leukotriene-b4 and Pruritus

Itch is a sensation that provokes a desire to scratch. Mast-cell histamine was thought to be a key itch mediator. However, histamine and mast-cell degranulation were reported not to elicit scratching in animals. It was difficult to investigate the pathophysiology of itching and to evaluate the antipruritic efficacy of chemical agents in the early 1990 s. We showed that hind-paw scratching and biting were elicited by stimulation with pruritogenic agents in mice. Those results demonstrated for the first time that cutaneous itching could be evaluated behaviorally in animals. We established various animal models of pathological itch of the skin (dry skin, mosquito allergy, surfactant-induced pruritus, and herpes zoster) and mucus membranes (pollen allergy). Mast-cell histamine did not play a key role in itching in any animal model examined except for the pollen allergy model. Histamine is not an exclusive itch mediator of mast cells; tryptase and leukotriene B4 released from mast cells also act as itch mediators. Epidermal keratinocytes release several itch mediators, such as leukotriene B4, sphingosylphosphorylcholine, thromboxane A2, nociceptin, nitric oxide, and histamine, which may play important roles in pathological itching. Appropriate animal models of pathological itching are needed for pharmacological evaluation of the antipruritic efficacy of chemical agents.

Topics: Animals; Antipruritics; Disease Models, Animal; Drug Evaluation, Preclinical; Histamine; Humans; Hypersensitivity; Leukotriene B4; Mast Cells; Mucous Membrane; Pruritus; Skin; Tryptases

Topics: Animals; Autocrine Communication; Drug Design; Free Radicals; Histamine; Humans; Hydrogen Peroxide; Immunoglobulin E; Keratinocytes; Leukotriene B4; Mast Cells; Nitric Oxide; Pruritus; Receptors, IgG; Substance P; Thromboxane A2

Itch, a skin sensation that provokes a desire to scratch, is a common complaint. Severe itch accompanying various skin diseases such as atopic dermatitis is an important issue related to the quality of life. Although histamine from mast cells has been thought to play an essential role in itch, many severe pruritic diseases respond poorly to the H(1) histamine receptor antagonists. Therefore the precise mechanisms and mediators of itch in most pruritic diseases are unclear. To investigate the detailed mechanisms of the induction of itch, we have developed a mouse model. Studies using this model have demonstrated that keratinocytes play an important role in the induction of itch. The identification of keratinocyte stimulus factors and of products in keratinocytes could lead to developing new antipruritic medicines.

Topics: Animals; Disease Models, Animal; Drug Design; Epidermal Cells; Histamine Release; Humans; Keratinocytes; Leukotriene B4; Mast Cells; Mice; Nitric Oxide; Pruritus; Receptor, PAR-2; Substance P

Atopic dermatitis is clearly characterized by altered cutaneous physiologic responses. There is a tendency to acral vasoconstriction. Rubbing causes skin pallor and white dermographism. Vascular instability is demonstrated by responses to cholinergic agents, histamine, and nicotinates. Psychophysiologic studies demonstrate exaggerated vasodilator responses to emotional stress with consequent pruritus and scratching. The itch threshold is low, duration is prolonged, and nighttime scratching movements may be frequent or almost continuous. Regardless of the inciting trigger factors, the scratching causes the damage and the severe dermatitis. Thermal as well as emotional stimuli to sweating cause severe itching in AD, yet the concept of a miliaria-type, poral occlusion mechanism remains unproven. Some studies suggest actually increased sweating along with erythema and pruritus during acute flares of AD. The concept of sweat-borne allergens causing skin reactions during sweating is interesting but has never been proven. Studies of sweat responses to pharmacologic agents have produced conflicting data, and attempts to link these responses to Szentivanyi's beta-adrenergic blockade theory are not convincing. The numerous variables of climate, season, sex, age, and habitus affect sweating greatly. Future studies must carefully control for each of these factors before pharmacologically induced sweat responses can be interpreted clearly. A number of lines of evidence suggest involvement of histamine and other mediators in the evolution of erythema, pruritus, and scratching in AD. Flares of the condition have been reproducibly evoked by only two incitants: experimental emotional stress interviews and specific food challenge in selected sensitive individuals. In the latter, increased plasma histamine has been demonstrated, presumably generated by antigen/IgE stimulated degranulation of mast cells in the gut and/or skin. The demonstrated increased histamine releasability of basophils from atopic individuals may be the result of defective cellular regulatory mechanisms. Recent studies have demonstrated increased cyclic AMP-phosphodiesterase activity in leukocytes from atopic individuals. The resultant decreased intracellular cyclic AMP removes an inhibitory factor, which in turn causes net cellular hyperresponsiveness. This effect has been shown to account, at least in part, for increased histamine release from leukocytes of patients with AD. These and other studies foc

