prostaglandin-d2 and Pruritus

Itching, or pruritus, can be defined as an unpleasant sensation that evokes the desire to scratch. Pruritus is most commonly associated with a primary skin disorder such as atopic dermatitis (AD), psoriasis, etc., and can have a major impact on the quality of life of those patients. Itch-induced scratching can further damage the skin barrier, leading to a worsening of symptoms. For that reason, it is important to manage pruritus. Topical glucocorticoids are commonly the first-line therapy in the management of AD and psoriasis patients. We found that topical glucocorticoids induce pruritus in mice under certain conditions. Topical glucocorticoids may induce pruritus in a mouse model of allergic contact dermatitis via inhibition of prostaglandin (PG)D

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Disease Models, Animal; Glucocorticoids; Humans; Mast Cells; Mice; Patient Education as Topic; Pharmacists; Professional Role; Prostaglandin D2; Pruritus; Psoriasis; Skin

Topics: Animals; Behavior, Animal; Dermatitis, Atopic; Drug Design; Mice; Prostaglandin D2; Pruritus; Receptors, Prostaglandin

The effects of topically applied prostaglandin (PG) D2 and BW245C, a potent PGD2 agonist, on intraocular pressure (IOP) were studied in normotensive human volunteers. Doses of 5 and 10 micrograms PGD2 induced a mean reduction in IOP of 0.8 and 1 mmHg, respectively. At a dose of 50 micrograms, hypotension was preceded by initial hypertension (4 mmHg at 0.5 h) and the magnitude of the mean IOP reduction during the hypotensive phase was 1.1 mmHg. The application of BW245C (2.5 micrograms) induced an IOP change similar to that observed following treatment with 50 micrograms PGD2. Side effects caused by these compounds included conjunctival hyperemia, itching, and foreign-body and mild burning sensations. However, miosis and signs of intraocular inflammation were not observed. These results indicate that although PGD2 and BW245C are effective in reducing human IOP, their clinical usefulness as anti-glaucoma drugs may be limited by the extraocular side effects.

Topics: Administration, Topical; Adult; Conjunctiva; Double-Blind Method; Female; Humans; Hydantoins; Hyperemia; Intraocular Pressure; Male; Prostaglandin D2; Pruritus; Tonometry, Ocular

Rebound is known to occur most typically when topical glucocorticoids are abruptly discontinued; however, its frequency and severity are poorly characterized. We previously created a novel murine model of topical glucocorticoid-induced pruritus; however, the mechanism underlying pruritus in this model has not been elucidated. Using this murine model, we aimed to determine the cause of augmentation of pruritus with a focus on the production of prostaglandin (PG) D(2). BALB/c mice with chronic allergic contact dermatitis induced by 5 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were treated topically with dexamethasone for 5 weeks immediately after the elicitation of dermatitis and after ear-swelling and scratching behavior were measured. RBL-2H3 mast cells were used to investigate the effect of dexamethasone on degranulation or PGD(2) production in IgE/antigen-stimulated mast cells. The scratching behavior induced by TNCB was augmented by topical application of dexamethasone, but dexamethasone did not have any effect on scratching bouts in mice that had not been treated with TNCB. Topical dexamethasone reduced the PGD(2) level, which increase in TNCB-treated mice, to the baseline level. Moreover, dexamethasone significantly decreased the PGD(2) production in IgE/antigen-stimulated RBL-2H3 mast cells; however, the same concentration of dexamethasone did not have any effect on the degranulation of stimulated mast cells. Topical glucocorticoids may exacerbate pruritus in a mouse model of allergic contact dermatitis via inhibition of PGD(2) production in antigen-mediated activated mast cells in the skin.

Topics: Administration, Topical; Animals; Dermatitis, Allergic Contact; Dexamethasone; Disease Models, Animal; Disease Progression; Female; Glucocorticoids; Mast Cells; Mice; Mice, Inbred BALB C; Picryl Chloride; Prostaglandin D2; Pruritus

