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)

In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t+30 h versus control. Other behavioral assessments revealed rapid persistent mechanical allodynia, but no thermal hyperalgesia or allodynia to heat and no hyperalgesia to mechanical stimuli. An immunohistochemical study in the superficial layers of the spinal dorsal horn revealed a marked increase in substance P immunoreactivity versus controls (12% versus 4%), whereas calcitonin gene-related peptide (CGRP) immunoreactivity was unchanged. This new animal model for the first time closely mimics the effects observed in humans after a single oxaliplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment.
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PMID:Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat. 1741 72

Coronary oxygen persufflation may serve as a means to improve storage conditions and organ preservation time for cardiac transplantation. We examined whether coronary oxygen persufflation and prolonged preservation time alter the endothelium-dependent relaxation of isolated coronary arteries. Isolated rabbit hearts were subjected to four different protocols: control (no preservation), 3 h cold storage in Bretschneider's solution, 18 h cold storage in Bretschneider's or University of Wisconsin solution, combined with coronary oxygen persufflation. After 2 h parabiotic reperfusion, intramural segments of coronary arteries were isolated and isometric tension was recorded using a small-vessel myograph. Endothelial function was examined using carbachol and substance P, applied after vessel constriction using high (30 mmol/l) K(+) or U 46.619, a thromboxane receptor agonist. In another series, coronary flow was measured after Bretschneider's +/-18 h coronary oxygen persufflation, or in freshly isolated, retrogradely perfused Langendorff hearts. Flow responses to substance P, acetylcholine or bradykinin were recorded. In saline-reperfused intact hearts no change in the normal effects of endothelium-dependent relaxants was detected after 18 h, irrespective of coronary oxygen persufflation. However, after isolation of the resistance vessels endothelium-dependent relaxation was abolished after long-term preservation and persufflation. Similar results were obtained after mechanical removal of the endothelium using control hearts. Short-term preservation without persufflation resulted in relaxations similar to those in non-preserved control hearts. Long-term preservation of rabbit heart including coronary oxygen persufflation results in unchanged endothelium-dependent relaxation in intact heart, but abolishes the endothelium-dependent relaxation after isolation of the vessels.
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PMID:Endothelial function after prolonged coronary artery oxygen persufflation in a rabbit model of heart preservation. 1766 49

Efferents from the brain of Limulus course toward its lateral eye and release octopamine and substance P into it. These neurotransmitters have previously been found to act as neuromodulators in this visual system by altering the size of its responses to light. We report here that both also modulate the timing of the receptor potentials (RPs) evoked by brief light flashes and that these timing effects are temperature dependent. Specifically: We extend our previous report that octopamine prolongs ambient RPs in a categorical fashion and here demonstrate that it does the same at colder temperatures. Categorical means that a given RP is either clearly prolonged in a dramatic fashion or its duration is otherwise unremarkable. Octopamine also accelerates the onsets of RPs when they are evoked by weak flashes under cold temperatures. Contrariwise, substance P accelerates RPs at all temperatures and this acceleration dramatically reduces the sluggishness that is otherwise typically present at low temperatures. Quantitative analysis of intensity-response functions also demonstrated that light sensitivity under substance P is significantly augmented. The plain temporal antagonism between these two modulators demonstrates that the visual system of Limulus possesses a well-poised mechanism which could be used to adjust the timing of its neural processing to interface well with the temporal characteristics of those visual stimuli that are currently present.
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PMID:Visual efference in Limulus: in vitro temperature-dependent neuromodulation of photoreceptor potential timing by octopamine and substance P. 1828 13

This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in CRPS, and can be prevented by anti-cytokine and anti-neuropeptide treatment. In CRPS patients, there is meanwhile also plenty of evidence that neurogenic inflammation contributes to clinical presentation. Increased cytokine production was demonstrated, as well as facilitated neurogenic inflammation. Very recently even "non-inflammatory" signs of CRPS (hyperhidrosis, cold skin) have been linked to neuropeptide signaling. Surprisingly, there was even moderately increased neurogenic inflammation in unaffected body regions. This favors the possibility that CRPS patients share genetic similarities. The future search for genetic commonalities will help us to further unravel the "mystery" CRPS.
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PMID:Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). 1842 63