Topics: Biofeedback, Psychology; Catecholamines; Cyclic AMP; Dermatitis, Atopic; Female; Histamine; Humans; Leukotriene B4; Lipid Metabolism; Menstruation; Nicotinic Acids; Parasympathomimetics; Pregnancy; Pruritus; Receptors, Histamine H2; Skin; Skin Temperature; Sweat Glands; Sympathomimetics; T-Lymphocytes; T-Lymphocytes, Regulatory; Thyroid Gland; Virulence Factors, Bordetella

To investigate the effect of supplementation with different sources of oils rich in long chain fatty acids, ie, fish oil (FO) and safflower oil (SO), on the production of leukotriene B4 (LTB4) by polymorphonuclear leukocytes (PMNLs) in hemodialysis patients and the consequent effects on the symptoms of pruritus.. Randomized, prospective, double-blind study for 2 treatment groups.. Three Medical Center-affiliated units.. Twenty-two patients on maintenance hemodialysis, of both sexes, age > or = 20 years with complaint of dry and/or itchy skin.. Two groups of patients receiving daily supplements of 6 g ethyl ester of FO or SO for 16 weeks.. Red blood cell (RBC) fatty acid profile, LTB 4 production by PMNLs, and pruritus symptoms at baseline and after supplementation.. After supplementation, the FO group had a higher RBC 22:6n3, total n-3 fatty acids, and ratio of total n-3 to total n-6 fatty acids (P < .05) than the SO group. The change in LTB4 production (pg/mL) from baseline to week 16 was 240.7 +/- 200.2 to 29.2 +/- 14.6 in the FO group and from 171.1 +/- 121.7 to 31.9 +/- 14.7 in the SO group. The overall pruritus score change was 16.7 +/- 11.4 to 8.9 +/- 9.2 in the FO group and from 17.5 +/- 8.8 to 13.1 +/- 5.6 in the SO group. FO supplementation did not result in a significant specific effect on LTB4 production by the PMNLs. There was a nonsignificant decrease in the pruritus scores that could be clinically significant and important to patients suffering with this condition.. Supplementation with FO results in significant incorporation of n-3 fatty acids in the RBCs. Intervention with both FO and SO resulted in a nonsignificant improvement of clinical symptoms of pruritus and a nonsignificant reduction in LTB 4 production by PMNLs in the hemodialysis patients. The percent decrease in total puritus score was greater for the FO group compared with the SO group.

Topics: Adult; Aged; alpha-Tocopherol; Arachidonate 5-Lipoxygenase; Dietary Fats, Unsaturated; Double-Blind Method; Erythrocytes; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Fish Oils; gamma-Tocopherol; Humans; Kidney Failure, Chronic; Leukotriene B4; Male; Middle Aged; Neutrophils; Prospective Studies; Pruritus; Renal Dialysis; Safflower Oil; Surveys and Questionnaires

Important roles of neutrophils as well as lymphocytes against invasive fungi has been suggested. Leukotriene B4 (LTB4) is a potent chemoattractant for neutrophils and its topical application to human skin has already been performed without serious side effects, forming intraepidermal neutrophil abscesses. Thus topical LTB4 therapy for tinea was attempted in a randomized, placebo-controlled study. LTB4 (100-900 ng depending on the area of each lesion) was applied to a whole lesion once a week until, as a rule, complete clearing was observed but maximum for 2 weeks (vesiculobullous type lesions), 5 weeks (patches with or without raised borders) or 7 weeks (macerated lesions between toes). As a result, 16 of 18 lesions treated with LTB4 were cleared either completely (13) or partially (3). In contrast, only 2 of 18 lesions treated with vehicle (50% ethanol) were cleared partially. Statistical analysis with chi 2 test revealed a significant efficacy of LTB4 over vehicle. Topical LTB4 will be used as a powerful antifungal regimen. LTB4 has not been used for infectious diseases before.

