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)

Many animal species invest a large amount of time in grooming behavior without deriving any apparent benefit. In order for this behavior to have survived, however, it must confer some survival advantage. In seven of eight humans tested, an elevation in the skin's temperature was documented after massaging of the cheeks of the face. The elevation of the skin's temperature reached a plateau after about 40 min of massaging and was correlated to visible erythema. This effect could be inhibited by repeated pretreatment of the skin with topical capsaicin, a chemical that results in the release of substance P from peripheral nerve endings. Thus, it appears that the temperature elevation induced by stroking of human skin is controlled, at least in part, by release of the neurotransmitter, substance P. In conclusion, it appears that the release of neurotransmitter(s) may be the survival advantage that grooming confers to animals.
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PMID:Firm stroking of human skin leads to vasodilatation possibly due to the release of substance P. 1067 28

Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E(2) and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10(-9) M. Substance P-induced (10(-8)-10(-6) M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 microg per ml). Only the highest concentration of substance P (10(-5) M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10(-11) M), but too low to induce protein extravasation (10(-8) M) or even mast cell degranulation (10(-5) M). J Invest Dermatol 115:1015-1020 2000
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PMID:Acute effects of substance P and calcitonin gene-related peptide in human skin--a microdialysis study. 1112 Nov 35

Skin reactivity to intradermal injections (0.1, 0.5 and 1 nM) of substance P (SP) was evaluated in 20 clinically normal dogs and 20 dogs with atopic dermatitis (AD). Saline and histamine were used as negative and positive controls, respectively. Wheal diameters were measured. Reactions were evaluated for erythema and induration and a subjective score, on a scale from 0 to 4+, was given. Evaluations were performed at 3, 5, 10, 15 and 30 min after the injections. Wheal diameters for histamine and SP injections were significantly smaller in dogs with AD compared with clinically normal dogs. In both groups, reactions to the various concentrations of SP were not significantly different from each other and were always smaller than histamine reactions. Erythema was not seen with SP injections. In addition, subjective scores for SP injections were significantly lower in dogs with AD compared with controls. The results of this study are similar to those reported in human medicine, where a role for SP in AD is proposed and desensitization of receptors to both SP and histamine is hypothesized. Further studies are needed to investigate the role of SP in the pathogenesis of canine AD.
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PMID:Intradermal skin test reactivity to histamine and substance P is blunted in dogs with atopic dermatitis. 1142 Sep 30

Activation of sensory unmyelinated neurons by noxious stimuli evokes the release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. These neuropeptides and subsequently released mediators cause a local oedema, hyperaemia and an erythema which extends beyond the site of stimulation (so-called flare response). Since these inflammatory signs depend on the function and integrity of peripheral sensory nervous systems, the response has been termed neurogenic inflammation. Due to the fact that nearly all tissues in mammals including humans are innervated by afferent sensory neurons, this neurogenic inflammation can occur ubiquitously throughout the body. Albeit first evidence showing that sensory neurons contribute to the inflammatory signs, described as antidromic vasodilatation, axon reflex, triple response, neurogenic inflammation, elicited at the level of tissue that they innervate was first obtained more than one hundred years ago, it was in the last two decades that inflammation caused by the release of neuropeptides from afferent nerve endings was recognised as a physiologically and pathologically relevant process. A large number of exogenous and endogenous substances and autacoids may stimulate or sensitise sensory nerve endings, thus simultaneously producing pain and nociceptive responses, as well as neurogenic inflammation. On the basis of recent research a variety of pharmacological substances and antagonists of putative mediators have been identified to modulate or suppress neurogenic inflammation, thus providing a rationale for therapeutical strategies for various diseases in which neurogenic inflammation is suggested to be involved. Among them, capsaicin and other newly developed agonists and antagonists at the vanilloid receptor have attracted particular attention, since they were found to be capable of desensitizing nociceptive nerve structures and thus of preventing development of neurogenic inflammation or even of abolishing an ongoing inflammatory process.
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PMID:[Neurogenic inflammation. I. Basic mechanisms, physiology and pharmacology]. 1206 84

