Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence that neuropeptides such as a substance P, neurotrophins or beta-endorphin, an endogenous agonist for mu-opioid receptor, are involved in the pathogenesis of atopic dermatitis in which mental stress and scratching deteriorate the disease. mu-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of mu-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of mu-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the mu-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the 'intensity' and 'pattern' hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that 'itch' is elicited in the epidermal unmyelinated nerve C-fibers and 'pain' in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the 'layer hypothesis'.
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PMID:Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis. 1572 90

Pruritus is a common, distressing and difficult to manage complication of many autoimmune diseases. A suitable animal model of autoimmune disease associated pruritus would contribute to a better understanding of the pathophysiology of this symptom and lead to the development of safe and effective antipruritic agents. We noticed spontaneous scratching behavior in aged MRL/lpr mice, a model of autoimmune disease. This scratching behavior was observed in a specific pathogen-free environment and was more frequent in female mice. In contrast to animal models of dermatitis; NC/Nga mice, the serum IgE and IgG1 levels in MRL/lpr mice were not elevated. These features indicate that this scratching behavior is similar to human autoimmune disease associated pruritus. The antipruritic effects of an antihistamine (chlorpheniramine), an opioid receptor antagonist (naltrexone), and a novel kappa-opioid receptor agonist (nalfurafine hydrochloride [TRK-820]) were evaluated. The frequency of scratching was not reduced by oral administration of chlorpheniramine, suggesting that the behavior is antihistamine-resistant. The oral administration of nalfurafine and subcutaneously administered naltrexone inhibited the scratching behavior without causing gross behavioral changes. In conclusion, MRL/lpr mice scratching behavior is a suitable model of pruritus that occurs in autoimmune diseases, and nalfurafine was shown to be efficacious against this behavior suggesting that it may be beneficial in patients with autoimmune disease associated pruritus.
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PMID:Spontaneous scratching behavior in MRL/lpr mice, a possible model for pruritus in autoimmune diseases, and antipruritic activity of a novel kappa-opioid receptor agonist nalfurafine hydrochloride. 1605 14

Uremic pruritus is a very common and frustrating condition for both patients and clinicians because no treatment has been demonstrated to be effective in relieving the itch. In this report, nalfurafine, a new kappa-opioid receptor agonist, was used to treat uremic pruritus in patients who were undergoing routine hemodialysis. Two multicenter, randomized, double-blind, placebo-controlled studies enrolled 144 patients with uremic pruritus to postdialysis intravenous treatment with either nalfurafine or placebo for 2 to 4 wk. A meta-analysis approach was used to assess the efficacy of nalfurafine. Statistically significant reductions in worst itching (P = 0.0212), itching intensity (P = 0.0410), and sleep disturbances (P = 0.0003) were noted in the nalfurafine group as compared with placebo. Improvements in itching (P = 0.0025) and excoriations (P = 0.0060) were noted for the nalfurafine-treated patients. Nalfurafine showed similar types and incidences of drug-related adverse events as did placebo. Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population.
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PMID:Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. 1625 Dec 41

6beta-Naltrexol is the major metabolite of the opioid receptor antagonist, naltrexone, in humans. However, there are no functional studies of 6beta-naltrexol in primates. The aim of this study was to compare the in vitro and in vivo potencies of naltrexone and 6beta-naltrexol in rhesus monkeys. Affinity and potency were determined using radioligand displacement and stimulation of 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in monkey brain membranes. In vivo apparent pA(2) analysis was applied to compare the mu-opioid receptor (MOR) antagonist potency of both compounds in nondependent monkeys. In addition, the potencies of both compounds were determined in precipitating withdrawal manifested by increased respiratory parameters in acute morphine-dependent monkeys. In vitro assays revealed that naltrexone displayed 2-fold higher affinity and potency than 6beta-naltrexol for the MOR binding site and for MOR agonist-stimulated [(35)S]GTPgammaS binding, respectively. 6beta-Naltrexol (0.32-3.2 mg/kg) dose-dependently produced parallel rightward shifts of the dose-response curve of alfentanil-induced antinociception. Nevertheless, the apparent pA(2) value of 6beta-naltrexol (6.5) was 100-fold less potent than that of naltrexone (8.5) determined previously. 6beta-Naltrexol was also less potent than naltrexone in antagonizing other MOR-mediated effects including respiratory depression and itch/scratching. Naltrexone (0.0032-0.032 mg/kg) and 6beta-naltrexol (0.32-3.2 mg/kg) retained the same potency difference in precipitating withdrawal to a similar degree. Furthermore, 6beta-naltrexol failed to block naltrexone-precipitated withdrawal in morphine-dependent monkeys. These results indicate that naltrexone and 6beta-naltrexol display similar pharmacological actions with a large in vivo potency difference in monkeys such that 6beta-naltrexol may play a minimal role in the therapeutic or antagonist effects of naltrexone in primates.
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PMID:Differential in vivo potencies of naltrexone and 6beta-naltrexol in the monkey. 1625 20

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.
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PMID:Involvement of skin barrier dysfunction in itch-related scratching in special diet-fed hairless mice. 1635 56

Pruritus is a key symptom of hepatic disease. In severe cases, this symptom ruins the patient's quality of life. Most likely it is caused by a protein-bound bile acid (metabolite) that stimulates opioid receptors in the brain. Symptomatic treatments that can reduce pruritus in selected patients include opioid receptor antagonists, biliary diversion, cholestyramine, ursodeoxycholic acid, rifampicin and phenobarbitone. Plasmapheresis or albumin dialysis may be useful when other treatment fails.
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PMID:[Hepatic pruritus]. 1649 40