Penetrating limb injuries are common and usually heal without long-lasting effects, even when nerves are cut. However, rare nerve-injury patients develop prolonged and disabling chronic pain (neuralgia). When pain severity is disproportionate to severity of the inciting injury, physicians and insurers may suspect exaggeration and limit care or benefits, although the nature of the relationship between lesion-size and the development and persistence of neuralgia remains largely unknown. We compared cellular changes in the spinal dorsal-horn (the initial CNS pain-processing area) after partial or total tibial-nerve axotomies in male Sprague-Dawley rats to determine if these changes are proportional to the numbers of peripheral axons cut. Unoperated rats provided controls. Plantar hind-paw responses to touch, pin, and cold were quantitated bilaterally to identify hyperalgesic rats. We also compared data from nerve-injured rats with or without hyperalgesic responses to mechanical hind-paw stimulation to evaluate concordance between pain behaviors and dorsal-horn cellular changes. Hyperalgesia was no less prevalent or severe after partial than after total axotomy. L(5) spinal-cord sections from rats killed 7 days postoperatively were labeled for markers of primary afferents (substance P calcitonin gene-related peptide isolectin B4, gamma aminobutyric acid, and glial fibrillary acidic protein), then labeled cells were stereologically quantitated in somatotopically defined dorsal-horn regions. Total axotomy reduced markers of primary afferents more than partial axotomy. In contrast, GABA-immunoreactive profiles were similarly reduced after both lesions, and in rats with sensory loss versus hyperalgesia. Numbers of GFAP-immunoreactive astrocytes increased independently of lesion size and pain status. Small nerve injuries can thus have magnified and disproportionate effects on dorsal-horn neurons and glia, perhaps providing a biological correlate for the disproportionate pain of post-traumatic neuralgias (including complex regional pain syndrome-I) that follow seemingly minor nerve injuries. However, the presence of similar dorsal-horn changes in rats without pain behaviors suggests that not all transcellular responses to axotomy are pain-specific.
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PMID:Effects of distal nerve injuries on dorsal-horn neurons and glia: relationships between lesion size and mechanical hyperalgesia. 1899 4

The complex regional pain syndrome (CRPS) is characterized by enhanced neurogenic inflammation, mediated by neuropeptides. Neutral endopeptidase (NEP) is a key enzyme in neuropeptide catabolism. We used NEP knock out (ko) mice to investigate whether NEP deficiency leads to increased pain behavior and signs of neurogenic inflammation after soft tissue trauma with and without nerve injury. After chronic constriction injury (CCI) of the right sciatic nerve, NEP ko mice were more sensitive to heat, to mechanical stimuli, and to cold than wild type mice. Tissue injury without nerve injury produced no differences between genotypes. After CCI, NEP ko mice showed increased hind paw edema but lower skin temperatures than wild type mice. Substance P (SP) and endothelin 1 (ET 1) determined by enzyme immuno assay (EIA) were increased in sciatic nerves from NEP ko mice after CCI. Tissue CGRP content did not differ between the genotypes. The results provide evidence that pain behavior and neurogenic inflammation are enhanced in NEP ko mice after nerve injury. These findings resemble human 'cold' CRPS and suggest that ET 1 plays an important role in the pathogenesis of CRPS with nerve injury.
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PMID:Increased pain and neurogenic inflammation in mice deficient of neutral endopeptidase. 1908 65

In a recent study we found that 4 weeks of human experimental forearm immobilization induced hypersensitivity to mechanical and cold stimuli and a higher skin temperature on the immobilized hand. Identical findings are reported in immobilization studies in rats where increased substance P signaling is suggested to play a central role. Capsaicin releases substance P from axon collaterals in the periphery initiating vasodilatation and plasma extravasation. The effect of immobilization on capsaicin-induced responses is, however, not known. Therefore, the present study examined the effect of experimental forearm immobilization on capsaicin-induced pain and flare responses in healthy subjects. Twenty-seven human volunteers were exposed to 4 weeks of scaphoid cast immobilization of the left forearm. Before and after immobilization, skin temperature and blood flow were measured at the thumbs of both hands during 5 min of rest. Subjects then received topical capsaicin (5%) randomly on the dorsum of the right and left hands. Time to sensory detection of capsaicin and pain onset was significantly increased on the immobilized left hand. Immobilization significantly reduced capsaicin-evoked pain, neurogenic flare area, and skin blood flow (perfusion units), and the reduced capsaicin-evoked pain was significantly correlated to an increase in peripheral skin temperature but not to skin blood flow. The correlation between reduced capsaicin-evoked pain and increased skin temperature suggests an increased substance P release while the delayed onset and diminished magnitude of capsaicin-induced pain may be due to reduced penetration of capsaicin into the epidermis.
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PMID:Experimental forearm immobilization in humans reduces capsaicin-induced pain and flare. 1936 13

