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Background: Parent-child saliva contact during infancy might stimulate the child's immune system for effective allergy prevention. However, few studies have investigated its relation to allergy development in school-age children. Objective: We sought to investigate the relationship between parent-child saliva contact during infancy and allergy development at school age. Methods: We performed a large multicenter cross-sectional study involving Japanese school children and their parents. The self-administered questionnaires including questions from the International Study of Asthma and Allergies in Childhood were distributed to 3570 elementary and junior high school children in 2 local cities. Data were analyzed for the relationship between saliva contact during infancy (age <12 months) and the risk of allergy development, specifically eczema, allergic rhinitis, and asthma. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. Results: The valid response rate was 94.7%. The mean and median age of children was 10.8 ± 2.7 and 11 (interquartile range, 9-13) years, respectively. Saliva contact via sharing eating utensils during infancy was significantly associated with a lower risk of eczema (odds ratio, 0.53; 95% CI, 0.34-0.83) at school age. Saliva contact via parental sucking of pacifiers was significantly associated with a lower risk of eczema (odds ratio, 0.24; 95% CI, 0.10-0.60) and allergic rhinitis (odds ratio, 0.33; 95% CI, 0.15-0.73), and had a borderline association with the risk of asthma in school-age children. Conclusions: Saliva contact during infancy may reduce the risk of developing eczema and allergic rhinitis in school-age children.
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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.
Assuntos
Colestase/complicações , Modelos Animais de Doenças , Prurido/etiologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Antipruriginosos/uso terapêutico , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Colestase/tratamento farmacológico , Colestase/patologia , Clonidina/uso terapêutico , Ligadura , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Prurido/tratamento farmacológico , Prurido/patologia , Receptores Opioides kappa/agonistasRESUMO
Chemotherapeutic drugs typically induce peripheral neuropathy, which is a major dose-limiting side effect of these drugs and is difficult to manage. In this study, we examined whether the traditional herbal formulation Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) could relieve the mechanical allodynia induced by chemotherapeutic drugs (oxaliplatin, paclitaxel, vincristine, and bortezomib) in mice. A single intraperitoneal injection of oxaliplatin, paclitaxel, vincristine, and bortezomib was used to induce mechanical allodynia, which peaked on days 10, 14, 14, and 12 after the injection, respectively. A single oral administration of KSOT did not inhibit mechanical allodynia after any of the treatments. However, prophylactic repetitive oral administrations of KSOT inhibited the exacerbation of mechanical allodynia induced by oxaliplatin but were not effective for allodynia induced by the other drugs. A single intraperitoneal injection of oxaliplatin did not alter the mRNA expression of the NMDA receptor NR2B in the spinal cord and that of neuregulin-1 in the sciatic nerve. In addition, the number of microglia in spinal dorsal horn did not increase in oxaliplatin-treated mice. However, the number of reactivated astrocytes in the spinal dorsal horn increased, which could be inhibited by repetitive administration of KSOT. These results suggest that prophylactic repetitive treatment of KSOT attenuates oxaliplatin-induced mechanical allodynia by decreasing the number of spinal astrocytes.
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Chronic renal failure (CRF) is a progressive disease with severe pruritus and dry skin as the major symptoms. However, the mechanisms of CRF-induced pruritus remain unclear. In this study, 5/6 nephrectomized (NPCT) mice were used as a mouse model of CRF. Serum concentrations of blood urea nitrogen and creatinine in 5/6 NPCT mice were increased. The stratum corneum water content in the skin of 5/6 NPCT mice was decreased. These findings suggest that 5/6 nephrectomy in mice results in a phenotype resembling human CRF. 5/6 NPCT mice showed spontaneous scratching, which was inhibited by µ-opioid receptor antagonist, suggesting that the scratching is an itch-related response. The number of cutaneous mast cells was not altered in 5/6 NPCT mice compared with sham-operated mice. The H1 histamine-receptor antagonist, proteinase-activated receptor 2-neutralizing antibody, and 5-HT3-receptor antagonist did not inhibit spontaneous scratching in 5/6 NPCT mice; therefore, the role of mast cells and serotonin in spontaneous scratching appears to be minimal. The anti-allergy agent azelastine, BLT leukotriene (LT) B4 receptor antagonist, and TP thromboxane (TX) A2 receptor antagonist inhibited spontaneous scratching in 5/6 NPCT mice, suggesting that LTB4 and TXA2 are involved in CRF-induced pruritus. Interestingly, in the skin of 5/6 NPCT mice, levels of two newly identified pruritogens (ß2-microglobulin and interleukin-31) were increased. Taken together, these findings suggest that 5/6 NPCT mice are useful for the study of itching in CRF. In addition to LTB4 and TXA2, it is also suggested that ß2-microglobulin and interleukin-31 are involved in itching associated with CRF-induced pruritus.
