A quantitative comparison of the effect of local analgesics on argon laser induced cutaneous pain and on histamine induced wheal, flare and itch

A quantitative comparison was made of the effect of infiltration of local analgesics and topical analgesic cream (EMLA) on laser-induced pain and histamine-induced wheal, flare and itch. Wheal and flare were quantified by planimetry and analgesia was quantified by the pricking pain threshold to argon laser stimulation. The intensity of histamine-induced itch was scored on a 4-point scale. Local analgesics had no effect on the wheal area. The flare reaction was abolished by infiltrating lignocaine, and gradually inhibited by increased application times of EMLA. Itch was abolished after local lignocaine infiltration, but not significantly reduced after EMLA cream applied for less than 120 min, although the skin was anaesthetized to laser-induced pain. The reduction of flare area correlated to the level of analgesia, which may therefore reflect the cutaneous responsiveness to neurogenic inflammation. It is suggested that itch and pricking pain are mediated by different populations of nerve fibres, as itch can be evoked even when the sensation of pricking pain is abolished. Surgery, skin prick tests and other traumatic procedures should therefore be performed under local anaesthesia to reduce neurogenic inflammation.     

Topically applied aspirin decreases histamine-induced wheal and flare reactions in normal and SLS-inflamed skin,but does not decrease itch. A randomized,double-blind and placebo-controlled human study

Topically applied aspirin has recently been reported to decrease histamine-induced itch in human volunteers. Our aim is to confirm this and to study the antipruritic ability of topical aspirin in inflamed skin. In 24 non-atopic volunteers, an inflammatory skin reaction was induced in forearm skin at 5 different sites by sodium lauryl sulphate contained in Finn Chambers. Aspirin 10%, aspirin 1%, mepyramine 5% and vehicle were applied to the inflamed and corresponding non-inflamed areas 20 min before itch induction with intradermal histamine injection. Itch and pain were scored on a visual analogue scale at regular intervals. Wheal and flare areas were measured. No difference in itch intensities was found after application of aspirin, mepyramine and vehicle, but more itch was induced in aspirin and mepyramine pretreated sites in inflamed skin compared to normal skin (p<0.05). In normal skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.05) and mepyramine (p<0.001), as were wheal areas after mepyramine (p<0.01), compared to vehicle pretreatments. In inflamed skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.01) and mepyramine (p<0.001), as were wheal areas after aspirin 10% (p<0.01), aspirin 1% (p<0.05) and mepyramine (p<0.001). We conclude that despite a significant skin penetration as measured by the influence on wheal and flare reactions, topically applied aspirin did not decrease histamine-induced itch in the model used.     

Patients with bone marrow failure demonstrate decreased cutaneous reactivity to human C5a

In vivo studies have shown that human C5a, a potent complement-derived anaphylatoxin and chemoattractant, produces immediate inflammatory reactions following intradermal injection in human skin. At concentrations within its potential physiologic range, intradermal injection of C5a elicits immediate wheal and flare reactions, increased vascular permeability, mast cell degranulation, and neutrophil-rich infiltrates. To assess the relative contribution of interacting cellular elements to C5a-induced inflammation in normal human skin, purified human C5a was tested intradermally in 8 patients with bone marrow failure (BMF). Reactions to C5a in patients with BMF were compared with responses at identical test sites in healthy volunteers and other patients with cutaneous disorders. Patients with BMF demonstrated significantly less wheal and flare reactivity following intradermal injection of C5a than controls (p less than 0.05 and less than 0.02, respectively). In these studies, patients with the greatest cytopenia generally showed the least cutaneous reactivity to human C5a. Biopsies of C5a test sites in patients with BMF revealed an absence of leukocytes in marked contrast to neutrophil-rich infiltrates observed at test sites in healthy volunteers. Avidin-fluorescent and/or Giemsa staining of skin biopsies revealed no difference between the number of dermal mast cells in patients with BMF and samples of normal human skin. In addition, skin test studies with histamine (2 micrograms) and morphine (5 micrograms) performed to assess cutaneous vascular and mast cell responsiveness in patients with BMF, normal volunteers and controls with rhinitis revealed no significant differences in cutaneous reactivity to these pharmacologic agents. These in vivo studies demonstrate that patients with BMF specifically exhibit decreased cutaneous reactivity to human C5a and suggest that neutrophils make an important and an immediate contribution to inflammatory responses elicited by this anaphylatoxin.     