Transient receptor potential ankyrin 1 (TRPA1), responding to noxious cold and pungent compounds, is implicated in the mediation of nociception, but little is known about the processing of the TRPA1-mediated nociceptive information within the trigeminal sensory nuclei (TSN) and the spinal dorsal horn (DH). To address this issue, we characterized the TRPA1-positive (+) neurons in the trigeminal ganglion (TG) and investigated the distribution of TRPA1(+) afferent fibers and their synaptic connectivity within the rat TSN and DH by using light and electron microscopic immunohistochemistry. In the TG, TRPA1 was expressed in unmyelinated and small myelinated axons and also occasionally in large myelinated axons. Many TRPA1(+) neurons costained for the marker for peptidergic neurons substance P (26.8%) or the marker for nonpeptidergic neurons IB4 (44.5%). In the CNS, small numbers of axons and terminals were immunopositive for TRPA1 throughout the rostral TSN, in contrast to the dense network of positive fibers and terminals in the superficial laminae of the trigeminal caudal nucleus (Vc) and DH. The TRPA1(+) terminals contained clear round vesicles, were presynaptic to one or two dendrites, and rarely participated in axoaxonic contacts, suggesting involvement in relatively simple synaptic circuitry with a small degree of synaptic divergence and little presynaptic modulation. Immunoreactivity for TRPA1 was also occasionally observed in postsynaptic dendrites. These results suggest that TRPA1-dependent orofacial and spinal nociceptive input is processed mainly in the superficial laminae of the Vc and DH in a specific manner and may be processed differently between the rostral TSN and Vc.
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PMID:Expression of transient receptor potential ankyrin 1 (TRPA1) in the rat trigeminal sensory afferents and spinal dorsal horn. 2003 57

Human skin blood flow responses to body heating and cooling are essential to the normal processes of physiological thermoregulation. Large increases in skin blood flow provide the necessary augmentation of convective heat loss during environmental heat exposure and/or exercise, just as reflex cutaneous vasoconstriction is key to preventing excessive heat dissipation during cold exposure. In humans, reflex sympathetic innervation of the cutaneous circulation has two branches: a sympathetic noradrenergic vasoconstrictor system, and a non-noradrenergic active vasodilator system. Noradrenergic vasoconstrictor nerves are tonically active in normothermic environments and increase their activity during cold exposure, releasing both norepinephrine and cotransmitters (including neuropeptide Y) to decrease skin blood flow. The active vasodilator system in human skin does not exhibit resting tone and is only activated during increases in body temperature, such as those brought about by heat exposure or exercise. Active cutaneous vasodilation occurs via cholinergic nerve cotransmission and has been shown to include potential roles for nitric oxide, vasoactive intestinal peptide, prostaglandins, and substance P (and/or neurokinin-1 receptors). It has proven both interesting and challenging that no one substance has been identified as the sole mediator of active cutaneous vasodilation. The processes of reflex cutaneous vasodilation and vasoconstriction are both modified by acute factors, such as exercise and hydration, and more long-term factors, such as aging, reproductive hormones, and disease. This review will highlight some of the recent findings in these areas, as well as interesting areas of ongoing and future work.
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PMID:Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. 2044 28

The thermogenic function and growth of brown adipose tissue (BAT) are known to be primarily under the control of the sympathetic nervous system. However, BAT also contains nerves containing neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) that are presumed to be sensory nerves. In a previous study we demonstrated an atrophy of BAT in capsaicin-desensitized (CAP-DES) rats. CAP-DES is known to bring about long-lasting impairment of a subpopulation of sensory nerves involved in nociception and characterized by the presence of SP and CGRP. The principal objectives of the present experiments were to find out whether CAP-DES of rats depleted BAT of its sensory neuropeptide, CGRP, whether CAP-DES impaired the sympathetic innervation of BAT and whether the atrophy of BAT induced by CAP-DES resembled that induced by sympathetic denervation. CAP-DES rats had a normal noradrenaline content in BAT (measured by HPLC) but absent CGRP (measured by immunohistochemistry). In CAP-DES rats living at 26 degrees C, BAT had lost 90% of its uncoupling protein (UCP) and 50% of its total protein; its thyroxine 5?-deiodinase (T5?D) concentration was, however, unaltered. Surgical denervation, in contrast, which did not abolish CGRP immunofluorescence in BAT, did not significantly reduce protein or UCP content. Cold-acclimation for 12 days produced large increases in protein and UCP content and T5?D level in intact BAT of control rats. These increases still occurred, although to a lower level, in CAP-DES rats but did not occur surgically denervated BAT. The combination of CAP-DES and surgical denervation resulted in an undetectable level of UCP in BAT of cold-acclimated rats, less than in denervated BAT of control cold-acclimated rats. We conclude that sensory nerves play a role in maintenance of BAT in a warm environment and in cold-induced growth of BAT. This role may be either a trophic effect on mitochondriogenesis or a repressive effect on mitochondrial destruction.
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PMID:Sympathetic and sensory nerves in control of growth of brown adipose tissue: Effects of denervation and of capsaicin. 2050 27


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