Prostaglandin D(2) (PGD(2)) is known to have antipruritic activity by suppressing histamine release. However, agents that can topically induce PGD(2) for itch relief are not well established. The antimycotic sertaconazole nitrate (STZ) has been shown to exhibit anti-itch properties; however, the mechanism for this activity has not been elucidated. STZ mitigated degranulation of RBL-2H3 (rat basophilic leukemia) mast cells induced by compound 48/80, a pruritogenic agent known to promote the release of histamine, and augmented PGD(2) production in mast cells and macrophages. Addition of exogenous PGD(2) abrogated compound 48/80-induced degranulation by acting through the prostanoid D receptor 1 (DP1). STZ induced p38 mitogen-activated protein kinase (MAPK) phosphorylation in mast cells and a pharmacological inhibitor of p38 MAPK, SB203580, resulted in the attenuation of PGD(2) levels. Finally, in a murine model of pruritus, the scratching behavior induced by compound 48/80 was mitigated by topical application of STZ. This effect was reversed by the addition of the cyclooxygenase inhibitor, ibuprofen, or a DP1 receptor antagonist (MK0524). Collectively, these results suggest that STZ mediates its anti-itch effects by boosting the antipruritic agent, PGD(2), by the activation of the p38-MAPK pathway. This is the first report to demonstrate a promising approach to topically induce PGD(2) for improving pruritus.

Topics: Administration, Topical; Animals; Antifungal Agents; Cell Degranulation; Cell Line; Drug Interactions; Histamine; Imidazoles; Indoles; Macrophages; Mast Cells; Mice; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; p38 Mitogen-Activated Protein Kinases; Prostaglandin D2; Pruritus; Rats; Receptors, Prostaglandin; Thiophenes

TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio} acetic acid monohydrate, inhibits ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of prostaglandin D(2) by the prostanoid DP(1) receptor antagonist (BW A868C). TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for patients with atopic dermatitis. We examined the effects of TS-022 on experimental pruritus, cutaneous barrier disruption, and atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by BW A868C. Tacrolimus (FK-506) and dexamethasone, used as reference drugs for atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this drug was also significantly antagonized by BW A868C. FK-506 and dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of FK-506 once a day for 6 weeks significantly improved the skin inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against concanavalin A-induced cytokine production by splenocytes was marginal as compared with that of FK-506 or dexamethasone. These results suggest that the beneficial therapeutic effects of TS-022 in NC/Nga mice with atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its prostanoid DP(1) receptor agonistic activity.

Topics: Acetates; Animals; Antipruritics; Concanavalin A; Cyclohexanes; Cytokines; Dermatitis, Atopic; Dexamethasone; Humans; Hydantoins; Immunosuppressive Agents; Inflammation; Male; Mice; Platelet Aggregation; Prostaglandin D2; Pruritus; Receptors, Immunologic; Receptors, Prostaglandin; Skin; Sulfhydryl Compounds; Tacrolimus; Wound Healing

In atopic dermatitis, scratching of the skin as a reaction to itching causes injury to the skin, which, in turn, further increases the itching resulting in the establishment of the so-called itch-scratch circle. We have shown that prostaglandin (PG) D2 plays an inhibitory role against pruritus in mice with atopic-like dermatitis; therefore, we examined the relationship between scratching and the cutaneous PGD2 level using an artificial scratching model with a wire brush. Mechanical scratching induced a temporary increase of the skin PGs levels (PGE2, PGD2, 6-ketoPGF1alpha, PGF2alpha). The skin PGD2 level and the ability of PGD2 production decreased at 48 h after repeated scratch, compared to that of normal skin, not so after single scratch. Immunohistochemical analysis and Western blotting revealed a decrease in the levels of cyclooxygenase-1 (COX-1) and hematopoietic PGD synthase in mechanically scratched skin. The reduced ability of the skin for PGD2 production following mechanical scratching could be caused by this decrease in the expression levels of COX-1 and PGD2 synthase. The results suggest that repeated scratching in mice decreases the ability of the skin to produce PGD2, which is an endogenous mediator that inhibits pruritus, resulting in the establishment of the itch-scratch circle.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dermatitis, Atopic; Intramolecular Oxidoreductases; Lipocalins; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pruritus; Skin

TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for atopic dermatitis. The drug has been shown to suppress scratching and improve the skin inflammation in the NC/Nga (NC) mouse, a model of atopic dermatitis. Corticosteroids are commonly used as effective agents for the treatment of atopic dermatitis. We examined the anti-pruritic efficacy of TS-022 in NC mice cohabited with skin-lesioned NC mice, which showed spontaneous scratching without skin lesions in the early phase and chronic itching with severe dermatitis in the late phase, in comparison with that of dexamethasone. We have previously reported that prostaglandin D(2) might have a physiological role in the inhibition of pruritus. While after 2 weeks of cohabitation with skin-lesioned NC mice (early phase of dermatitis, characterized by the appearance of spontaneous scratching), topically applied TS-022 exhibited a weak anti-pruritic effect in the NC mice, after 6 weeks of cohabitation (late phase, characterized by both chronic scratching and dermatitis), the drug exerted potent anti-pruritic activity. In contrast, dexamethasone exerted potent anti-pruritic effect in both the early and late phases. Indomethacin aggravated the scratching in the early phase, but had no effect in the late phase. The skin prostaglandin D(2) level was significantly increased in the early phase, to subsequently declined and return to the basal level in the late phase. The cutaneous ability for prostaglandin D(2) production following topical application of arachidonic acid or mechanical scratching was decreased in the late phase. Moreover, the expression level of the prostanoid DP(1) receptor in the skin was increased in the late phase. These findings suggest that the potent anti-pruritic activity of TS-022 in the late phase might be attributable to the decrease of endogenous prostaglandin D(2) production and increase of prostanoid DP(1) receptor expression.

Topics: Acetates; Animals; Anti-Inflammatory Agents; Antipruritics; Arachidonic Acid; Cyclohexanes; Dermatitis, Atopic; Dexamethasone; Gene Expression Regulation; Male; Mice; Prostaglandin D2; Pruritus; Receptors, Prostaglandin; Skin; Sulfhydryl Compounds; Water Loss, Insensible

NC/Nga mice are known to develop scratching dermatitis akin to atopic dermatitis, under conventional (Conv), but not under the specific-pathogen-free (SPF) condition. In this study, we examined the effects of mechanical-scratching on the spontaneous scratching counts (sign of itching), in relation to the cutaneous prostaglandin D2 (PGD2) levels in NC/Nga or BALB/c mice. Mechanical-scratching increased the cutaneous barrier damage and PGD2 levels in both strain mice under the SPF condition. By 4 weeks of cohabitation with the skin-lesioned NC/Nga mice, both the increase in the spontaneous scratching and development of dermatitis score were higher in the Conv-NC/Nga than in the Conv-BALB/c mice. At this time-point, the cutaneous PGD2 level induced by mechanical-scratching was significantly lower in the Conv-NC/Nga when compared with that in the SPF-NC/Nga mice, and that in the Conv-BALB/c was almost equal to that in the SPF-BALB/c mice. With mechanical scratches, the cohabitation-induced scratching was suppressed in the Conv-BALB/c, but not in the Conv-NC/Nga mice. These results suggest that the scratch-induced cutaneous PGD2 inhibits scratching and the subsequent development of dermatitis in BALB/c, while the impaired scratch-induced cutaneous PGD2 production in the NC/Nga mice resulted in no suppression of scratching, and aggravated the dermatitis.

Topics: Animals; Behavior, Animal; Blotting, Western; Cyclooxygenase 1; Cyclooxygenase 2; Dermatitis, Atopic; Intramolecular Oxidoreductases; Lipocalins; Male; Mice; Mice, Inbred BALB C; Prostaglandin D2; Pruritus; Skin; Specific Pathogen-Free Organisms; Stress, Mechanical

The role of prostaglandins (PGs) on mechanical scratching-induced cutaneous barrier disruption in mice was investigated by comparing the observed effects of arachidonic acid (AA) application. Scratching of the mouse skin with a stainless-steel wire brush (mechanical scratching) was associated with significant, scratch-count-dependent elevation of the transepidermal water loss (TEWL) and skin PG levels (especially PGD(2) and PGE(2)). Histological evidence of inflammation (crusta, acanthosis and neutrophilic infiltration) in the skin also became evident 24 h after mechanical scratching. On the other hand, while topical application of 0.1% AA to the mouse skin also increased the skin PG levels, but did not produce any increase of TEWL or histological evidence of inflammation in the skin. Topical application of cyclooxygenase inhibitors (indomethacin, piroxicam, aspirin, diclofenac and ketoprofen) decreased the spontaneous recovery rates from cutaneous barrier disruption. These results suggest that the elevation of cutaneous PG production induced by mechanical scratching is involved in the repair of the skin damage caused by the scratching.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Epoprostenol; Male; Mice; Mice, Inbred BALB C; Permeability; Physical Stimulation; Prostaglandin D2; Prostaglandins; Pruritus; Recovery of Function; Skin; Water

