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Itching is the most important symptom in atopic dermatitis because the persistent scratching in response to itching aggravates the disease. However, the etiologic mechanisms of itching in atopic dermatitis remain uncertain. HR-1 hairless mice fed a special diet, HR-AD, develop atopic dermatitis-like symptoms with prolonged scratching episodes. The purpose of this study was to examine whether skin nerve fiber changes were involved in the prolonged scratching seen in this mouse model. On day 56 after the start of feeding, prolonged scratching, as well as atopic dermatitis-like skin changes, were clearly observed in HR-AD-fed mice, while no abnormal changes were observed in mice fed a normal diet. Immunohistochemical analyses of the skin using antibody to protein gene product 9.5 showed the development of numerous immunoreactive nerve fibers in the epidermis of HR-AD-fed mice. Furthermore, after cessation of HR-AD feeding, the reduction in intraepidermal nerve fibers coincided with decreased scratching. Neither the prolongation of scratching nor the increase in intraepidermal nerve fibers was affected by dexamethasone treatment. Thus, the increased number of intraepidermal nerve fibers could be involved in the aggravation of itch-related scratching observed in this model. Keywords:: itch, atopic dermatitis, nerve fiber, hairless mice, protein gene product 9.5

：アレルギー性鼻炎はくしゃみ，鼻汁分泌亢進および鼻閉を主症状とする典型的なI型アレルギー疾患である．くしゃみおよび鼻汁分泌は抗ヒスタミン薬で強く抑制されるが，患者にとって最も苦痛を強いる鼻閉の治療にはグルココルチコイドが繁用され，これに代わる鼻閉の治療薬が望まれる．我々はスギ花粉を抗原としたモルモットアレルギー性鼻炎モデルを作成し，主として抗原惹起後に誘起される2相性の鼻閉ならびに抗原以外の刺激に対する鼻過敏症の発症メカニズムについて解析し，有効な治療薬の候補について検討した．遅発性の鼻閉はシステイニルロイコトリエン（CysLTs）ならびにトロンボキサン（TX）A2の受容体拮抗薬で強く抑制された．また，低濃度のLTD4およびTXA2類似薬，U-46619の点鼻は感作-惹起動物において相乗的に鼻閉を惹起することから，これらのアラキドン酸代謝物は鼻粘膜の効果器において相乗的な作用で遅発性の鼻閉を惹起している可能性が示唆された．鼻過敏性の発症はB1およびB2受容体に対する拮抗薬で抑制され，さらにこれらの受容体のアゴニストであるdes-Arg9-カリジンおよびブラジキニンの点鼻は感作-惹起動物においていずれも鼻過敏症を惹起することから，本鼻炎症状の発症にはキニン類が大きな役割を演ずる可能性が示唆された．実際の鼻アレルギー患者では，抗原惹起が繰り返され，2相性の鼻閉と鼻過敏症がオーバーラップして発症していることから，これらの鼻閉をコントロールするためには，アラキドン酸代謝物の作用を抑制することに加えて，キニン類の作用を阻害することが有効である可能性が示唆された．

To develop an allergic dermatitis model showing persistent scratching in mice, toluene-2,4-diisocyanate (TDI) was repeatedly painted onto the skin of hairless HR-1 mice, and induction of itch-associated scratching behavior was observed. When HR-1 mice were epicutaneously sensitized with 1% TDI and then challenged by repeated painting the cervicodorsal skin with 0.1% TDI once every 10 days until the 10th challenge, delayed type scratching responses peaked at 1 – 2 days after challenge. TDI at 0.1% hardly induced scratching in non-sensitized HR-1 mice. The delayed scratching response was influenced by neither an H1 nor 5-HT1/2 receptor antagonist. On the other hand, intradermal injection of histamine and serotonin induced frequent scratching in HR-1 mice. In conclusion, repeated application of TDI can induce delayed type allergic scratching. Although HR-1 mice are high responders to both histamine and serotonin, induction of the delayed response depends on neither of these chemical mediators. This delayed response may be useful in analyzing the mechanisms of allergic pruritis.

Peptide-leukotrienes (p-LTs) (LTC4, LTD4 and LTE4) are major metabolites of the arachidonate 5-lipoxygenase pathway. Although a number of papers have reported that p-LTs induce potent bronchial smooth muscle constriction as well as airway mucus secretion, vascular permeability and proliferation of airway smooth muscle cells, it had not been recognized that they are pivotal chemical mediators in asthmatic diseases until recently. Yet, several potent and selective antagonists against p-LTs and inhibitors of p-LT formation revealed that p-LTs play significant roles in not only allergic but non-allergic asthma including exercise- and aspirin-induced asthma. In addition, it has been reported that p-LTs participate in rhinitis, especially nasal blockage. In this article, recent development of drugs relating to p-LTs and their therapeutic effects for asthma are mainly reviewed.