Assuntos
Ácido Araquidônico/metabolismo , Globulinas/metabolismo , Interleucinas/metabolismo , Falência Renal Crônica/metabolismo , Leucotrieno B4/metabolismo , Prurido/metabolismo , Tromboxano A2/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Antagonistas de Entorpecentes/farmacologiaAssuntos
Dermatite Atópica/metabolismo , Prurido/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Comportamento Animal , Dermatite Atópica/genética , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Prurido/genética , Receptores Purinérgicos P2X3/genética , Pele/metabolismoRESUMO
Fentanyl is an opioid commonly prescribed for cancer pain. Using melanoma-bearing mice, we investigated whether peripheral action would contribute to fentanyl analgesia in cancer pain. Intravenous injection of fentanyl inhibited mechanical nociception in healthy mice, which was markedly inhibited by the opioid antagonist naloxone, but not naloxone methiodide, a peripherally acting opioid antagonist. Melanoma-bearing mice showed mechanical allodynia and spontaneous licking, a pain-related behavior, which were suppressed by intravenous and local injections of fentanyl. Both naloxone and naloxone methiodide inhibited the analgesic effect of intravenous fentanyl to the same degree. Electrophysiological analysis showed that melanoma growth increased the spontaneous and mechanical stimuli-evoked activity of the tibial nerve, which were inhibited by intravenous fentanyl. There was a greater expression of µ- opioid receptors in skin with a melanoma mass than in the contralateral normal skin. In addition, we found µ-opioid receptors in cultured melanoma cells. There was no difference between the number of µ-opioid receptors in the dorsal root ganglia and spinal cord of the melanoma-bearing and contralateral skin side. These results suggest that the analgesic effect of systemic fentanyl is produced via central and peripheral µ- opioid receptors in cancer pain, and cancer cells are a key site of peripheral action.
Assuntos
Analgésicos Opioides/farmacologia , Dor do Câncer/tratamento farmacológico , Fentanila/farmacologia , Hiperalgesia/tratamento farmacológico , Receptores Opioides mu/metabolismo , Potenciais de Ação/efeitos dos fármacos , Analgésicos Opioides/antagonistas & inibidores , Analgésicos Opioides/uso terapêutico , Animais , Dor do Câncer/etiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fentanila/antagonistas & inibidores , Fentanila/uso terapêutico , Humanos , Hiperalgesia/etiologia , Injeções Intramusculares , Injeções Intravenosas , Masculino , Melanoma/complicações , Camundongos , Camundongos Endogâmicos C57BL , Naloxona/análogos & derivados , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Compostos de Amônio Quaternário/farmacologia , Receptores Opioides , Pele/patologia , Neoplasias Cutâneas/complicações , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Nervo Tibial/efeitos dos fármacos , Nervo Tibial/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The antipruritic activity of gabapentin, an anticonvulsant, was studied in a mouse model of allergic itch. In mice sensitized by an extract of the salivary glands of the mosquito (ESGM), an intradermal injection of ESGM elicited scratching and increased peripheral nerve firing. Oral or intradermal administration of gabapentin at the ESGM injection site inhibited ESGM-induced scratching and peripheral nerve firing. However, gabapentin did not affect histamine-induced scratching. The distributions of immunoreactivity to the voltage-dependent calcium channel α2δ-1 subunit, a site of gabapentin action, and the histamine H1 receptor differed in the mouse dorsal root ganglia. The α2δ-1 subunit was mainly found in neurons that were 15-20⯵m in diameter, whereas the H1 receptor was mainly in 20-30⯵m neurons. In addition, α2δ-1 subunit immunoreactivity co-localized with that of transient receptor potential vanilloid 1 (TRPV1). These results suggest that gabapentin regulates allergic itch by acting on the calcium channel α2δ-1 subunit in peripheral TRPV1-positive neurons.