Topics: Administration, Topical; Adult; Aged; Erythema; Female; Humans; Leukotriene B4; Male; Middle Aged; Pruritus; Random Allocation; Tinea; Tinea Pedis

Topics: Amyloidosis; Arachidonate 5-Lipoxygenase; Case-Control Studies; Humans; Leukotriene B4; Lichen Planus; Physical Stimulation; Pruritus; Sensation

A recent study suggests that interleukin-31 (IL-31) exerts its effect via indirect mechanisms rather than through direct stimulation of cutaneous nerves. However, the underlying peripheral mechanisms of IL-31-induced itch in the skin remain unclear. Therefore, the present study investigated the peripheral mechanisms underlying IL-31-induced itch in mice. IL-31-induced itch-related response was inhibited by anti-allergic drugs (tranilast and azelastine), but not by an H1 histamine receptor antagonist (terfenadine). Furthermore, a 5-lipoxygenase inhibitor (zileuton), but not a cyclooxygenase inhibitor (indomethacin), and a leuko-triene B4 (LTB4) receptor antagonist (CMHVA) attenuated the action of IL-31. IL-31 receptor-immunoreactivity was observed in the epidermis and primary sensory neurones. IL-31 receptor mRNA was expressed in mouse keratinocytes and dorsal root ganglia neurones. IL-31 increased the production of LTB4 in mouse keratinocytes. These results suggest that IL-31 elicits itch not only through direct action on primary sensory neurones, but also by inducing LTB4 production in keratinocytes.

Topics: Animals; Anti-Allergic Agents; Behavior, Animal; Cells, Cultured; Disease Models, Animal; Interleukins; Keratinocytes; Leukotriene Antagonists; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice, Inbred ICR; Oncostatin M Receptor beta Subunit; Pruritus; Receptors, Interleukin; Receptors, Leukotriene B4; Sensory Receptor Cells; Signal Transduction; Skin

Proteinase-activated receptor-2 (PAR2) is involved in dermatophyte-induced scratching and leukotriene B4 (LTB4) release from keratinocytes. We investigated whether PAR2-mediated LTB4 production is involved in dermatophyte-induced scratching.. Dermatophyte extract was injected intradermally and scratching was observed in mice. LTB4 was determined by enzyme immunoassay.. Dermatophyte extract-induced scratching was inhibited by zileuton (5-lipoxygenase inhibitor), ONO-4057 (LTB4 antagonist), FSLLRY-NH2 (PAR2 antagonist), and anti-PAR2 antibody. Dermatophyte extract injection increased the cutaneous content of LTB4, which was inhibited by zileuton and FSLLRY-NH2.. These results suggest the involvement of LTB4 in dermatophyte-associated itch. LTB4 production might be due to PAR2 stimulation in the skin.

Topics: Animals; Antibodies, Monoclonal; Arthrodermataceae; Dermatomycoses; Hydroxyurea; Keratinocytes; Leukotriene Antagonists; Leukotriene B4; Male; Mice, Inbred Strains; Oligopeptides; Pruritus; Receptor, PAR-2

Phosphodiesterase 4 (PDE4), which catalyses the conversion of cyclic adenosine 3',5'-monophosphate (cAMP) to 5'-AMP, plays a critical role in the pathogenesis of inflammatory disorders. Pruritus is the main symptom of dermatitides, such as atopic dermatitis, and is very difficult to control. Recent studies have shown that the activation of proteinase-activated receptor 2 (PAR2) is involved in pruritus in dermatoses in humans and rodents.. To investigate the inhibitory effect of E6005, a topically effective PDE4 inhibitor, on PAR2-associated itching in mice.. Mice were given an intradermal injection of SLIGRL-NH2 (100 nmol/site), a PAR2 agonist peptide, into the rostral part of the back. E6005 and 8-bromo-cAMP were applied topically and injected intradermally, respectively, to the same site. Scratching bouts were observed as an itch-related behavior, and firing activity of the cutaneous nerve was electrophysiologically recorded. Keratinocytes were isolated from the skin of neonatal mice and cultured for in vitro experiments. The concentrations of cAMP and leukotriene B4 (LTB4) were measured by enzyme immunoassay. The distribution of PDE4 subtypes in the skin was investigated by immunostaining.. Topical E6005 and intradermal 8-bromo-cAMP significantly inhibited SLIGRL-NH2-induced scratching and cutaneous nerve firing. Topical E6005 increased cutaneous cAMP content. Topical E6005 and intradermal 8-bromo-cAMP inhibited cutaneous LTB4 production induced by SLIGRL-NH2, which has been shown to elicit LTB4-mediated scratching. E6005 and 8-bromo-cAMP inhibited SLIGRL-NH2-induced LTB4 production in the cultured murine keratinocytes also. PDE4 subtypes were mainly expressed in keratinocytes and mast cells in the skin.. The results suggest that topical E6005 treatment inhibits PAR2-associated itching. Inhibition of LTB4 production mediated by an increase in cAMP may be partly involved in the antipruritic action of E6005.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Administration, Topical; Animals; Antipruritics; Cells, Cultured; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Injections, Intradermal; Keratinocytes; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Oligopeptides; Phosphodiesterase 4 Inhibitors; Phthalic Acids; Pruritus; Quinazolines; Receptor, PAR-2; Skin; Tryptases