The antiallergic effects of 10-(3-quinuclidinylmethyl)phenothiazine (mequitazine) were investigated in vitro. The results obtained were as follows: 1) In the isolated trachea and lung parenchyma of guinea pigs, mequitazine showed a fairly potent antagonistic action against contractions induced by both histamine (Hi) and acetylcholine (ACh). Mequitazine was much less potent in antihistaminic action and slightly more potent in anticholinergic action than ketotifen. The contractions of the preparation by leukotriene (LT) D4 were antagonized by mequitazine, although the potency was moderate, showing an IC50 value of 2.3 x 10(-5) g/ml in the trachea and 5.1 x 10(-5)g/ml in the lung parenchyma. Mequitazine had no effect on the contraction of the trachea by PGF2 alpha, but inhibited that of the lung parenchyma with pA2 = 7.0. 2) Mequitazine (10(-6) g/ml) slightly inhibited the Schultz-Dale reaction of the isolated guinea pig trachea, while ketotifen at the same concentration did not show any effect. 3) The contraction of the isolated guinea pig trachea by Ca2+ influx was slightly inhibited by mequitazine (10(-5) g/ml). 4) Mequitazine competitively inhibited the cyclic AMP-dependent phosphodiesterase activity from the rat lung with a potency of 10 times and 5 times more than those of ketotifen and theophylline, respectively. 5) Mequitazine (10(-6) to 10(-5) M) suppressed both the anaphylactic and phospholipase A2-induced histamine release from the peritoneal cells of rats. 6) Mequitazine (10(-5) g/ml) also inhibited the anaphylactic and Ca ionophore-induced histamine release from the leukocytes of the atopic patients and normal subjects. 7) The anaphylactic releases of histamine, LTB4 and peptide LT from the human lung fragments were dose-dependently inhibited by mequitazine (10(-7) approximately 10(-5) g/ml).

The effects of tricyclic antidepressant drugs on cardiac receptor binding sites and Ca2+ binding to cardiac sarcoplasmic reticulum were investigated in rats. 1) Quinupramine was found to possess higher affinity for muscarinic cholinergic receptor binding sites in brain and heart, compared with imipramine. 2) Repeated quinupramine treatment induced a significant increase in the Bmax value in cardiac muscarinic cholinergic receptors. 3) In imipramine treated heart, isoproterenol-induced stimulation of ornithine decarboxylase activity was significantly decreased compared with that in the vehicle control. 4) Repeated quinupramine and imipramine treatment caused a significant reduction of Bmax of 45Ca2+ binding in cardiac sarcoplasmic reticulum fractions. 5) After single quinupramine treatment, its concentrations in heart were higher than those in brain and plasma. 6) After the repeated quinupramine treatment, its concentration in heart was 2.4 times higher than that after single treatment. These results demonstrate that repeated tricyclic antidepressant drug treatment caused a functional impairment in Ca2+ binding sites of cardiac sarcoplasmic reticulum and adaptive changes of receptor binding sites.

Effects of the clathrate compound of mobenzoxamine (MBX) with beta-cyclodextrin (MBX-CD), a new gastro-intestinal function modulator, on the digestive system were studied in comparison with those of metoclopramide, domperidone and trimebutine. MBX-CD showed inhibitory effects that were approximately 1/4 times as potent as metoclopramide on both apomorphine- and copper sulfate-induced emesis and about 1/40 times as potent as domperidone on apomorphine-induced emesis in dogs. In rats, MBX-CD enhanced gastric emptying as potently as metoclopramide, and only MBX-CD showed a clear amelioration of the delayed gastric emptying induced by BaCl2. Similarly, only MBX-CD showed an ameliorative effect on small intestinal transport accelerated by BaCl2 in mice. Though both MBX and trimebutine inhibited spontaneous contractions of the isolated guinea pig stomach and rabbit intestine, it seemed that the properties of these effects were different from those of papaverine. On isolated guinea pig ileum, MBX inhibited contractions induced by various agonists equally to or more potently than trimebutine or papaverine. The results suggest that MBX-CD or MBX acts extensively on the gastro-intestinal system for the reason that it has not only the respective properties of the gastro-intestinal function modulators used as the standards, but also its own characteristic effects.