Assuntos
Aminas , Antipruriginosos , Canais de Cálcio/metabolismo , Culicidae/imunologia , Ácidos Cicloexanocarboxílicos , Hipersensibilidade/tratamento farmacológico , Prurido/tratamento farmacológico , Saliva/imunologia , Ácido gama-Aminobutírico , Aminas/farmacologia , Aminas/uso terapêutico , Animais , Antipruriginosos/farmacologia , Antipruriginosos/uso terapêutico , Ácidos Cicloexanocarboxílicos/farmacologia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Gabapentina , Hipersensibilidade/metabolismo , Masculino , Camundongos Endogâmicos ICR , Neurônios/metabolismo , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Prurido/metabolismo , Receptores Histamínicos H1/metabolismo , Canais de Cátion TRPV/metabolismo , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Chronic skin diseases with itch and dry skin show increased peripheral nerve fiber elongation into the epidermis. However, the characteristics of the elongated nerve fibers remain unclear. Therefore, we investigated the characteristics of the elongated nerve fibers using a dry skin mouse model with itch. In this mouse model, prepared via repetitive treatments with an acetone/ether mixture and water, the stratum corneum water content was decreased, whereas spontaneous scratching and epidermal hyperplasia were increased. In addition, the number of substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers (C-fibers) was increased in the epidermis of treated mice compared to that in non-treated control mice. However, neurofilament 200-immunoreactive nerve fibers (A-fibers) were not detected in the epidermis of treated mice. These results suggest that the elongated epidermal peripheral nerve fibers comprise SP/CGRP-containing C-fibers but not A-fibers. Thus, these fibers may be involved in the induction of dry skin pruritus.
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Epiderme/inervação , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Prurido/fisiopatologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Epiderme/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Amielínicas/metabolismo , Pele/inervação , Pele/fisiopatologia , Substância P/metabolismoRESUMO
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.
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Interleucinas , Queratinócitos/metabolismo , Leucotrieno B4/metabolismo , Prurido/metabolismo , Pele/metabolismo , Animais , Antialérgicos/farmacologia , Comportamento Animal , Células Cultivadas , Modelos Animais de Doenças , Queratinócitos/efeitos dos fármacos , Antagonistas de Leucotrienos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos Endogâmicos ICR , Subunidade beta de Receptor de Oncostatina M/genética , Subunidade beta de Receptor de Oncostatina M/metabolismo , Prurido/induzido quimicamente , Prurido/prevenção & controle , Prurido/psicologia , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores do Leucotrieno B4/antagonistas & inibidores , Receptores do Leucotrieno B4/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/inervaçãoRESUMO
Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells.
Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hiperalgesia/prevenção & controle , Glucosídeos Iridoides/administração & dosagem , Paclitaxel/toxicidade , Profilaxia Pré-Exposição/métodos , Células de Schwann/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular , Estresse do Retículo Endoplasmático/fisiologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Paclitaxel/antagonistas & inibidores , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Ratos , Células de Schwann/metabolismoRESUMO
BACKGROUND: The chemotherapeutic agent paclitaxel (PTX) causes refractory peripheral neuropathy as a side effect. Prophylactic oral administration of the traditional herbal medicine Shakuyakukanzoto containing Paeoniae Radix and Glycyrrhizae Radix prevents the development of PTX-induced mechanical allodynia in mice via peripheral effects, mostly due to Paeoniae Radix. However, the bioactive component responsible for the prevention of PTX-induced neuropathic pain remains unknown. PURPOSE: To determine whether a monoterpene glycoside paeoniflorin (PF), which is the principal bioactive constituent of Paeoniae Radix, has inhibitory effects on PTX-induced mechanical allodynia and investigate the underlying mechanisms. METHODS: C57BL/6NCr mice received a single intraperitoneal injection of PTX and then were topically administered PF to the planar surface twice daily for 13 days. Mechanical allodynia was evaluated by the von Frey filament test, peripheral nerve activity was recorded using bipolar electrodes, and demyelination in peripheral nerves was analysed by electron microscopy. Schwann cell line LY-PPB6 pre-treated with PF and then treated with PTX was used to analyse the expression of the transcription factor CHOP, a marker of endoplasmic reticulum (ER) stress, by western blotting. RESULTS: PTX caused mechanical allodynia and increased both spontaneous and mechanical stimuli-evoked peripheral nerve activities, whereas repetitive topical application of PF significantly attenuated PTX-induced allodynia, suppressed saphenous nerve firing, and inhibited demyelination in the plantar nerve. Moreover, in cultured Schwann cells, PF downregulated PTX-induced expression of CHOP, indicating the inhibition of ER stress. The attenuation of mechanical allodynia in mice and downregulation of CHOP levels in cell cultures was inhibited by adenosine A1 receptor (A1R) antagonist 8-cyclopentyl-1,3-diprooylxanrhine, suggesting the involvement of A1R in PF-associated analgesic effects. CONCLUSION: These results suggest that prophylactic topical application of PF is effective in alleviating PTX-induced mechanical allodynia by protecting sensory nerves from demyelination via activation of the A1R.
