naloxone and Dermatitis--Atopic

Pruritus is the most common and distressing skin symptom, and treatment of itch is a problem for thousands of people. The currently available therapies are not very effective. Therefore there is an urgent need to find new effective topical drugs against itching.. We conducted two separate studies to evaluate the efficacy of topically applied naltrexone, an opioid receptor antagonist, in the treatment of severe pruritus. The objective of the first open study was to correlate the clinical efficacy of topically applied naltrexone in different pruritic skin disorders to a change of epidermal mu-opiate receptor (MOR) expression. The second study was a double-blind, placebo-controlled, crossover study on pruritus in atopic dermatitis.. Initially we performed an open pilot study on 18 patients with different chronic pruritic disorders using a topical formulation of 1% naltrexone for 2 weeks. A punch biopsy was performed in 11 patients before and after the application of the naltrexone cream and the staining of epidermal MOR was measured. Subsequently, a randomized, placebo-controlled, crossover trial was performed with the same formulation. We included in this trial 40 patients with localized and generalized atopic dermatitis with severe pruritus.. In the open study more than 70% of the patients using the 1% naltrexone cream experienced a significant reduction of pruritus. More interestingly, the topical treatment with naltrexone caused an increase of epidermal MOR staining. The regulation of the epidermal opioid receptor correlated with the clinical assessment. The placebo-controlled, crossover trial demonstrated clearly that the cream containing naltrexone had an overall 29.4% better effect compared with placebo. The formulation containing naltrexone required a median of 46 minutes to reduce the itch symptoms to 50%; the placebo, 74 minutes.. We could only take biopsy specimens in 11 patients, which means that a satisfactory statistical analysis of the changes of epidermal MOR staining was not possible. In addition, there was an insufficient number of patients with nephrogenic pruritus and pruritic psoriasis to draw definitive conclusions.. The placebo-controlled study showed a significant advantage of topically applied naltrexone over the placebo formulation. This finding is supported by the biopsy results from the open studies, showing a regulation of MOR expression in epidermis after treatment with topical naltrexone, especially in atopic dermatitis. These results clearly show potential for topically applied opioid receptor antagonist in the treatment of pruritus. The placebo formulation also had some antipruritic effects. This underlines the importance of rehydration therapy for dry skin in the treatment of pruritus.

Topics: Administration, Topical; Adult; Aged; Cross-Over Studies; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Naltrexone; Narcotic Antagonists; Pilot Projects; Prospective Payment System; Pruritus

The present study was performed to develop a new atopic dermatitis model characterized by not only itching but also inflammatory skin using BALB/c mice. From 18 days after the first systemic immunization, daily epicutaneous application of ovalbumin was performed for 2 weeks. Antigen challenge (ovalbumin) resulted in a significant increase of scratching behavior from day 23 to day 32. Moreover, skin symptoms such as erythema/hemorrhage, edema, excoriation/erosion and dryness/desquamation were also observed from day 19 to day 32. The frequency of scratching in the first stage (from day 24 to day 26 after the systemic first immunization) was decreased by chlorpheniramine and epinastine; however, in the last stage (from day 27 to day 30 after the systemic first immunization), both drugs showed no inhibition of scratching behavior. Therefore, an endogenous mediator other than histamine may be responsible for provoking the itching sensation in the last stage. Naloxone dose-dependently reduced the frequency of scratching in the last stage. Moreover, repeated local application of dexametasone significantly inhibited both scratching behavior and skin symptoms from day 24 to day 30. From these findings, it may be concluded that this model is essentially similar to atopic dermatitis in humans and could be used to elucidate the pathogenic mechanisms of atopic dermatitis and to develop appropriate new drugs for therapy.