Methotrexate inhibits the human C5a-induced skin response in patients with psoriasis

In this study we examined the effects of intradermal injections of human complement split product C5a in 10 patients with psoriasis in long-term treatment with methotrexate (MTX). The C5a was injected at the end of the weekly MTX cycle just before the intake of the first MTX dose and 3 h after the second of the 3 doses. The C5a-induced skin response was evaluated by measuring the diameter of the wheal and the area of the flare and by erythema index (EI), which was determined objectively by reflectance spectrophotometry. In all patients the skin response was significantly depressed when C5a was injected after MTX intake. The decrease of wheal, flare, and EI averaged 61.6%, 71.1%, and 57.5%, respectively, when all parameters were obtained at maximal skin response. The in vitro chemotaxis of peripheral blood neutrophils and monocytes from the patients toward C5a was markedly inhibited after intake of MTX (p less than 0.01). The skin biopsies obtained after C5a injection before intake of MTX revealed a perivascular inflammatory infiltrate and considerable dermal edema. After MTX intake the number of infiltrating leukocytes and the degree of dermal edema was markedly reduced. This study indicates that MTX is a potent inhibitor of C5a-induced skin inflammation, and that this inhibition may be caused by a direct effect on circulating neutrophils and monocytes. The results obtained in this work support the idea that anti-inflammatory effects of MTX may be partially responsible for its antipsoriatic effect.     

Histamine is released following aminolevulinic acid-photodynamic therapy of human skin and mediates an aminolevulinic acid dose-related immediate inflammatory response

Acute skin inflammation occurs following topical aminolevulinic acid-photodynamic therapy (ALA-PDT), but its nature and mediation are ill defined. As we observed an urticarial response, a potential role for histamine was explored. In 13 healthy volunteers, we assessed the time course and dose-response of the acute cutaneous response(s) to ALA-PDT, the impact of H(1) antihistamine blockade, and measured dermal histamine release. An ALA dose series was iontophoresed into ventral forearm skin and exposed to red light. All participants exhibited an immediate urticarial response, both wheal and flare correlating with log ALA dose. Subsequently, a dose-related erythema developed at treatment sites by 3 hours and persisted at 24 hours. H(1) blockade with oral cetirizine doubled the median minimal urticating dose of ALA and reduced the slope of dose-response for wheal and flare, whereas at the highest ALA dose, mean wheal and flare areas reduced by 68 and 60%, respectively. In contrast, cetirizine did not influence the 24 hour minimal phototoxic dose or erythema dose-response. Histamine release after ALA-PDT mirrored the urticarial response, levels peaking within 30 minutes and returning to baseline by 24 hours. Thus, two discrete acute inflammatory responses to topical ALA-PDT occur in human skin; histamine mediates the immediate response, but does not appear involved in the delayed phototoxicity.     

花生四烯酸人体皮肤炎症模型

目的　建立花生四烯酸 (arachidonicacid ,AA)人体皮肤炎症模型。方法　在健康志愿者前臂屈侧做0 .0 3 %AA、0 .16%AA、0 .8%AA、4%AA、2 0 %AA、40 %AA浓度的点刺试验 ,分别记录其 3 0min红斑面积、风团面积。结果　点刺AA后 5min左右即可产生红斑、风团 ,大约 3 0min产生最大红斑与风团 (个别在 3 0～ 60min达最高峰 ) ,2～ 4h后消退(个别在 6h后消退 )。炎症模型中以 2 0 %AA产生的红斑、风团表现较为稳定。结论　通过点刺试验可建立稳定的AA人体皮肤炎症模型。     

Reactions to intradermally injected substance P and topically applied mustard oil in atopic dermatitis patients.