Both, pruritus and pain are aversive, but clearly distinct sensations originating in the peripheral and central nervous system. During the last years, many interactions between itch and pain in acute transmission and sensitization processes have been identified. It is common experience that the itch sensation can be reduced by the painful sensations caused by scratching. Vice versa analgesia may reduce this inhibition and thus enhance itch. This phenomenon is particularly relevant to spinally administered mu-opioid receptor agonists, which induce segmental analgesia often combined with segmental pruritus. The peripheral and central sensitization to pain and to itch exhibits striking similarities. Classical inflammatory mediators such as bradykinin have been shown to sensitize nociceptors for both itch and pain. Also regulation of gene expression induced by trophic factors, such as NGF, plays a major role in persistently increased neuronal sensitivity for itch and pain. Finally, itch and pain exhibit corresponding patterns of central sensitization. The knowledge of antagonistic interaction, but also of similar sensitization processes has major implication for antipruritic therapeutic approaches.
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PMID:Chronic itch and pain--similarities and differences. 1667 56

Nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide that is an endogenous ligand for the N/OFQ peptide (NOP) receptor. The aim of this study was to investigate the behavioral responses of N/OFQ and its major fragment N/OFQ(2-17) in monkeys following i.t. administration. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was used to quantify the amounts of N/OFQ and N/OFQ(2-17) in the cerebrospinal fluid at specific time points when effects of i.t. N/OFQ were sustained and disappeared. Intrathecal administration of N/OFQ dose dependently (10-100 nmol) produced long-lasting antinociception against a noxious stimulus, 50 degrees C water, and did not elicit itch/scratching responses in monkeys. Subcutaneous pretreatment with a selective NOP receptor antagonist, (+)J-113397 [(1-[3R,4R)-1-cyclooctymethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3,-dihydro-2H-benzimidazol-2-one] (0.1 mg/kg), completely blocked i.t. N/OFQ (100 nmol)-induced antinociception. In contrast, a classic opioid receptor antagonist, naltrexone (0.01 and 1 mg/kg), failed to reverse i.t. N/OFQ-induced antinociception. MALDI-TOF-MS showed that the amount of N/OFQ(2-17) was 4-fold higher than that of N/OFQ at 1.5 h after i.t. administration of 100 nmol N/OFQ. Intrathecal N/OFQ-induced antinociception disappeared at 4.5 h, which corresponded to nearly undetectable cerebrospinal fluid levels of N/OFQ. No other metabolite of N/OFQ was detected at appreciable levels at either the 1.5- or 4.5-h time points. Although significant amounts of N/OFQ(2-17) were detected at the 1.5- and 4.5-h time points, 100 nmol N/OFQ(2-17) i.t. was inactive in changing the monkeys' nociceptive threshold. These results provide the first functional evidence of spinal N/OFQ-induced antinociception in primates and indicate that activation of spinal NOP receptors may be a potential target for spinal analgesics.
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PMID:Effects of intrathecally administered nociceptin/orphanin FQ in monkeys: behavioral and mass spectrometric studies. 1676 18

The mu- (MOR) and kappa- (KOR) opioid receptors have been implicated in the regulation of homeostasis of non-neuronal cells, such as keratinocytes, and sensations like pain and chronic pruritus. Therefore, we have studied the phenotype of skin after deletion of MOR and KOR. In addition, we applied a dry skin model in these knockout mice and compared the different mice before and after induction of the dermatitis in terms of epidermal thickness, epidermal peripheral nerve ending distribution, dermal inflammatory infiltrate (mast cells, CD4 positive lymphocytes), and scratching behavior. MOR knockout mice reveal as phenotype a significantly thinner epidermis and a higher density of epidermal fiber staining by protein gene product 9.5 than the wild-type counterparts. Epidermal hypertrophy, induced by the dry skin dermatitis, was significantly less developed in MOR knockout than in wild-type mice. Neither mast cells nor CD4 T(h)-lymphocytes are involved in the changes of epidermal nerve endings and epidermal homeostasis. Finally, behavior experiments revealed that MOR and KOR knockout mice scratch less after induction of dry skin dermatitis than wild-type mice. These results indicate that MOR and KOR are important in skin homeostasis, epidermal nerve fiber regulation, and pathophysiology of itching.
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PMID:Deletion of mu- and kappa-opioid receptors in mice changes epidermal hypertrophy, density of peripheral nerve endings, and itch behavior. 1750 59

The micro-opioid (beta-endorphin/micro-opioid receptor) and kappa-opioid (dynorphin A (DynA)/kappa-opioid receptor) systems play pivotal roles in the modulation of pruritus in the central nervous system. The micro-opioid system has also been identified in human epidermis, raising the possibility that the system controls the peripheral itch. However, the precise distribution of the kappa-opioid system has not yet been clarified in human epidermis. To address this issue, reverse transcription-PCR and immunohistochemical analyses were performed on cultured keratinocytes and normal skins from humans. The analyses revealed that epidermal keratinocytes express kappa-opioid receptor and its ligands, DynA (1-17) and DynA (1-8). Moreover, expression for micro- and kappa-opioid systems was examined immunohistochemically in skin biopsies from healthy volunteers and patients with atopic dermatitis (AD) before and after psoralen-ultraviolet A (PUVA) therapy. Our expression analyses showed that only the kappa-opioid system, not the micro-opioid system, was downregulated in the epidermis of AD patients. The downregulation of the micro-opioid system and the restoration of the kappa-opioid system by PUVA therapy were observed in the AD patients, concomitant with a decrease of VAS (visual analogue scale) scores. These results suggest epidermal opioid systems are associated with the modulation of pruritus in AD. This new finding may help us to understand the control mechanism of peripheral itch.
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PMID:Possible roles of epidermal opioid systems in pruritus of atopic dermatitis. 1761 80


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