Concepts related to the pathophysiology of reflex sympathetic dystrophy syndrome (RSDS) are changing. Although sympathetic influences are still viewed as the most likely mechanism underlying the development and/or perpetuation of RSDS, these influences are no longer ascribed to an increase in sympathetic tone. Rather, the most likely mechanism may be increased sensitivity to catecholamines due to sympathetic denervation with an increase in the number and/or sensitivity of peripheral axonal adrenoceptors. Several other pathophysiological mechanisms have been suggested, including neurogenic inflammation with the release of neuropeptides by primary nociceptive afferents and sympathetic efferents. These neuromediators, particularly substance P, calcitonin gene-related peptide, and neuropeptide Y (NPY), may play a pivotal role in the genesis of pain in RSDS. They induce an inflammatory response (cutaneous erythema and edema) and lower the pain threshold. Neurogenic inflammation at the site of the lesion with neuromediator accumulation or depletion probably contributes to the pathophysiology of RSDS. However, no single neuromediator has been proved responsible, and other hypotheses continue to arouse interest.
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PMID:Reflex sympathetic dystrophy syndrome and neuromediators. 1263 12

Endogenous neuropeptides released from nociceptors can induce vasodilation and enhanced protein extravasation (neurogenic inflammation). The role of nitric oxide (NO) in the induction of neurogenic inflammation is controversial. In this study, dermal microdialysis was used in awake humans (n = 39) to deliver substance P (SP; 10(-7) and 10(-6)M) or calcitonin gene-related peptide (CGRP; 5 x 10(-7)M and 2 x 10(-6)M). Neuropeptide-induced local and axon reflex erythema was assessed by laser Doppler imaging. Total protein concentration in the dialysate was measured to quantify local protein extravasation. The responses were assessed in the absence and the presence of the nitric oxide synthase inhibitor, N-nitro-L-arginine-methyl ester (L-NAME) added to the perfusate at concentrations of 5, 10 or 20 mM. L-NAME (5 mM) applied via the dialysis catheters reduced local blood flow by approximately 30%. In addition, L-NAME inhibited SP-induced vasodilation by about 40% for 10(-7)M SP and 30% for 10(-6)M SP (n = 11, p < 0.01). In contrast, CGRP-induced vasodilation was only marginally inhibited by L-NAME. SP, but not CGRP, provoked a dose-dependent increase in protein extravasation. L-NAME (5 mM) inhibited this increase by up to 40% for both SP concentrations used (n = 11, p < 0.01). Higher concentrations of L-NAME did not further reduce SP- or CGRP-induced vasodilation or SP-induced protein extravasation. Exogenously applied SP induces vasodilation and protein extravasation, which is partly NO mediated, whereas CGRP-induced vasodilation appears to be NO independent.
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PMID:The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester on neuropeptide-induced vasodilation and protein extravasation in human skin. 1280 46

Rosacea is a chronic disorder characterized by hypersensitivity of the facial vasculature, presenting with intense flushing eventually leading to chronic erythema and telangiectasia. Although the precise aetiology of rosacea is not known, numerous associations with inflammatory gastrointestinal tract disorders have been reported. Furthermore, substance P-immunoreactive neurones occur in considerably greater numbers in tissue surrounding affected blood vessels suggesting involvement of neurogenic inflammation and moreover plasma kallikrein-kinin activation is consistently found in patients. In this report, a patient without digestive tract disease is described, who experienced complete remission of rosacea symptoms following ingestion of a material intended to sweep through the digestive tract and reduce transit time below 30 h. It is possible that intestinal bacteria are capable of plasma kallikrein-kinin activation and that flushing symptoms and the development of other characteristic features of rosacea result from frequent episodes of neurogenic inflammation caused by bradykinin-induced hypersensitization of facial afferent neurones. The possible relevance of this hypothesis to other conditions featuring afferent hypersensitivity, such as fibromyalgia, is considered.
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PMID:Remission of rosacea induced by reduction of gut transit time. 1511 15