Skin reactions and itch or burning pain sensations following intradermal injection of the neuropeptide substance P and topical application of the substance P releasing agent mustard oil were studied in 20 atopic dermatitis patients and 20 healthy controls. Changes in skin blood flow were measured with a Laser Doppler flowmeter. Areas of wheal and flare reactions were evaluated planimetrically. Simultaneous with Laser Doppler flowmeter measurements, subjective itch and burning pain ratings were verbally reported on a category partitioning scale at 10-second intervals. Substance P evoked dose-dependent wheal, flare, and itch reactions in both patients and controls. However, substance P doses of 10(-9) -10(-11) mol elicited smaller flares in patients than in the controls whereas the wheal sizes were similar in both groups. Substance P-induced itch ratings were lower in patients at a dose of 10(-10) mol, and the onset of itching was delayed at all substance P levels applied. Mustard oil elicited similar neurogenic inflammatory reactions in both groups, although pain sensations were significantly delayed in atopic dermatitis patients at two mustard oil concentrations, which is further indication of a desensitization of afferent nerve endings contributing to the neurogenic inflammatory reactions in the skin of these patients.     

Doxepin affects acetylcholine induced cutaneous reactions in atopic eczema

BACKGROUND: Atopic eczema (AE) is a chronic inflammatory skin disease with strong itching as the prominent symptom. The pathology of itch is still in discussion, but acetylcholine (ACH) seems to be a relevant pruritogenic mediator in AE. Since efficient benefit on pruritus and excoriations has been demonstrated with tricyclic agents, we investigated how the topical treatment with doxepin (5%, Boehringer Standard, Mannheim, Germany), a tricyclic compound with anticholinergic properties, may influence ACH induced itch and cutaneous sensations (erythema, wheal, axonreflex flare). METHODS: Eleven patients with AE were included in this double blind study. For 3 days we applied doxepin cream to a defined area on the volar forearm and basic ointment to the other side 4 times daily. On day 4, ACH and sodium chloride were i.c. injected into the pretreated arms. Vasoreactions and cutaneous sensations were measured similar to studies described in previous publications from our group. RESULTS: Doxepin treatment over 3 days reduced ACH provoked flare size more than 53% (P<0.005) and wheal size about 48% (P<0.005) whereas the maximal antipruritic effect was similiar to the basic therapy. The itch intensity, which is expressed as the mean AUC value, was rated at 6.12 arbitrary units after the neutral cream application and 5.9 arbitrary units after doxepin. CONCLUSIONS: The clinical and experimental effectiveness of doxepin as an antipruritic drug has been known for years. However, studies focusing on ACH as a pruritogenic mediator have not been performed. The duration of the doxepin application in our study seems to be appropriate since flare and wheal development were diminished. The reason why doxepin did not develop more antipruritic action compared to the vehicle cream may be due to the fact that the doxepin free cream already possessed an antipruritic action in this experimental study design. This is probably caused by rehydrating and moisturizing effects.     

Skin irritation typing and grading based on laser Doppler perfusion imaging

Background/aims: Vasodilation with increased cutaneous perfusion is an essential part of an irritant inflammatory response. The aim of the present study was to investigate the usefulness of the high-resolution laser Doppler perfusion imaging (HR-LDPI) technique for investigating irritant skin reactions. Irritants may elicit clinically different reactions due to different skin penetration profiles and different modes of irritant action on the exposed tissue.
Methods: Twelve subjects were tested on the forearms using 24 h occlusive application of three concentrations of the irritants sodium lauryl sulphate (SLS) and nonanoic acid (NON) and with the topical acne drug all-trans retinoic acid (RA). Cutaneous blood flow at baseline, the increase in cutaneous blood flow and the skin area having increased perfusion were measured on day 2, day 3 and day 5.
Results: Based both on measurement of mean perfusion and area with increased perfusion, it was possible to differentiate between different clinical irritation grades on any study day. The area with increased perfusion exceeded the area with clinically visible skin reactions for irritant reactions of grade ¹/₂ and above. Irritant reactions for individual irritants could furthermore be typed using HR-LDPI. It was possible to differentiate between vehicle treatment and the different dose levels of the irritant compounds. A correlation was found between clinical scores for the individual irritants and the mean flow and the area with increased flow. The individual irritants could be differentiated due to different time courses of their skin irritation.
Conclusion: Laser Doppler imaging was found to be an important new method for characterization and grading of the inflammatory response of single exposure irritant reactions. However, standardised study procedures cannot be emphasised enough in order to obtain reliable and useful data.     