The underlying mechanisms of itch are poorly understood. We have investigated a model involving the chemoattractant leukotriene B₄ (LTB₄) that is up-regulated in common skin diseases. Intradermal injection of LTB4 (0.1 nmol/site) into female CD1 mice induced significant scratching movements (used as an itch index) compared with vehicle-injected (0.1% bovine serum albumin-saline) mice. Intraperitoneal transient receptor potential (TRP) channel antagonist treatment significantly inhibited itch as follows: TRP vanilloid 1 (TRPV1) antagonist SB366791 (0.5 mg/kg, by 97%) and the TRP ankyrin 1 (TRPA1) antagonists TCS 5861528 (10 mg/kg; 82%) and HC-030031 (100 mg/kg; 76%). Leukotriene B₄ receptor 2 antagonism by LY255283 (5 mg/kg i.p.; 62%) reduced itch. Neither TRPV1-knockout (TRPV1-KO) nor TRPA1-knockout (TRPA1-KO mice exhibited LTB₄-induced itch compared with their wild-type counterparts. The reactive oxygen species scavengers N-acetylcysteine (NAC; 204 mg/kg i.p.; 86%) or superoxide dismutase (SOD; 10 mg/kg i.p.; 83%) also inhibited itch. LTB4-induced superoxide release was attenuated by TCS 5861528 (56%) and HC-030031 (66%), NAC (58%), SOD (50%), and LY255283 (59%) but not by the leukotriene B4 receptor 1 antagonist U-75302 (9 nmol/site) or SB366791. Itch, superoxide, and myeloperoxidase generation were inhibited by the leukocyte migration inhibitor fucoidan (10 mg/kg i.v.) by 80, 61, and 34%, respectively. Myeloperoxidase activity was also reduced by SB366791 (35%) and SOD (28%). TRPV1-KO mice showed impaired myeloperoxidase release, whereas TRPA1-KO mice exhibited diminished production of superoxide. This result provides novel evidence that TRPA1 and TRPV1 contribute to itch via distinct mechanisms.

Topics: Animals; Ankyrins; Female; Leukocytes; Leukotriene B4; Mice; Mice, Knockout; Pruritus; Receptors, Leukotriene B4; Superoxides; Transient Receptor Potential Channels; TRPV Cation Channels

To elucidate the mechanisms of severe itch in atopic dermatitis, we investigated the role of leukotriene B(4) , a potent itch mediator, in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Topical application of the BLT leukotriene B(4) receptor antagonist ONO-4057 inhibited spontaneous itch-related behaviour. The concentration of leukotriene B(4) was significantly increased in the lesional skin. The expression levels of 5-lipoxygenase were also elevated in the lesional skin, yet present throughout the epidermis of both healthy and lesional skin. These results suggest a role for leukotriene B(4) in chronic dermatitis-related itch. Sphingosylphosphorylcholine (SPC) was increased in the epidermis of the lesional skin. Moreover, intradermal injection of SPC elicited itch-related behaviours in healthy mice. Because SPC induces itch-related responses through the production of leukotriene B(4) in keratinocytes (J Invest Dermatol, 129, 2009, 2854), these results suggest that an increase in SPC induces leukotriene B(4) -mediated itching in chronic dermatitis. BLT1 receptor and 5-lipoxygenase in the skin may be effective pharmacological targets for the treatment of itch in atopic dermatitis.

Topics: Administration, Topical; Animals; Arachidonate 5-Lipoxygenase; Dermatitis, Atopic; Disease Models, Animal; Leukotriene B4; Mice; Phenylpropionates; Phosphorylcholine; Pruritus; Receptors, Leukotriene B4; Skin; Sphingosine

Although glycyrrhetinic acid (GA) has been used for the prevention of itch in chronic dermatitis, the mechanism underlying the antipruritic effects of GA is still unclear. Recently, several mediators other than histamine, such as substance P and tryptase, were found to participate in chronic itch. Here, we investigated the effect of GA on pruritus induced by various pruritic agents including histamine in mice. We also determined the level of leukotriene (LT)B(4) in mouse skin injected with substance P in an effort to uncover part of the antipruritic mechanism of GA. Scratching events were counted for 10 min after intradermal injection of histamine, substance P (100 nmol per site each), protease-activated receptor-2 (PAR-2) agonistic peptide (50 nmol per site), or LTB(4) (0.03 nmol per site) with or without GA (4 nmol per site) into male ICR mice. Levels of LTB(4) in the skin after injection of substance P were determined by ELISA. GA did not suppress scratching behavior induced by histamine and LTB(4), but markedly and dose-dependently suppressed that induced by substance P and PAR-2 agonistic peptide. LTB(4) levels in skin elevated by substance P were lowered by GA. These data support the efficacy of GA in counteracting itch in chronic dermatitis because GA reduced scratching behavior induced by substance P and PAR-2 agonistic peptide. GA may exert antipruritic effects via inhibition of LTB(4) production in skin.