In this study we aimed to assess in vivo, the vasodilator effects of adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP) and amylin in human skin vasculature and compare the responses to the effects mediated by the endogenous neuropeptides calcitonin gene-related peptide (CGRP) and substance P and to examine the mRNA expression of calcitonin receptor-like receptor (CL-R) and receptor-activity modifying proteins, RAMP1, RAMP 2 and RAMP3 in human subcutaneous arteries. Changes in skin blood flow of the forearm were measured using a Laser Doppler Imager after intradermal injection of the peptides. The mRNA expression was assessed by real-time reverse transcriptase-polymerase chain reaction (real-time PCR). CGRP, adrenomedullin and amylin induced concentration-dependent, long-lasting increases in skin blood flow. The response to PAMP was shorter in duration appearing similar to the transient response induced by substance P. PAMP (10(-6)-10(-5) M) caused distinct itch sensation and local erythema. This effect could be abolished when combining the histamine H1-receptor antagonist mepyramin and PAMP. Real-time PCR data showed a higher level of mRNA for RAMP2 than CL-R, RAMP1 and RAMP3 in the tissue. Though the PCR data demonstrated the presence of mRNA for both CGRP1 and adrenomedullin receptors the rank order of potency (CGRP>adrenomedullin>amylin) for the blood flow increase indicated vasodilatation for these peptides was induced by activation of CGRP1 receptors. Intradermal injection of CGRP, adrenomedullin and amylin induces long lasting dilatation of human skin vasculature by activation of CGRP1 receptors. PAMP induces transient vasodilatation. PAMP but not CGRP, adrenomedullin and amylin causes itch sensation and local erythema. The transient effect on vasodilatation as response to PAMP is discussed.
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PMID:The vasorelaxant effect of adrenomedullin, proadrenomedullin N-terminal 20 peptide and amylin in human skin. 1691 18