Topics: Animals; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Female; Histamine H1 Antagonists; Immunoglobulin E; Mice; Mice, Inbred BALB C; Naloxone; Ovalbumin; Pruritus; Skin

HR-1 hairless mice fed with a special diet develop atopic-like dry skin, characterized by increased transepidermal water loss, and prolonged bouts of spontaneous scratching. In this study, the role of the skin barrier dysfunction in the prolongation of scratching was evaluated. Although the prolonged scratching was dose-dependently inhibited by opioid receptor antagonist naloxone, neither H(1) receptor antagonist, mepyramine, nor 5-HT(1/2) receptor antagonist, methysergide, affected it. Thus, the prolonged scratching could be itch-related response independent of histamine and serotonin. The application of petrolatum ointment on the skin temporarily alleviated the increase of transepidermal water loss for 60 min after treatment. Due to this alleviation in barrier dysfunction, the prolongation of scratching was significantly suppressed. However, when the barrier dysfunction relapsed, the scratching worsened. Taken together, a skin barrier dysfunction is associated with the itch-related response.

Topics: Animals; Behavior, Animal; Dermatitis, Atopic; Dose-Response Relationship, Drug; Epidermis; Erythema; Female; Food, Formulated; Injections, Intraperitoneal; Injections, Subcutaneous; Methysergide; Mice; Mice, Hairless; Naloxone; Ointments; Petrolatum; Pruritus; Pyrilamine; Recurrence; Skin Diseases; Time Factors; Water Loss, Insensible

Itching is the most important problem in many allergic and inflammatory skin diseases especially in atopic dermatitis. However, animal models for allergic dermatitis useful for the study of itching have rarely been established. We established a mouse allergic dermatitis model involving frequent scratching behavior by repeated painting with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse skin, and comparatively examined the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior. Repeated DNFB painting caused typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behavior. An apparent thickening of the epidermis and dermis, and the significant accumulation of inflammatory cells were observed. Increased interferon (IFN)-gamma mRNA expression and the induction of interleukin (IL)-4 and IL-5 mRNA expression were also observed in the skin lesion. The scratching behavior was inhibited by dibucaine and naloxone. Although tacrolimus reduced the increased expression of IFN-gamma and IL-4 mRNA, dexamethasone potently depressed that of IFN-gamma, IL-4 and IL-5 mRNA. Dexamethasone inhibited the accumulation of lymphocytes and eosinophils, although tacrolimus did not. Both drugs failed to inhibit the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior that was associated with the inhibition of nerve fiber extension into the epidermis, whereas dexamethasone failed to have any effect. The mouse dermatitis model seems to be beneficial for the study of itching associated with allergic dermatitis, such as atopic dermatitis, and tacrolimus seems to exhibit an anti-itch effect through the inhibition of nerve fiber extension at least in part.

Topics: Allergens; Anesthetics, Local; Animals; Antipruritics; Behavior, Animal; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dexamethasone; Dibucaine; Dinitrofluorobenzene; Disease Models, Animal; Glucocorticoids; Immunoglobulin E; Interferon-gamma; Interleukin-4; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Pruritus; RNA, Messenger; Skin; Tacrolimus

We investigated the effects of several agents on the established itching model in NC/Nga mice, model of atopic dermatitis-like disease, to elucidate related characteristics. The number of spontaneous scratching behaviors (the duration time is over 1.5 s) by NC/Nga mice with severe skin lesions was measured before and after administration of agents for 24 h. The scratching behavior by NC/Nga mice was significantly suppressed by administration of dexamethasone or tacrolimus, but not by chlorpheniramine maleate or cyproheptadine hydrochloride. These results suggest that this method shows a good correlation with the effectiveness of drugs prescribed for itching in humans with atopic dermatitis, and histamine and serotonin do not play an important role in causing the scratching behavior seen by NC/Nga mice. The scratching behavior was also significantly suppressed by naloxone hydrochloride, dibucaine or capsaicin. These results suggest that the scratching behavior seen in this model is caused by itching signal transmission through neural system. Furthermore, we found that theophylline, pinacidil or limaprost had scratching suppression effects in this model.

Topics: Alprostadil; Animals; Antipruritics; Behavior, Animal; Capsaicin; Chlorpheniramine; Cyproheptadine; Dermatitis, Atopic; Dexamethasone; Dibucaine; Male; Mice; Mice, Inbred Strains; Naloxone; Pinacidil; Pruritus; Tacrolimus; Theophylline; Time Factors