Topics: Animals; Antipruritics; Behavior, Animal; Glycyrrhetinic Acid; Histamine; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Pruritus; Receptor, PAR-2; Skin; Substance P

We investigated the role of leukotriene (LT) B(4) in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses using SA6541, an LTA(4) hydrolase inhibitor. Itch-associated responses were induced by intradermal injection of 5-hydroperoxyeicosatetraenoic acid (HPETE), a precursor of 5-lipoxygenase metabolites, and passive cutaneous anaphylaxis in ICR mice. By screening molecules related to arachidonic acid metabolism or pruritus, SA6541 was found to be a specific inhibitor of LTA(4) hydrolase. Pharmacokinetic studies confirmed the specificity of SA6541 at an oral dose of 100 mg/kg in mice. 5-HPETE induced scratching behavior, which was inhibited by SA6541 (100 mg/kg). However, SA6541 (100 mg/kg) hardly attenuated the 5-HPETE-induced increase in vascular permeability. Moreover, SA6541 (100 mg/kg) partially attenuated scratching behavior, but did not affect the increase in vascular permeability caused by passive cutaneous anaphylaxis. On the other hand, ketotifen fumarate, a histamine H1 antagonist, strongly inhibited the scratching behavior and the increase in vascular permeability caused by passive cutaneous anaphylaxis. These results suggest that LTB(4) is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions.

Topics: Animals; Arachidonic Acid; Behavior, Animal; Capillary Permeability; Epoxide Hydrolases; Histamine H1 Antagonists; Hypersensitivity; Ketotifen; Leukotriene B4; Lipoxygenase; Male; Mice; Mice, Inbred ICR; Passive Cutaneous Anaphylaxis; Protease Inhibitors; Pruritus; Skin

In atopic dermatitis, the concentration in the skin of sphingosylphosphorylcholine (SPC), which is produced from sphingomyelin by sphingomyelin deacylase, is increased. In the present study, we investigated the itch-eliciting activity of SPC and related substances and the mechanisms of SPC action in mice. An intradermal injection of SPC, but not sphingomyelin and sphingosine, induced scratching, an itch-associated response, which was not suppressed by a deficiency in mast cells or the H(1) histamine receptor antagonist terfenadine. The action of SPC was inhibited by the mu-opioid receptor antagonist naltrexone. SPC action also was inhibited by the 5-lipoxygenase inhibitor zileuton and the leukotriene B(4) antagonist ONO-4057, but not by the cyclooxygenase inhibitor indomethacin. Moreover, SPC action was inhibited by the antiallergic agent azelastine, which suppresses the action and production of leukotriene B(4). Administration of SPC to the skin and to primary cultures of keratinocytes increased leukotriene B(4) production. SPC increased intracellular Ca(2+) ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. These results suggest that SPC induces itching through a direct action on primary afferents and leukotriene B(4) production of keratinocytes. Sphingomyelin deacylase and SPC receptors may be previously unreported targets for antipruritic drugs.

Topics: Animals; Calcium; Dermatitis, Atopic; Ganglia, Spinal; Histamine; Histamine H1 Antagonists, Non-Sedating; Injections, Intradermal; Keratinocytes; Leukotriene B4; Male; Mast Cells; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Neurons; Phosphorylcholine; Pruritus; Skin; Sphingomyelins; Sphingosine; Terfenadine

Protease-activated receptor-2 (PAR2) has been shown to play a key role in the pathophysiology of itch. However, the precise mechanism of PAR2-mediated itch remains largely unknown. In the present study, we investigated the effects of several agents on the scratching behavior induced by PAR2-activating peptide (SLIGRL-NH2). Pretreatment of experimental animals with tacrolimus or the 5-lipoxygenase inhibitor zileuton significantly reduced SLIGRL-NH2-induced scratching behavior, whereas histamine H(1) receptor antagonist cetirizine or the cyclooxygenase inhibitor indomethacin had little effect. Furthermore, intradermal injection of SLIGRL-NH2 increased cutaneous levels of LTB(4) and PGE(2). In vitro, SLIGRL-NH2 treatment enhanced LTB(4) and PGE(2) release from primary keratinocytes in a concentration-dependent manner. Preincubation of keratinocytes with zileuton resulted in a significant decrease of LTB(4) release and treatment of indomethacin led to a significant decrease of PGE(2) in response to SLIGRL-NH2 stimulation. In addition, SLIGRL-NH2-induced secretion of LTB(4) and PGE(2) was significantly inhibited by tacrolimus, whereas cetirizine had no effect. These results indicate that SLIGRL-NH2 stimulates LTB(4) and PGE(2) release from mouse keratinocytes and that enhancement of LTB(4) and PGE(2) secretion contributes to SLIGRL-NH2-induced scratching behavior in ICR mice.