We examined the involvement of cyclooxygenase (COX)-1 and COX-2 on mechanical scratching-induced prostaglandins (PGs) production in the skin of mice. The dorsal regions of mice were scratched using a stainless brush. COXs expressions in the skin were analyzed using real-time PCR and Western blotting. The effect of acetylsalicylic acid (ASA) on the ability of PGs production were determined based on skin PGs level induced by arachidonic acid (AA) application. Mechanical scratching increased PGD2, PGE2, PGI2 and PGF(2 alpha). COX-1 was constitutively expressed and COX-2 expression was enhanced by scratching. Intravenous administration of ASA inhibited PGs biosynthesis in the normal skin. PGs levels of the skin 6h after ASA administration (ASA 6 h) were almost equal to those of the skin 10 min after ASA administration (ASA 10 min). In the scratched skin, AA-induced PGE2 and PGI2 of ASA 6 h were significantly higher than those of ASA 10 min. The skin PGD2 and PGF(2 alpha) of ASA 10 min were almost same to those of ASA 6 h. In the normal skin of COX-1-deficient mice, skin PGD2 level was lower than that of wild-type mice, although PGE2, PGI2 and PGF(2 alpha) levels were almost equal to those of wild type. In the scratched skin of COX-1-deficient mice, PGD2, PGE2, PGI2 and PGF(2 alpha) levels were lower than those of wild-type mice. These results suggested that cutaneous PGD2 could be mainly produced by COX-1, and PGE2 and PGI2 could be produced by COX-1 and COX-2, respectively, in mice.

Topics: Animals; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Epoprostenol; Mice; Prostaglandin D2; Prostaglandins; Pruritus; Skin; Up-Regulation

NC/Nga (NC) mice, spontaneously develop an eczematous atopic dermatitis (AD)-like skin lesion when kept under conventional condition (Conv), but not under specific pathogen-free (SPF) conditions, have been thought to be an animal model of AD. We have previously shown that PGD(2) and arachidonic acid inhibited the scratching behaviour of NC mice, while indomethacin enhanced it. This study was designed to assess the role of cyclooxygenase (COX)-1 and COX-2 in the itch-related scratching behaviour of NC mice. We examined the expression of COX in the skin using real-time PCR and Western blotting and the effects of SC-560 (a COX-1 selective inhibitor) or NS-398 (a COX-2 selective inhibitor) on scratching behaviour in relation to skin prostaglandin (PG) levels in NC mice. COX-1 mRNA expression was unchanged and protein expression decreased in Conv NC mice compared with that of SPF mice. By contrast, COX-2 mRNA and protein expression increased in Conv NC mice. SC-560 increased scratching behaviour and significantly reduced skin PGD(2), PGE(2) and PGF(2alpha) levels, but NS-398 did not have effects on scratching and skin PG level. Moreover, the topical application of PGD(2), which might be the endogenous inhibitor of itching, suppressed the SC-560-induced enhancement of scratching behaviour by NC mice. These results suggest COX-1-coupled skin PGD(2) biosynthesis plays a physiological role in inhibiting regulation of pruritus in NC mice with AD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Carrageenan; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dermatitis, Atopic; Edema; Mice; Nitrobenzenes; Prostaglandin D2; Pruritus; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides

NC/Nga (NC) mice are known to develop dermatitis resembling atopic dermatitis (AD) in conventional (Conv) conditions, but not in specific pathogen-free (SPF) conditions. We reported that the ability of skin prostaglandin D(2) (PGD(2)) production, which might be the endogenous inhibitor of itching, was attenuated in skin-lesioned Conv-NC mice. We examined the age-related change in scratching, dermatitis symptoms, and skin PGs of SPF- and Conv-NC mice. In Conv-NC, PGD(2) increased at 7 weeks, at which scratching counts increased, but dermatitis did not develop. PGE(2), PGI(2) and PGF(2alpha) increased at 10 and 13 weeks, at which dermatitis developed. The ability to produce skin PGs was examined by measuring PGs after application of arachidonic acid or after mechanical scratching using a wire brush. In Conv-NC, PGD(2) production at 13 weeks was lower than at 7 weeks. In Conv-NC, hematopoietic PGD synthase (hPGDS) expression in the skin at 13 weeks was lower than at 7 weeks by Western blotting and immunohistochemical analysis. The increase of skin PGD(2) level in the early phase of the development of dermatitis is due to the stress of extensive scratching, but did not increase in spite of the stress of extensive scratching in the late phase, due to decreasing capacity of PGD(2) production attributable to decreasing hPGDS expression in Conv-NC mice. These results suggest that a decreased ability to produce skin PGD(2) production could enhance scratching and aggravate dermatitis in Conv-NC mice.

