathways involved in the control of heart rate and arterial pressure. 168 94

Although it seems highly likely that mammalian isocortex evolved from a structure resembling reptilian telencephalic cortex, it has been uncertain if this occurred by the laminar differentiation of three-layered reptilian cortex into six-layered mammalian isocortex without the addition of new cell types or by laminar differentiation with the addition of new cell types. To distinguish between these two possibilities, immunohistochemical techniques were used to study turtles to see if the same major neuronal cell types, as defined by neurotransmitter or neuropeptide content, present in mammalian isocortex are also present in the specific part of reptilian cortex thought to be the forerunner of at least parts of isocortex, namely the dorsal cortex. Neurons containing the following substances are the major transmitter-specific types of neurons known to be present in mammalian isocortex: cholecystokinin-8 (CCK8), vasoactive intestinal polypeptide (VIP), acetylcholine, substance P (SP), neuropeptide Y (NPY), somatostatin (SS), LANT6, enkephalin, GABA and glutamate (GLUT). In turtles, only those of the above substances that are found in large numbers of neurons in layers V-VI in mammalian isocortex, irrespective of whether they are also present in layers II-IV (i.e. SP, NPY, SS, LANT6, GABA and GLUT), were present in neurons in dorsal cortex. The neurons containing these substances in dorsal cortex in turtles were generally highly similar in morphology to their counterparts in mammalian isocortex. In contrast, neurons labeled for CCK8, VIP or acetylcholine, which are mainly found in neurons of layers II-IV of mammalian isocortex, were absent or extremely rare in dorsal cortex. The absence or paucity of neurons labeled for these latter substances in dorsal cortex in turtles did not reflect an overall staining failure of the antisera used since the same antisera yielded excellent labeling of neurons, fibers and terminals in many other brain regions in turtles. Thus, dorsal cortex in turtles appears to lack several of the major cell types characteristic of layers II-IV of mammalian isocortex, but possesses a number of the major cell types characteristic of layers V-VI of isocortex. The findings support and extend a previous suggestion by Ebner [1976], based on hodological data, that dorsal cortex in turtles may lack the types of neurons found in the more superficial layers of mammalian isocortex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A comparison of neurotransmitter-specific and neuropeptide-specific neuronal cell types present in the dorsal cortex in turtles with those present in the isocortex in mammals: implications for the evolution of isocortex. 168 5

1. Each segmental ganglion of the leech Hirudo medicinalis contains 6 touch (T) cells, 4 pressure (P) cells and 4 nociceptive (N) cells. The receptive terminals of these cells innervate the skin in discrete areas. These cells are known to have extrasynaptic receptors. 2. We tested the effect of transmitter substances present in leech CNS on the sensitivity of T and P cells to mechanical stimuli. Substances tested included octopamine, FMRFamide, proctolin, substance P, glutamate, GABA, acetylcholine and serotonin. 3. Only acetylcholine and serotonin had consistent effects. Serotonin (1 x 10(-3) M) increased the number of action potentials of T cells elicited by a standard stimulus. Serotonin (1 x 10(-4) M) and acetylcholine (1 x 10(-3) M) increased the number and frequency of action potentials in P cells.
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PMID:Neuromodulatory effects of acetylcholine and serotonin on the sensitivity of leech mechanoreceptors. 168 9

The phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor, the kainic acid (KA) receptor and the quisqualate (QA) receptor were visualised, using autoradiography in the human spinal cord and the distributions compared with that of benzodiazepine (BDZ) receptors and substance P (SP). All of the receptor types, and SP, were concentrated in lamina II of the dorsal horn, consistent with physiological data indicating that glutamate is a neurotransmitter of primary afferent terminals in the spinal cord.
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PMID:Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord. 168 76

Extensive evidence implicates Substance P [SP(1-11)] as a primary afferent neurotransmitter or modulator of nociceptive information, and there is increasing evidence that the excitatory amino acids aspartate (Asp) and glutamate (Glu) may also act as nociceptive neurotransmitters. We have previously demonstrated that nociceptive stimulation (metatarsal injection of formalin) caused a tetrodotoxin (TTX)-sensitive release of Asp and a TTX-insensitive release of Glu from the dorsal spinal cord. We have also shown release of Asp and Glu following the direct infusion of SP(1-11), suggesting that formalin-induced Asp or Glu changes could be secondary to an initial release of SP(1-11). In contrast to nociception, pretreatment with TTX, reported here, had no effect on the SP(1-11)-induced release of Asp, suggesting a presynaptic mechanism. Behavioral experiments, in both our laboratory, and others, now suggest that the N-terminal products of SP metabolism play a distinct role in the modulation of SP(1-11) nociception, possibly through an interaction with an opiate receptor. To test the hypothesis that N- and C-terminal fragments of SP produce opposite effects on biochemical events potentially involved in nociception, we compared the effects of infusion of the N-terminal metabolite SP(1-7) and the C-terminal metabolite SP(5-11) on changes in the ECF concentration of amino acids in the spinal cord as a measure of their apparent release, using microdialysis. Intradiaylsate infusion of SP(5-11) increased the release of Asp, Glu, asparagine (Asn), glycine (Gly), and taurine (Tau). The changes in Asp, Glu, and Tau were similar in direction and magnitude to changes produced by SP(1-11) or formalin injection, further supporting the hypothesis that the C-terminal is responsible for the nociceptive effects of SP(1-11). In contrast, infusion of SP(1-7) significantly decreased the release of Asn, Tau, Glu, and Gly. This inhibition of amino acid release is consistent with the hypothesis that N-terminal metabolites produce opposite effects to those of C-terminal metabolites of SP(1-11). The decreases in Glu, Asn, Gly, and Tau following SP(1-7) infusion were significantly reduced by i.p. or intradialysate naloxone. Systemic naloxone had no significant effects on the SP(5-11)-induced amino acid changes; however, it did inhibit the SP(1-11)-induced increase in Asp and Glu. Intradialysate naloxone had no effect on the SP(1-11)-induced increases.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential effects of C- and N-terminal substance P metabolites on the release of amino acid neurotransmitters from the spinal cord: potential role in nociception. 169 75


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