Capsicum-derived ingredients function as skin-conditioning agents--miscellaneous, external analgesics, flavoring agents, or fragrance components in cosmetics. These ingredients are used in 19 cosmetic products at concentrations as high as 5%. Cosmetic-grade material may be extracted using hexane, ethanol, or vegetable oil and contain the full range of phytocompounds that are found in the Capsicum annuum or Capsicum frutescens plant (aka red chiles), including Capsaicin. Aflatoxin and N-nitroso compounds (N-nitrosodimethylamine and N-nitrosopyrrolidine) have been detected as contaminants. The ultraviolet (UV) absorption spectrum for Capsicum Annuum Fruit Extract indicates a small peak at approximately 275 nm, and a gradual increase in absorbance, beginning at approximately 400 nm. Capsicum and paprika are generally recognized as safe by the U.S. Food and Drug Administration for use in food. Hexane, chloroform, and ethyl acetate extracts of Capsicum Frutescens Fruit at 200 mg/kg resulted in death of all mice. In a short-term inhalation toxicity study using rats, no difference was found between vehicle control and a 7% Capsicum Oleoresin solution. In a 4-week feeding study, red chilli (Capsicum annuum) in the diet at concentrations up to 10% was relatively nontoxic in groups of male mice. In an 8-week feeding study using rats, intestinal exfoliation, cytoplasmic fatty vacuolation and centrilobular necrosis of hepatocytes, and aggregation of lymphocytes in the portal areas were seen at 10% Capsicum Frutescens Fruit, but not 2%. Rats fed 0.5 g/kg day-1 crude Capsicum Fruit Extract for 60 days exhibited no significant gross pathology at necropsy, but slight hyperemia of the liver and reddening of the gastric mucosa were observed. Weanling rats fed basal diets supplemented with whole red pepper at concentrations up to 5.0% for up to 8 weeks had no pathology of the large intestines, livers, and kidneys, but destruction of the taste buds and keratinization and erosion of the gastrointestinal (GI) tract were noted in groups fed 0.5% to 5.0% red pepper. The results of 9-and 12-month extension of this study showed normal large intestines and kidneys. In rabbits fed Capsicum Annuum Powder at 5 mg/kg day-1 in the diet daily for 12 months damage to the liver and spleen was noted. A rabbit skin irritation test of Capsicum Annuum Fruit Extract at concentrations ranging from 0.1% to 1.0% produced no irritation, but Capsicum Frutescens Fruit Extract induced concentration-dependent (at 25 to 500 microg/ml) cytotoxicity in a human buccal mucosa fibroblast cell line. An ethanol extract of red chili was mutagenic in Salmonella typhimurium TA98, but not in TA100, or in Escherichia coli. Other genotoxicity assays gave a similar pattern of mixed results. Adenocarcinoma of the abdomen was observed in 7/20 mice fed 100 mg red chilies per day for 12 months; no tumors were seen in control animals. Neoplastic changes in the liver and intestinal tumors were observed in rats fed red chili powder at 80 mg/kg day-1 for 30 days, intestinal and colon tumors were seen in rats fed red chili powder and 1,2-dimethyl hydrazine, but no tumors were observed in controls. In another study in rats, however, red chile pepper in the diet at the same dose decreased the number of tumors seen with 1,2-dimethylhydrazine. Other feeding studies evaluated the effect of red chili peppers on the incidence of stomach tumors produced by N-methyl-N'-nitro-N-nitrosoguanidine, finding that red pepper had a promoting effect. Capsicum Frutescens Fruit Extract promoted the carcinogenic effect of methyl(acetoxymethyl)nitrosamine (carcinogen) or benzene hexachloride (hepatocarcinogen) in inbred male and female Balb/c mice dosed orally (tongue application). Clinical findings include symptoms of cough, sneezing, and runny nose in chili factory workers. Human respiratory responses to Capsicum Oleoresin spray include burning of the throat, wheezing, dry cough, shortness of breath, gagging, gasping, inability to breathe or speak, and, rarely, cyanosis, apnea, and respiratory arrest. A trade name mixture containing 1% to 5% Capsicum Frutescens Fruit Extract induced very slight erythema in 1 of 10 volunteers patch tested for 48 h. Capsicum Frutescens Fruit Extract at 0.025% in a repeated-insult patch test using 103 subjects resulted in no clinically meaningful irritation or allergic contact dermatitis. One epidemiological study indicated that chili pepper consumption may be a strong risk factor for gastric cancer in populations with high intakes of chili pepper; however, other studies did not find this association. Capsaicin functions as an external analgesic, a fragrance ingredient, and as a skin-conditioning agent--miscellaneous in cosmetic products, but is not in current use. Capsaicin is not generally recognized as safe and effective by the U.S. Food and Drug Administration for fever blister and cold sore treatment, but is considered to be safe and effective as an external analgesic counterirritant. Ingested Capsaicin is rapidly absorbed from the stomach and small intestine in animal studies. Subcutaneous injection of Capsaicin in rats resulted in a rise in the blood concentration, reaching a maximum at 5 h; the highest tissue concentrations were in the kidney and lowest in the liver. In vitro percutaneous absorption of Capsaicin has been demonstrated in human, rat, mouse, rabbit, and pig skin. Enhancement of the skin permeation of naproxen (nonsteroidal anti-inflammatory agent) in the presence of Capsaicin has also been demonstrated. Pharmacological and physiological studies demonstrated that Capsaicin, which contains a vanillyl moiety, produces its sensory effects by activating a Ca2 +-permeable ion channel on sensory neurons. Capsaicin is a known activator of vanilloid receptor 1. Capsaicin-induced stimulation of prostaglandin biosynthesis has been shown using bull seminal vesicles and rheumatoid arthritis synoviocytes. Capsaicin inhibits protein synthesis in Vero kidney cells and human neuroblastoma SHSY-5Y cells in vitro, and inhibits growth of E. coli, Pseudomonas solanacearum, and Bacillus subtilis bacterial cultures, but not Saccharomyces cerevisiae. Oral LD50 values as low as 161.2 mg/kg (rats) and 118.8 mg/kg (mice) have been reported for Capsaicin in acute oral toxicity studies, with hemorrhage of the gastric fundus observed in some of the animals that died. Intravenous, intraperitoneal, and subcutaneous LD50 values were lower. In subchronic oral toxicity studies using mice, Capsaicin produced statistically significant differences in the growth rate and liver/body weight increases. Capsaicin is an ocular irritant in mice, rats, and rabbits. Dose-related edema was observed in animals receiving Capsaicin injections into the hindpaw (rats) or application to the ear (mice). In guinea pigs, dinitrochlorobenzene contact dermatitis was enhanced in the presence of Capsaicin, injected subcutaneously, whereas dermal application inhibited sensitization in mice. Immune system effects have been observed in neonatal rats injected subcutaneously with Capsaicin. Capsaicin produced mixed results in S. typhimurium micronucleus and sister-chromatid exchange genotoxicity assays. Positive results for Capsaicin were reported in DNA damage assays. Carcinogenic, cocarcinogenic, anticarcinogenic, antitumorigenic, tumor promotion, and anti-tumor promotion effects of Capsaicin have been reported in animal studies. Except for a significant reduction in crown-rump length in day 18 rats injected subcutaneously with Capsaicin (50 mg/kg) on gestation days 14, 16, 18, or 20, no reproductive or developmental toxicity was noted. In pregnant mice dosed subcutaneously with Capsaicin, depletion of substance P in the spinal cord and peripheral nerves of pregnant females and fetuses was noted. In clinical tests, nerve degeneration of intracutaneous nerve fibers and a decrease in pain sensation induced by heat and mechanical stimuli were evident in subjects injected intradermally with Capsaicin. An increase in mean inspiratory flow was reported for eight normal subjects who inhaled nebulized 10(-7) M Capsaicin. The results of provocative and predictive tests involving human subjects indicated that Capsaicin is a skin irritant. Overall, studies suggested that these ingredients can be irritating at low concentrations. Although the genotoxicity, carcinogenicity, and tumor promotion potential of Capsaicin have been demonstrated, so have opposite effects. Skin irritation and other tumor-promoting effects of Capsaicin appear to be mediated through interaction with the same vanilloid receptor. Given this mechanism of action and the observation that many tumor promoters are irritating to the skin, the Panel considered it likely that a potent tumor promoter may also be a moderate to severe skin irritant. Thus, a limitation on Capsaicin content that would significantly reduce its skin irritation potential is expected to, in effect, lessen any concerns relating to tumor promotion potential. Because Capsaicin enhanced the penetration of an anti-inflammatory agent through human skin, the Panel recommends that care should be exercised in using ingredients that contain Capsaicin in cosmetic products. The Panel advised industry that the total polychlorinated biphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and agreed on the following limitations for other impurities: arsenic (3 mg/kg max), heavy metals (0.002% max), and lead (5 mg/kg max). Industry was also advised that aflatoxin should not be present in these ingredients (the Panel adopted < or =15 ppb as corresponding to "negative" aflatoxin content), and that ingredients derived from Capsicum annuum and Capsicum Frutescens Plant species should not be used in products where N-nitroso compounds may be formed. (ABSTRACT TRUNCATED)
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PMID:Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin. 1736 37

