ABSTRACT
The innate immune system has an emerging role as a mediator of neuro-immune communication and a therapeutic target for itch. Toll-like receptor 3 (TLR3) plays an important role in itch, as shown in TLR3 knock-out mice. In this study, to evaluate effects of TLR3 inhibitors on histamine-independent itch, we used two kinds of isothiocyanate (ITC). Both phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) inhibited Poly I:C (PIC)-induced signaling in the RAW264.7 cell line. We then investigated the anti-pruritic effect of these compounds on PIC- and chloroquine (CQ)-induced scratching behavior. PEITC and SFN both suppressed PIC-evoked scratching behavior in mice, and PEITC also inhibited CQ-induced acute itch. Finally, we examined the oxazolone-induced chronic itch model in mice. Surprisingly, oral dosing of both compounds suppressed scratching behaviors that were observed in mice. Our findings demonstrate that TLR3 is a critical mediator in acute and chronic itch transduction in mice and may be a promising therapeutic target for pruritus in human skin disorders. It is noteworthy that SFN has potential for use as an antipruritic as it is a phytochemical that is used as a supplement.
Subject(s)
Antipruritics , Toll-Like Receptor 3 , Animals , Humans , Mice , Antipruritics/pharmacology , Antipruritics/therapeutic use , Chloroquine , Mice, Knockout , Pruritus/chemically induced , Pruritus/drug therapy , Pruritus/metabolism , Skin/metabolism , Toll-Like Receptor 3/therapeutic useABSTRACT
Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H1 receptor antagonist with membrane-stabilizing activity) slightly reduced scratching. However, terfenadine (H1 receptor antagonist), methysergide (serotonin (5-HT)2 receptor antagonist), ondansetron (5-HT3 receptor antagonist), proteinase-activated receptor 2-neutralizing antibody, fluvoxamine (selective serotonin reuptake inhibitor), milnacipran (serotonin-noradrenalin reuptake inhibitor), and cyproheptadine (H1 and 5-HT2 receptor antagonist) did not affect scratching. These results suggested that partial obstruction of bile secretion in mice induced anti-histamine-resistant itching and that central opioid system is involved in cholestatic itching.
Subject(s)
Cholestasis/complications , Disease Models, Animal , Pruritus/etiology , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/therapeutic use , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Animals , Antipruritics/therapeutic use , Bile Ducts/pathology , Bile Ducts/surgery , Cholestasis/drug therapy , Cholestasis/pathology , Clonidine/therapeutic use , Ligation , Liver/pathology , Male , Mice, Inbred ICR , Naloxone/therapeutic use , Narcotic Antagonists/therapeutic use , Pruritus/drug therapy , Pruritus/pathology , Receptors, Opioid, kappa/agonistsABSTRACT
κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.
Subject(s)
Analgesics/pharmacology , Drug Discovery , Morphinans/pharmacology , Pain/drug therapy , Receptors, Opioid, kappa/agonists , Spiro Compounds/pharmacology , Acetic Acid , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Conformation , Morphinans/chemical synthesis , Morphinans/chemistry , Pain/chemically induced , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.
Subject(s)
Amines/chemistry , Anti-Anxiety Agents/chemical synthesis , Receptor, Metabotropic Glutamate 5/chemistry , Administration, Oral , Allosteric Regulation , Amines/chemical synthesis , Amines/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Crystallography, X-Ray , Disease Models, Animal , Hyperthermia, Induced , Mice , Molecular Conformation , Receptor, Metabotropic Glutamate 5/metabolism , Rectum/drug effects , Rectum/physiology , Stereoisomerism , Structure-Activity Relationship , TemperatureABSTRACT
In this study, the antipruritic effect of the methanol extract of Ganoderma lucidum (MEGL) was studied in mice. Oral administration of MEGL (10-1000 mg/kg) produced a dose-dependent inhibition of scratching, an itch-related response, induced by intradermal 5-hydroxytryptamine (5-HT) (100 nmol/site), alpha-methyl-5-HT (100 nmol/site), and proteinase-activated receptor-2 (PAR(2))-activating peptide SLIGRL-NH(2) (50 nmol/site). However, MEGL (100-1000 mg/kg) did not inhibit the scratching induced by histamine (100 nmol/site), substance P (100 nmol/site), and compound 48/80 (10 microg/site). These results raise the possibility that MEGL is effective against pruritus mediated by proteinases and 5-HT and that primary afferents expressing PAR(2) and 5-HT(2A) receptors are the sites of its action.
Subject(s)
Behavior, Animal/drug effects , Biological Products/therapeutic use , Phytotherapy , Pruritus/drug therapy , Reishi , Skin/drug effects , Afferent Pathways/drug effects , Afferent Pathways/metabolism , Animals , Biological Products/pharmacology , Dose-Response Relationship, Drug , Histamine , Male , Mice , Mice, Inbred ICR , Oligopeptides , Pruritus/chemically induced , Receptor, PAR-2 , Receptors, Serotonin/metabolism , Serotonin , Skin/innervation , Substance P , p-Methoxy-N-methylphenethylamineABSTRACT
The present study was conducted to determine whether cutaneous itch involves mu-opioid receptors in either of the spinal cord or lower brainstem or in both regions in mice. An intraplantar injection of serotonin hydrochloride (100 nmol/site) induced biting, an itch-related behavior. The behavior was inhibited by subcutaneous (0.3-1 mg/kg) and intracisternal (1--10 nmol/site), but not intrathecal (1--10 nmol/site), injections of naloxone hydrochloride. An intradermal injection of serotonin (100 nmol/site) to the rostral back induced scratching, an itch-related behavior, which was inhibited by subcutaneous (1 mg/kg) and intracisternal (10 nmol/site) injections of naloxone. These results suggest that mu-opioid receptor in the lower brainstem, but not spinal cord, is a site of central pruritogenic action of opioids and is involved in the facilitatory regulation of itch signaling.
Subject(s)
Behavior, Animal/drug effects , Cisterna Magna/metabolism , Naloxone , Narcotic Antagonists , Pruritus/drug therapy , Animals , Brain Stem/drug effects , Brain Stem/metabolism , Cisterna Magna/drug effects , Injections, Spinal , Injections, Subcutaneous , Ligands , Male , Mice , Mice, Inbred ICR , Naloxone/administration & dosage , Naloxone/pharmacology , Naloxone/therapeutic use , Narcotic Antagonists/administration & dosage , Narcotic Antagonists/pharmacology , Narcotic Antagonists/therapeutic use , Pruritus/metabolism , Receptors, Opioid, mu/metabolism , Serotonin/pharmacology , Spinal Cord/drug effects , Spinal Cord/metabolismABSTRACT
The common adverse effect of centrally-injected mu-opioid receptor (mu-OR) agonists is pruritus. This study was conducted using mice to examine whether different subtypes of mu-OR would be responsible for pruritus and analgesia. Intracisternal injections of morphine and morphine-6beta-glucronide (M6G), but not M3G, produced an antinociceptive effect. Morphine, but neither M6G nor M3G, induced facial scratching, a pruritus-related response. Facial scratching following morphine was not affected by the mu(1)-OR antagonist naloxonazine at doses that inhibited the antinociceptive effects. The results suggest that different subtype and/or splice variants of mu-OR are separately involved in pruritus and antinociception of opioids.