Skin reactions and itch sensation induced by epicutaneous histamine application in atopic dermatitis and controls

Itch sensations and skin reactions induced by histamine iontophoresis at six different current intensities were studied in 27 atopic dermatitis (AD) patients and 20 healthy controls. Subjective itch ratings were assessed on a visual analogue scale (VAS) for 8-min periods after 10-sec histamine application, while changes of skin blood flow were simultaneously measured using two Laser Doppler flowmeters. Ten minutes after each histamine application, the areas of wheal and flare reactions were planimetrically evaluated. When no or weak current was applied, AD patients revealed stronger wheal and flare reactions than controls, possibly due to disturbed skin barrier function. Higher histamine doses, however, produced weaker subjective and vascular reactions in AD patients. In contrast to the controls, AD patients were unable to distinguish between weak and strong histamine stimulation, as shown by their VAS ratings. These results imply that AD patients have an altered histamine response. In particular, their afferent cutaneous nerve fibers show a decreased ability to signal itching to the central nervous system and to release vasoactive neuropeptides upon histamine stimulation.     

息斯敏和息斯敏联合雷尼替丁对组胺诱导人皮肤反应强度的比较

目的探讨组胺Ｈ１和Ｈ２受体拮抗剂联合使用治疗Ⅰ型过敏性疾病的可行性。方法对三组志愿者（每组１２人）分别服用息斯敏１０ｍｇ,１次／ｄ;息斯敏１０ｍｇ和雷尼替丁３００ｍｇ,各１次／ｄ,息斯敏１０ｍｇ,１次／ｄ和雷尼替丁３００ｍｇ,每１２ｈ１次。５天后停雷尼替丁,继续服用息斯敏２天。第１～５天,每日比较服药前和服药后第３ｈ、第６ｈ组胺（１００μｇ）诱导即刻型皮肤（风团和红晕）的反应强度（％）。第８天组胺皮试重复１次。结果息斯敏１０ｍｇ,１次／ｄ和雷尼替丁３００ｍｇ,每１２ｈ１次组对组胺诱导皮肤风团和红晕的反应强度在各个时间点均明显低于息斯敏１０ｍｇ,１次／ｄ组,统计学处理除第２次服药前风团强度无显著性差异外（Ｐ＞０．０５）,其它各时间点均有显著性差异（Ｐ＜０．０１或＜０．０５）。结论息斯敏联合雷尼替丁与息斯敏单独使用相比,明显加快和加强组胺诱导皮肤反应抑制作用,该方案为临床治疗Ⅰ型过敏反应性疾病提供了可行性依据。     

Exogenous topical lactoferrin inhibits allergen-induced Langerhans cell migration and cutaneous inflammation in humans

BACKGROUND: Lactoferrin (LF), an iron-binding protein found in exocrine secretions, is known to possess antibacterial properties. It has recently been proposed that LF may also influence inflammatory reactions. OBJECTIVES: To characterize in humans the ability of recombinant homologous LF to inhibit the induced migration of epidermal Langerhans cells (LCs) from the skin, a process known to be dependent upon the proinflammatory cytokines tumour necrosis factor (TNF)-alpha and interleukin 1beta and to influence cutaneous inflammatory reactions. METHODS: We investigated the anti-inflammatory properties of LF in human volunteers. RESULTS: Topical exposure to LF 2 h prior to sensitization caused a significant reduction in contact allergen (diphenylcyclopropenone, DPC)-induced LC migration from the epidermis as judged by the altered frequency of cells expressing either HLA-DR or CD1a determinants. That this reduction was secondary to an inhibition of TNF-alpha production was indicated by the fact that LF failed to influence LC migration induced by intradermal injection of this cytokine. In approximately 50% of those volunteers who displayed local inflammation in response to DPC, LF was found to cause a discernible reduction in the clinical severity of the reaction, associated with reduced infiltration of inflammatory cells. CONCLUSIONS: These data demonstrate that LF is able to influence cutaneous immune and inflammatory responses, possibly because of an impaired production of local proinflammatory cytokines.     

Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.     