Topics: Animals; Arachidonic Acid; Blotting, Western; Dermatitis; Dinoprost; Dinoprostone; Epoprostenol; Immunohistochemistry; Intramolecular Oxidoreductases; Lipocalins; Male; Mice; Mice, Mutant Strains; Prostaglandin D2; Prostaglandins; Pruritus; Severity of Illness Index; Skin; Time Factors

Effects of prostaglandin (PG) D(2), PGE(2), and PGI(2) on itch-associated scratching responses of mice and histamine release from the rat basophilic leukemia cell line RBL-2H3 were examined. PGD(2) and ketotifen but not PGE(2) and PGI(2) suppressed the scratching caused by ovalbumin injected into ovalbumin-sensitized mice. Ketotifen also suppressed compound 48/80-induced scratching but not PGD(2), PGE(2), and PGI(2). In vitro, PGD(2) suppressed the antigen-induced histamine release from RBL-2H3 cells, but PGE(2) and PGI(2) did not. These findings suggest that PGD(2) specifically suppressed IgE-mediated scratching by inhibiting IgE-mediated histamine release from mast cells.

Topics: Animals; Cell Line, Tumor; Histamine Release; Immunoglobulin E; Male; Mast Cells; Mice; Mice, Inbred BALB C; Prostaglandin D2; Pruritus; Rats

The role of prostaglandins in mechanical scratching-induced cutaneous barrier disruption in mice was investigated. Skin prostaglandins contents were measured after cutaneous barrier function was disrupted by scratching using a stainless-steal wire brush (mechanical scratching), then effects of prostanoids on recovery of cutaneous barrier functions were examined. This mechanical scratching increased transepidermal water loss and skin prostaglandins (prostaglandin D2, prostaglandin E2, 6-keto-prostaglandin F1alpha and prostaglandin F2alpha) contents, count-dependently. Topical application of indomethacin immediately after cutaneous barrier disruption delayed the recovery period of cutaneous barrier disruption. We examined effects of several prostanoids (prostaglandin D2, prostaglandin E2, prostaglandin F2alpha, prostaglandin I2 and U46619) on delay of the recovery process of mechanical scratching-induced cutaneous barrier disruption with treatment of indomethacin. Topically applied prostaglandin D2 and prostaglandin E2 accelerated the recovery of cutaneous barrier disruption and topical application of prostaglandin J2, limaprost, sulprostone and ONO-4819, but not 13,14-dihydro-15-keto-prostaglandin D2, 15-deoxy-Delta(12,14)-prostaglandin J2, 17-phenyl-trinor-prostaglandin E2 or butaprost had effects on recovery of the cutaneous barrier. These results suggest that prostaglandin D2 and prostaglandin E2 accelerate the recovery process of cutaneous barrier disruption caused by mechanical scratching, via specific prostanoid DP1, EP3 and EP4 receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Heptanoates; Indomethacin; Male; Mice; Mice, Inbred BALB C; Prostaglandin D2; Pruritus; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Skin; Stress, Mechanical; Time Factors; Water Loss, Insensible

Spontaneous and 2,4,6-trinitrochlorobenzene (TNCB)-induced dermatitis models using NC/Nga mice have been recognized as animal models of atopic dermatitis. We reported that scratching behavior leads to dermatitis in a spontaneous dermatitis but not in a TNCB-induced dermatitis. Prostaglandin D2 (PGD2) suppressed the scratching behavior of NC/Nga mice, suggesting that PGD2 plays a physiological role on inhibiting pruritus. We studied whether there was a difference in skin PG contents between spontaneous and TNCB-induced dermatitis. Spontaneous dermatitis was induced by cohabitation with NC/Nga mice having severe skin lesions. TNCB-induced dermatitis was caused by applications of TNCB. PGD2, PGE2, 6keto-PGF1alpha, and PGF2alpha contents in the skin were examined using enzyme-immunoassay kits. For studying ability to produce skin PGs, PG contents were evaluated after topical treatment of arachidonic acid (AA) or mechanical scratching. In spontaneous dermatitis, PGE2, 6keto-PGF1alpha, and PGF2alpha contents increased with dermatitis, but only PGD2 did not do so. In TNCB-induced dermatitis, PGD2, PGE2, 6keto-PGF1alpha, and PGF2alpha increased. Determination of skin PG contents after AA treatment or mechanical scratching revealed that skin PGD2 production of conventional group of spontaneous dermatitis was lower than the specific pathogen-free group. It seemed that ability of skin PGD2 production was attenuated in spontaneous dermatitis. These results suggest that enhancement of scratching behavior in spontaneous dermatitis was caused by the defect of ability to produce PGD2, which plays a physiological role in inhibiting pruritus, resulting in development of dermatitis.