Topics: Animals; Cetirizine; Dinoprostone; Dose-Response Relationship, Drug; Drug Interactions; Hydroxyurea; Indomethacin; Injections, Intradermal; Keratinocytes; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Oligopeptides; Pruritus; Skin; Tacrolimus

The itch-associated responses evoked by intradermal injection of 12(S)-HPETE and leukotriene B4 were compared in ICR-mice. 12(S)-HPETE and leukotriene B4 (0.01-0.2 nmol/site) induced scratching of the injected site, respectively; the dose-responses were a peak at 0.05 nmol/site (12(S)-HPETE) or 0.03 nmol/site (leukotriene B4). The scratching response by 12(S)-HPETE (0.05 nmol/site) started within 1 min, peaked in the first 10 min period, had almost subsided by 25 min whereas the effect of leukotriene B4 peaked in the second 10 min. The effect of leukotriene B4 is slightly stronger than that of 12(S)-HPETE in 40 min of count. The scratching induced by 12(S)-HPETE was inhibited by capsaicin, naltrexon, and LY255283. These results suggest the possibility that 12-lipoxygenase product can be added to a new member of an endogenous itch mediator in the skin.

Topics: Animals; Capsaicin; Dose-Response Relationship, Drug; Leukotriene B4; Leukotrienes; Male; Mice; Mice, Inbred ICR; Naltrexone; Pruritus; Receptors, Leukotriene B4

This study investigated endogenous mediators involved in mosquito allergy-associated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg/kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg/kg), and the glucocorticoid betamethasone 17-valerate (3 mg/kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B(4) antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D(4) antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester, the H(2) histamine-receptor antagonist cimetidine, the H(1) histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT(1/2) serotonin receptors. Zileuton (100 mg/kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 microM) did not affect high K(+)-induced increase in intracellular Ca(2+) concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B(4) and cysteinyl leukotrienes are involved in mosquito allergy-associated itching.

Topics: Animals; Arachidonate 5-Lipoxygenase; Betamethasone Valerate; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Chromones; Cimetidine; Culicidae; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Hydrazines; Hydroxyurea; Hypersensitivity; Indoles; Indomethacin; Ketoprofen; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; NG-Nitroarginine Methyl Ester; Phenylpropionates; Phospholipid Ethers; Propionates; Pruritus; Quinolines; Terfenadine

Anti-pruritic effects of the antihistamine bepotastine besilate were studied in mice. Bepotastine besilate (10 mg/kg) inhibited scratching induced by an intradermal injection of histamine (100 nmol/site), but not serotonin (100 nmol/site). Bepotastine besilate (1-10 mg/kg, oral) dose-dependently suppressed scratching induced by substance P (100 nmol/site) and leukotriene B(4) (0.03 nmol/site). An intradermal injection of substance P (100 nmol/site) increased the cutaneous concentration of leukotriene B(4), which was not affected by bepotastine besilate (10 mg/kg, oral). Leukotriene B(4) increased Ca(2+) concentration in cultured neutrophils, which was suppressed by bepotastine besilate (1-100 microM). Leukotriene B(4) increased Ca(2+) concentration in cultured dorsal root ganglion neurons, which was also suppressed by bepotastine besilate (100 microM). The results suggest that the inhibition of the actions of leukotriene B(4) as well as histamine is involved in the anti-pruritic effect of bepotastine besilate.

