This invention provides an antipruritic comprising an opiate .kappa. receptor agonist as an effective component, a new morphinan quaternary ammonium salt derivative and a new morphinan-N-oxide derivative which are useful in treating pruritus complicated with some diseases.

TECHNICAL FIELD
 The present invention relates to an opiate .kappa. receptor agonist and an
 antipruritic comprising it which are useful for the treatment of pruritus
 associated with various diseases.
 BACKGROUND ART
 Pruritus is an indication that is peculiar to skin, and is observed in a
 variety of dermatoses with inflammation. Pruritus may be provoked by some
 internal diseases (malignant tumors, diabetes mellitus, hepatic diseases,
 renal failure, hemodialysis, gout, thyroid diseases, hemopathy, and iron
 deficiency), pregnancy, and vermination. In some cases, drugs and
 psychogenic causes may also provoke pruritus.
 Since pruritus is a subjective sensation, it is difficult to evaluate it
 quantitatively and objectively. The mechanism that induces pruritus has
 not yet been completely clarified.
 Now, among the stimulants that are known to induce pruritus included are
 histamine, substance P, bradykinin, proteinases, prostaglandins, and
 opiate peptides. It is considered that pruritus is provoked by reaction of
 these pruritic stimulants to multistimuli-reacting nerve terminals
 existing at the border area between the epidermis and dermis (pruritic
 receptors), and by transfer of the resulting impulse to tractus
 spinothalamicus, thalamus, and cortex cerebri in that order ("The approach
 to the therapy for pruritus cutaneous", by Yoshiki Miyaji, p.22, 1996,
 Sentan Igakusya).
 Pruritus is a symptom in which patients experience significant discomfort,
 and in severe cases may cause significant disturbance of normal life. In
 the therapy for pruritus, primarily the treatment of dermatitis or an
 underlying disease that induces pruritus is necessary, and particularly in
 cases of dermatoses, simultaneous therapy for pruritus itself is
 necessary, because stratching by a patient causes aggravation of symptoms.
 Excoriation is the most exacerbating factor of dermatitis, because
 stratching injures the skin resulting in defect of barrier function, and
 erosion by physical or chemical stimuli and bacterial infection may easily
 occur. Also, since the epidermis becomes thin and fragile and nerves are
 sensitized, pruritus readily occurs. As a result, a vicious cycle of
 repeated stratching begins.
 For example, although the period of stratching resulting from pruritus
 during sleep is only 0.1% in healthy cases, the average period of
 stratching by patients with severe atopic dermatitis amounts to 24%. If an
 average period of sleep is assumed to be 8 hours, the period of stratching
 will reach about 2 hours. It is clear that the stratching during sleep
 exacerbates atopic dermatitis and becomes a factor in the occurrence of
 atopic exanthema ("NIKKEI MEDICAL", JUL. 10, 1996, p13).
 Thus the therapy for pruritus itself may be a radical treatment,
 particularly in cases of dermatosis with significant pruritus.
 Examples of dermatoses generally subjected to therapy for such pruritus
 include atopic dermatitis, nervous dermatitis, contact dermatitis,
 seborrheic dermatitis, autosensitization dermatitis, caterpillar
 dermatitis, asteatosis, senile pruritus cutaneuos, insect sting,
 photosensitive dermatosis, urticaria, prurigo, herpes, impetigo, eczema,
 tinea, lichen, psoriasis, scabies, and acne vulgaris; and examples of
 visceral diseases complicated with pruritus and being particular problems
 include malignant tumors, diabetes mellitus, hepatic diseases, renal
 failure, hemodialysis, and pregnancy.
 Examples of drugs generally used for therapy for such pruritus include oral
 drugs, e.g. antihistamines, and antiallergic drugs; and topical
 preparations, e.g. antihistamines, adrenocortical steroid dermatologic
 preparations, nonsteroidal anti-inflammatory drugs, camphor, menthol,
 phenol, salicylic acid, tar, crotamiton, capsaicin, and humectants (urea,
 Hirudoid, and petrolatum). However, oral drugs have some problems, e.g. a
 long lag time before presenting effects, and adverse events such as
 suppressive effects on the central nervous system (drowsiness and fatigue)
 and impairment of the gastrointestinal system. Topical preparations also
 have some problems, e.g. insufficient antipruritic effect, while topical
 steroids particularly cause some problems of adverse events such as
 decreased adrenocortical function caused by protracted administration and
 the rebound phenomenon.
 With regard to the relationship between opiates and pruritus, it has been
 clear that opiates have function not only as analgesics but also as
 chemical mediators of pruritus. It was first reported that endogenous
 opiate peptides such as .beta.-endorphin and enkephalin induced pruritus
 (B. Fjeller, Acta. Dermato-Venereol. , 61 (suppl. 97), 1-34,1981). It has
 been shown that morphine or opiate compounds induced pruritus as an
 adverse event when administered epidurally or intrathecally (J. H. Jaffe
 and W. R. Martin, Goodman and Gilman's Pharmacological Basis of
 Theraputics, Macmillan, New York, 1985). On the other hand, it has been
 also shown that pruritus which induced by morphine administered
 intrathecally was suppressed by naloxone, a morphine antagonist (J.
 Bernstein et al., J. Invest. Dermatol. , 78, 82-83, 1982), and severe
 pruritus induced by increasing concentration of endogenous opiate peptides
 in cases of cholestasia with hepathopathy was suppressed by nalmefene (J.
 R. Thornton and M. S. Losowsky, Br. Med. J., 297, 1501-1504, 1988).
 Generally, opiate agonists induce pruritus, whereas opiate antagonists are
 antipruritic. Recently, it has become evident that the serum concentration
 of .beta.-endorphin in children with atopic dermatitis is significantly
 higher than that of healthy children. And it was reported that opiate
 antagonists were effective in pruritus induced by atopic dermatitis (S.
 Georgala et al., J. Dermatol. Sci., 8, 125-128, 1994).
 Thus, it has been generally recognized that opiate agonists induce pruritus
 and opiate antagonists have a possibility as antipruritic. However, opiate
 antagonists do not have a practical use as an antipruritic at the present
 stage.
 An object of this invention is to provide an opiate .kappa. receptor
 agonist and an antipruritic comprising it that solves the above problems
 and which has a significantly prompt and potent antipruritic activity.
 DISCLOSURE OF INVENTION
 The present invention provides an opiate .kappa. receptor agonist and an
 antipruritic comprising it as an effective component.