Topics: Administration, Topical; Animals; Arachidonic Acid; Dermatitis, Atopic; Mice; Mice, Inbred Strains; Nitrobenzenes; Physical Stimulation; Prostaglandin D2; Prostaglandins; Pruritus; Skin; Water Loss, Insensible

NC/Nga mice have similar pathological and behavioral features of human atopic dermatitis and are used as a model of the disease. Under conventional circumstances, spontaneous and persistent scratching is frequent and can lead to the onset of skin inflammation. We examined the effects of several prostanoids and their related compounds on the scratching behavior of NC/Nga mice. Among them, topically applied prostaglandin D2, prostaglandin E1, prostaglandin E2 and prostaglandin I2 significantly suppressed the scratching, the order of inhibitory activities being prostaglandin D2>>prostaglandin I2>prostaglandin E1=prostaglandin E2. Prostaglandin D2 metabolite, prostaglandin J2 also significantly suppressed the scratching but not so 13,14-dihydro-15-keto-prostaglandin D2, and 15-deoxy-Delta12,14-prostaglandin J2. The order of the inhibitory activities of these prostaglandin D2 metabolites depended on affinity of the prostanoid DP1 receptor but not on the DP2 receptor (chemoattractant receptor-homologous molecule expressed on T helper2 cells, CRTH2) and PPAR-gamma receptors. Likewise, topically applied arachidonic acid significantly suppressed the scratching while indomethacin enhanced it. Pretreatment of arachidonic acid increased the skin prostaglandins (prostaglandin D2, prostaglandin E2, prostaglandin F2alpha and 6-keto-prostaglandin F1alpha) contents, but indomethacin decreased the prostaglandin D2 and prostaglandin E2 contents. On the other hand, prostaglandin D2 and indomethacin had no apparent effects on histamine-induced scratching of ICR mice. These results suggested that prostaglandin D2 plays a physiological role in inhibiting pruritus of NC/Nga mice via their specific prostanoid DP1 receptors, and that prostaglandin D2 and/or a prostanoid DP1 receptor agonist may have therapeutic effects for cases of consecutive skin inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Behavior, Animal; Dermatitis, Atopic; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Histamine; Indomethacin; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Prostaglandin D2; Prostaglandins; Pruritus; Receptors, Prostaglandin; Skin; Time Factors

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on experimental allergic conjunctivitis, induced by ocular challenge with antigen in actively sensitized guinea pigs, were investigated. NSAIDs reduced the increase in prostaglandin D2 (PGD2) and E2 (PGE2) in the ocular lavage fluid. The inhibition of NSAIDs to these increases was approximately 90%-95%. NSAIDs also lowered itch-scratch response (ISR) to approximately one-third to one-half of the vehicle-treated group. However, these drugs scarcely affected plasma exudation in the conjunctiva. Ketotifen, an H1 histamine receptor antagonist, inhibited both pathophysiological changes (inhibition: 70%-80%). However, this drug was less efficacious than NSAIDs in reducing PGD2 and PGE2 levels. Moreover, topical administration of histamine induced ISR and plasma exudation; in contrast, PGD2 induced ISR exclusively. These results suggest that a part of antigen-induced ISR may be attributable to PGs. However, PGs may not play a key role in plasma exudation; other mediators such as histamine may be involved.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Benzophenones; Benzopyrans; Bromobenzenes; Conjunctivitis, Allergic; Diclofenac; Dinoprostone; Disease Models, Animal; Evans Blue; Exudates and Transudates; Eye; Guinea Pigs; Histamine; Histamine Release; Immunization; Injections, Intraperitoneal; Injections, Subcutaneous; Ketotifen; Male; Ovalbumin; Propionates; Prostaglandin D2; Pruritus; Therapeutic Irrigation