Topics: Administration, Oral; Animals; Behavior, Animal; Calcium; Dose-Response Relationship, Drug; Ganglia, Spinal; Histamine H1 Antagonists; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Neurons; Neutrophils; Piperidines; Pruritus; Pyridines; Skin; Substance P

Nociceptin, the endogenous peptide ligand for opioid receptor like-1 (ORL1) receptor, has been implicated in the inflammation and pain in the skin. We examined whether nociceptin is a pruritogen in mice. Intradermal injections of nociceptin (1-100 nmol per site) concentration dependently increased scratching in ICR mice; the effect started within 1 min, peaked at 10-20 min, and almost subsided by 30 min. The nociceptin action was absent in ORL1 receptor-deficient (ORL1(-/-)) mice. Systemic, but not local, treatment with naloxone significantly inhibited scratching induced by nociceptin. The action of nociceptin was inhibited by the leukotriene B(4) receptor antagonist ONO-4057 and azelastine, which inhibits the action and production of leukotriene B(4) in the skin. Prepronociceptin and ORL1 receptor mRNAs were substantially expressed in the skin, whereas their expression levels were very low in the dorsal root ganglia. In the skin, nociceptin- and ORL1 receptor-like immunoreactivities were localized in the epidermis. Administration of nociceptin to primary cultures of keratinocytes from ICR and C57BL/6 (ORL1(+/+)) mice, but not ORL1(-/-) mice, produced leukotriene B(4). The results suggest that nociceptin acts on ORL1 receptor on the keratinocytes to produce leukotriene B(4), which induces itch-associated responses in mice.

Topics: Animals; Anti-Allergic Agents; Dermatitis; Immunosuppressive Agents; Injections, Intradermal; Keratinocytes; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Mutant Strains; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Phenylpropionates; Phthalazines; Protein Precursors; Pruritus; Receptors, Opioid; Terfenadine; Vasodilator Agents

The anti-pruritic mechanisms of azelastine were studied in mice. Scratching induced by intradermal histamine was inhibited by azelastine (30 mg/kg) and chlorpheniramine (30 mg/kg). Substance P-induced scratching was dose dependently suppressed by azelastine (3-30 mg/kg), but not by chlorpheniramine (10 and 30 mg/kg). Azelastine (30 mg/kg) inhibited the substance P-induced production of leukotriene B4, but not prostaglandin E2, in the skin. Azelastine (3-30 mg/kg) suppressed scratching induced by intradermal injection of leukotriene B4. The results suggest that inhibition of the production and action of leukotriene B4, as well as an anti-histamine action, is involved in the anti-pruritic action of azelastine.

Topics: Animals; Anti-Allergic Agents; Behavior, Animal; Calcium; Dinoprostone; Dose-Response Relationship, Drug; Histamine; Histamine H1 Antagonists; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Neutrophils; Phthalazines; Pruritus; Skin; Substance P

Intradermal injection of substance P elicits an itch sensation in human subjects and an itch-associated response in mice. The substance P-induced itch-associated response in mice is not inhibited by antihistamine. Therefore, the mechanisms of substance P-induced itch-associated response are unclear. In this study, we demonstrated one of the mechanisms. Substance P induces an arachidonate cascade to produce prostaglandins and leukotriene. In this study we considered whether arachidonate metabolites are involved in the substance P-induced itch-associated response. A phospholipase A(2) inhibitor arachidoryltrifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pre treatment with the glucocorticoids betamethasone and dexamethasone also produced inhibition of the substance P-induced itch-associated response in mice as well as humans. The 5-lipoxygenase inhibitor zileuton, but not the cyclooxygenase inhibitors indomethacin and diclofenac, suppressed substance P-induced itch-associated response. The leukotriene B(4) receptor antagonist 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid produced inhibition, whereas pranlukast (leukotriene C(4)/D(4)/E(4) receptor antagonist) and 5(Z)-7-[1S,2S, 3S,5R-3-(trans-b-styren)sulfonamido-6,6-dimethylbi cyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP(1) receptor antagonist) were without effect. Furthermore, when the production of leukotriene B(4) and prostaglandin E(2) was measured in skin injected with substance P and in mouse keratinocytes applied with substance P, the level of both products increased. As leukotriene B(4), but not prostaglandin E(2), also induces the itch-associated response in mice, these results suggest that leukotriene B(4) and keratinocytes, cutaneous cells which produced leukotriene B(4), play an important role in substance P-induced itch-scratch response in mice. Leukotriene B(4) receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Cyclooxygenase Inhibitors; Dexamethasone; Dinoprostone; Enzyme Inhibitors; Glucocorticoids; Immunosuppressive Agents; Indomethacin; Keratinocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mast Cells; Mice; Mice, Inbred ICR; Mice, Mutant Strains; Phenylpropionates; Phospholipases A; Pruritus; Receptors, Leukotriene B4; Receptors, Neurokinin-1; Substance P

The anti-pruritic activity of emedastine difumarate was studied in mice. Emedastine (0.03-0.3 mg/kg) inhibited scratching induced by intradermal injection of histamine (100 nmol/site). Scratching induced by substance P (100 nmol/site) and leukotriene B(4) (0.03 nmol/site), but not by serotonin (100 nmol/site), was also suppressed by emedastine (0.03-0.3 mg/kg). Intradermal injection of substance P increased the cutaneous concentration of leukotriene B(4), which was not affected by emedastine. These results suggest that the inhibition by emedastine of substance P-induced itch-associated response is mediated by the blockade of leukotriene B(4) action. Anti-leukotriene B(4) action, as well as the anti-histamine action, may contribute to the anti-pruritic effects of emedastine.