Correlations between histamine-induced wheal,flare and itch

Correlations between the skin reactions wheal and flare and the subjectively reported degree of itch were investigated in response to 1% histamine, intradermally applied by standardized skin prick and by iontophoresis. Experiments were performed with 15 male volunteers using a threefold repeated measures design (skin prick, and iontophoresis with 0.13 mA for 10 s and with 2.0 mA for 10 s). Skin reactions (perpendicular diameters) were determined at the time of their maximum (10 min). Itch was rated on a computerized visual analogue scale which was anchored upon the individual scratch threshold. Most effective in producing itch was the skin prick which caused strong sensations markedly above the scratch threshold during the entire period of measurement (30 min), whereas iontophoresis induced only transient itch sensations. On the other hand, the largest wheals were generated by iontophoresis of both intensities (mean 10 or 14 mm vs 6 mm with skin prick). The higher current induced higher itch, wheal and flare responses, but after eliminating this effect of stimulus intensity, no correlations were found. In contrast, skin prick-induced flare reactions varied with the degree of itch above the scratch threshold ( r = 0.56; P < 0.01). Repeated measurements showed a higher stability for the itch reaction with skin prick compared with iontophoresis. It is hypothesized that in iontophoresis the brief (10-s) histamine bolus passed the most superficial pruritoceptive C fibres too quickly to induce long-lasting itch sensations, whereas the skin prick caused a deposit at the dermal-epidermal junction releasing histamine during the entire time of measurement. Consequently, both the C fibre-mediated itch and the axon reflex flare were more pronounced with the skin prick, and the wheal resulting from a permeability increase in the postcapillary venule walls was an independent phenomenon. Received: 21 June 1995     

Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions

The subjective sensation of itch is a complex emotional experience depending on a variety of factors. In this study, the central nervous processing of pruritus was investigated in a human model. Activation of involved cerebral areas was correlated to scales of nociception and skin reactions. Six healthy male right-handed subjects participated in a standardized epidermal stimulus model with nine increasing doses of histamine dihydrochloride (0.03%-8%) on their right forearms. Controls consisted of three NaCl stimuli. Cerebral activation patterns were determined by H(2)(15)O positron emission tomography 120 s after stimulation. Dermal reactions to the stimulus (wheal, flare, temperature) were coregistered during the procedure. Itch sensation was determined by visual analog scale rating. Pain was not reported during the study; all volunteers had localized itch from 0.03% histamine on. Subtraction analysis versus control revealed significant activation of the left primary sensory cortex and motor-associated areas (mainly primary motor cortex, supplementary motor area, premotor cortex). Predominantly left-sided activations of frontal, orbitofrontal, and superior temporal cortex and anterior cingulate were also observed. Correlation analysis revealed coactivation of dermal reactions and cerebral response to itch in the following Brodmann areas with a Z score greater than 5: wheal, areas 5 (bilateral) and 19 (right); flare, areas 2-5 (left); temperature, area 10 (left) and left insula. Itch intensity ratings were mainly correlated with activation of the left sensory and motor areas. Functional covariates of the itch sensation in the central nervous system were identified. The intention to pruritofensive movements is probably mirrored by the activation of motor areas in the cortex. Other areas may be involved in emotional processing of sensations. Skin reactions wheal and flare also had significantly activated covariate areas in the central nervous system.J Invest Dermatol 115:1029-1033 2000     

Effects of local corticosteroids on acute experimental urticaria

Corticosteroids are often used in the treatment of acute or chronic urticaria. However, their effects on mastocyte activation as well as on the histamine-induced dermal oedema remain poorly investigated. The aim of the present study was to investigate the effects of corticosteroids (CS) on the development of acute experimental urticaria induced by prick-tests with histamine and codeine. This experimental model corresponds to the common form of urticaria. CS were administered at the site of the histamine and codeine prick tests in order to test for a direct effect on the development of acute urticaria. Two types of experiments were performed: 1) after a 48-hour period of topical CS application on the forearm, 7 healthy volunteers were skin prick-tested with histamine and codeine simultaneously in duplicate, one series in the pretreated area and the other in a non-treated area. 2) six other volunteers were prick-tested with histamine and codeine on their forearm, in duplicate. Immediately after testing, intradermal methyprednisolone was injected at the site of the prick-tests in the last series. Skin wheal and flare responses were measured after 20 mns and statistically compared with and without CS treatment. Whereas short-term CS topical application did not appear to modify cutaneous reactivity to histamine and codeine, local CS injection was associated with a significant increase in the flare induced by histamine and codeine (respectively + 18 +/- 3% and + 38 +/- 3%; P = 0.05). The wheal tended to be increased after injected CS. In conclusion, these results show that CS are neither able to prevent nor to improve experimental urticaria, i.e. wheal and flare, and even increase the histamine and codeine-induced erythema. That a similar result could apply to patients with chronic urticaria and with systemic CS remains to be studied.     