5% lidocaine medicated plasters are available for local treatment of neuropathic pain. Treatment is generally poorly effective but has few adverse effects, other than local erythema. Capsaicin is a natural chilli pepper extract that depletes sensory nerve endings of substance P, a pain neurotransmitter. It is authorised in the European Union for the treatment of nondiabetic neuropathic pain, in the form of cutaneous patches containing 8% capsaicin. Clinical evaluation of capsaicin patches does not include any trials versus lidocaine plasters. Eight double-blind trials have compared 8% capsaicin patches versus 0.04% capsaicin patches, 5 in postherpetic neuralgia, and 3 in HIV-related neuropathic pain. These trials are only vaguely described in the European Medicines Agency report. Taken separately, they yielded divergent results. It was only when some of the trials were pooled for analysis that any differences emerged between the two doses of capsaicin. The clinical implications are unclear, but efficacy is at best modest. Capsaicin is an irritant that frequently provokes pain and erythema at the site of patch application, and 3% of patients using the patches experienced transient arterial hypertension that the investigators attributed to this pain. Some pharmacological data suggest that repeated application of 8% capsaicin patches might provoke painful nerve damage in the long-term. Patch application and removal by a third party is delicate, due to the strong irritant potential of capsaicin. In practice, when a patient with neuropathic pain requires local treatment, in the absence of a better alternative, it is better to use lidocaine plasters, which are better tolerated and with which we have more experience.
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PMID:Capsaicin. Neuropathic pain: playing with fire.... 2093 41


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