Topics: Animals; Anti-Allergic Agents; Benzimidazoles; Dose-Response Relationship, Drug; Histamine; Injections, Intradermal; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Pruritus; Serotonin; Substance P

The antipruritic effect of DA-5018, a capsaicin derivative, was examined in mice. Male ICR mice were topically pretreated with Zostrix-HP (0.075% capsaicin cream), 0.1%, 0.3% DA-5018 cream or cream base (control) twice daily for 4 days. One hour after the last application, itch was induced either by compound 48/80 (50 microg, s.c.) or leukotriene B4 (0.03 nmol, i.d.) injection into the rostral back of the animals, and the number of scratches made by the animals at the injection site was counted for 60 min post-injection. DA-5018 cream (both 0.1 and 0.3%) significantly inhibited compound 48/80-induced scratching when compared with the cream base control (p<0.01), while Zostrix-HP showed minimal inhibition of the scratching behavior. In leukotriene B4-induced itch model, Zostrix-HP and 0.3% DA-5018 cream significantly inhibited the scratching during the first 10-min period (p<0.01). The results suggest that DA-5018 cream can be used as an antipruritic agent and warrant clinical evaluation.

Topics: Administration, Topical; Animals; Antipruritics; Capsaicin; Drug Interactions; Leukotriene B4; Male; Mice; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; Pruritus; Time Factors

The itch-associated responses induced by intradermal injection of leukotriene B4 and prostaglandin E2 were studied in mice. Leukotriene B4(0.001-1 nmol/site) elicited scratching of the injected site; the dose-response curve was bell-shaped with a peak effect at 0.03 nmol/site. The effect of leukotriene B4 (0.03 nmol/site) started within 3 min, peaked in the second 10-min period, had almost subsided by 30 min, and was inhibited by the simultaneous injection of the leukotriene B4 receptor antagonist ONO-4057, 5-[2-(2carboxyethyl)-3-(6-( p-methoxyphenyl)-5E-hexenyl) oxyphenyoxy] valeric acid. Prostaglandin E2 (0.003-300 nmol/site) did not significantly elicit scratching. The results raise the possibility that leukotriene B4 is an endogenous itch mediator in the skin.

Topics: Animals; Dinoprostone; Injections, Intradermal; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Phenylpropionates; Pruritus; Receptors, Leukotriene B4

Pruritus is a very common complication in chronic hemodialysis (HD) patients, however the exact mechanism for this affliction is still not known. Anti-histaminics usually failed to alleviate uremic pruritus. In others, an anti-allergic drug, which inhibits the release of chemical mediators, such as leukotrienes or histamine from mast cells, was reported to be effective. We evaluated the values of leukotriene B4 and interleukin 6 in HD patients with pruritus and the effect of an anti-allergic drug on these factors. Leukotriene B4, interleukin-6, C3a, C5a, the number of eosinophil and IgE at 0, 15 and 180 minutes after the start of regular HD in 11 HD patients suffering from pruritus and as well as in 11 HD patients without pruritus were examined. These HD patients in both groups showed significantly higher (p < 0.001) values of leukotriene B4 and C3a compared to healthy non-HD subjects. There was no difference in the leukotriene B4, interleukin-6, IgE, C3a and C5a levels between the patients with and without pruritus. Two mg/day of azelastin hydrochloride, an anti-allergic drug was orally given to the pruritus group for 3 weeks. In 5 of 11 patients, the pruritus symptoms disappeared, while in 4 of 11 they improved. Independent of the effect of the drug on pruritus, leukotriene B4 levels significantly decreased compared with those before the administration of this drug in the pruritus group (p < 0.01). Interleukin 6, C3a, C5a and the number of eosinophils demonstrated no significant change. In conclusion, although azelastin hydrochloride was effective in treating pruritus and also suppressed leukotriene B4 levels in hemodialysis patients, the high leukotriene B4 activity itself did not seem to be related to the development of pruritus in these patients.

Topics: Histamine Antagonists; Histamine H1 Antagonists; Humans; Interleukin-6; Leukotriene B4; Phthalazines; Pruritus; Renal Dialysis