Minocycline modulation of alpha-MSH production by keratinocytes in vitro.

The anti-inflammatory mechanisms of minocycline, an antibiotic used in the treatment of the inflammatory component of acne, are only partially understood. In addition to inflammation due to cytokines (IL-1, IL-6, TNF-alpha, etc.), recent studies have shown that neuropeptide-mediated neurogenic inflammation may play an important role in cutaneous inflammation. The purpose of this study was to investigate minocycline-induced modulation of cutaneous production of alpha-melanocyte-stimulating hormone (alpha-MSH), a neuropeptide with known anti-inflammatory activity. Two different skin models were used: explants of inflammatory skin and reconstituted skin, both incubated with minocycline at different concentrations and for different time periods. Epidermal production of alpha-MSH, as evaluated by immunofluorescence and immunoperoxidase techniques, showed increased expression in both models. This neuropeptide, which has an anti-inflammatory activity (notably through production of IL-10, antagonism of IL-1 and inhibition of the chemotaxis of polymorphonuclear leukocytes), thus plays a role in the anti-inflammatory action of minocycline.     

Inflammatory skin responses induced by icatibant injection are mast cell mediated and attenuated by H(1)-antihistamines

Icatibant, a bradykinin-2 receptor antagonist, is administered by subcutaneous injection for the treatment of attacks of type I and type II hereditary angioedema. Following injection, patients feel transient pain followed by a short-lived wheal and flare response at the injection site. We hypothesized that the icatibant-induced wheal and flare response follows histamine release from activated skin mast cells and would therefore be reduced by an H(1)-antihistamine. Intradermal injection of 100 μl of 100 μg/ml histamine and 10 mg/ml icatibant into the forearms of health volunteers caused wheal and flare responses of a similar magnitude which were reduced by cetirizine pretreatment by 49% and 41% (histamine) and 35% and 41% (icatibant). Studies in vitro showed that icatibant at 1 × 10(-4) and 1 × 10(-5) M caused significant (P < 0.05) histamine release from isolated human cutaneous mast cells. In conclusion, icatibant induces histamine-mediated wheal and flare responses that may be reduced in severity by prophylactic administration of an H(1)-antihistamine.     

Regulation of wheal and flare by tea tree oil: complementary human and rodent studies

When applied 20 min after injection of histamine into human forearm skin, tea tree oil (TTO) reduces the developing cutaneous vascular response. In this study, the effect of TTO on inflammatory microvascular changes was dissected at the base of an experimental blister on rat skin. 1,8-Cineole, representing 2% of TTO, reduced vascular changes induced by sensory neuropeptides released when the distal portion of a cut sciatic nerve was electrically stimulated. The pre-terminal modulatory effect of 1,8-Cineole was confirmed in tests in sensory-denervated rats. Terpinen-4-ol (approximately 40% TTO) reduced substance P-induced microvascular changes and protein extravasation by a direct nitric oxide-mediated effect on the microvasculature, without sensory nerve involvement. alpha-Terpineol (3% of TTO) regulated both pre- and post-sensory nerve terminals. In human skin, terpinen-4-ol applied 10 min after histamine injection, but not alpha-terpineol or 1,8-cineole, regulated the developing wheal and flare suggesting that the histamine-induced responses in humans (at the dose used in this study, 50 microL of 330 microM histamine) are in large part determined by histamine directly affecting the vasculature via post-terminal-mediated events. The underlying strength of these studies is the use of a well-established rat physiologic model to differentiate the mechanism of regulation of microvascular changes by modulatory agents.     

The effect of capsaicin on some experimental inflammations in human skin

Topical application of capsaicin is thought to deplete substance P from local sensory nerve terminals. In experiments on human skin inflammation was induced by injection of substance P (SP) or histamine intradermally, UV irradiation, non-immunologic contact urticaria, tuberculin reaction, contact allergens and benzalkonium chloride with or without capsaicin pretreatment. The flare response to SP and histamine was suppressed by capsaicin pretreatment whereas the wheal was enlarged. Interestingly, capsaicin pretreatment enhanced the responses to all other inflammatory agents.