Assuntos
Glucosídeos/farmacologia , Hiperalgesia/metabolismo , Monoterpenos/farmacologia , Neuralgia/metabolismo , Paclitaxel/efeitos adversos , Paeonia/química , Extratos Vegetais/farmacologia , Receptor A1 de Adenosina/metabolismo , Administração Tópica , Animais , Antineoplásicos/efeitos adversos , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/prevenção & controle , Glucosídeos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos/uso terapêutico , Neuralgia/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêuticoRESUMO
Oxaliplatin-induced peripheral neuropathy characterized especially as cold dysesthesia is a major dose-limiting side effect of the drug and is very difficult to control. In the present study, we examined whether the traditional herbal formulation Shakuyakukanzoto (SKT: Sháo Yào Gan CÇo Tang) could relieve oxaliplatin-induced cold dysesthesia in mice. The inhibitory mechanisms were also investigated. Repetitive administration of SKT (0.1-1.0 g/kg) starting from the day after oxaliplatin injection inhibited cold dysesthesia in a dose-dependent manner. Our previous report has shown that the mRNA expression of transient receptor potential melastatin 8 (TRPM8), characterized as a cold-sensing cation channel, is increased in the dorsal root ganglia of mice treated with oxaliplatin. In addition, TRPM8 antagonist TC-I 2014 (10 and 30 mg/kg) also attenuated cold dysesthesia in oxaliplatin-treated mice. Taken together, it is suggested that TRPM8 is involved in the cold dysesthesia induced by oxaliplatin. Repetitive administration of SKT inhibited the mRNA expression of TRPM8 induced by oxaliplatin in the dorsal root ganglia. These results suggested that prophylactic repetitive administration of SKT is effective in preventing the exacerbation of oxaliplatin-induced cold dysesthesia by inhibiting the mRNA expression of TRPM8 in the dorsal root ganglia.
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BACKGROUND: Our previous study showed that the µ-opioid receptor agonist fentanyl citrate inhibits endothelin-1-and bradykinin-mediated pain responses in mice orthotopically inoculated with melanoma cells. We also demonstrated that bradykinin induces endothelin-1 secretion in melanoma cells. However, the analgesic mechanisms of fentanyl citrate remain unclear. Thus, the present study was conducted to determine whether fentanyl citrate affects bradykinin-induced endothelin-1 secretion in B16-BL6 melanoma cells. METHODS: The amount of endothelin-1 in the culture medium was measured using an enzyme immunoassay. The expression of endothelin-1, kinin B2 receptors, and µ-opioid receptors in B16-BL/6 melanoma cells was determined using immunocytochemistry. RESULTS: Fentanyl citrate inhibited bradykinin-induced endothelin-1 secretion. The inhibitory effect of fentanyl citrate on the secretion of endothelin-1 was attenuated by the µ-opioid receptor antagonist naloxone methiodide. The immunoreactivities of endothelin-1, kinin B2 receptors, and µ-opioid receptors in B16-BL6 melanoma cells were observed. CONCLUSION: These results suggest that fentanyl citrate regulates bradykinin-induced endothelin-1 secretion through µ-opioid receptors in melanoma cells.
Assuntos
Analgésicos Opioides/farmacologia , Bradicinina/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/metabolismo , Fentanila/farmacologia , Melanoma Experimental/metabolismo , Animais , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismoAssuntos
Dermatite de Contato/etiologia , Epiderme/inervação , Histamina/metabolismo , Fibras Nervosas/efeitos dos fármacos , Dodecilsulfato de Sódio/efeitos adversos , Animais , Epiderme/efeitos dos fármacos , Feminino , Histidina Descarboxilase/genética , Masculino , Camundongos Endogâmicos ICR , Camundongos KnockoutRESUMO
Accumulating evidence indicates that purinergic P2X4 receptors (P2X4R: cation channels activated by extracellular ATP) expressed in spinal microglia are crucial for pathological chronic pain caused by nerve damage, suggesting a potential target for drug discovery. We identified NP-1815-PX (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In in vivo assay for acute and chronic pain, intrathecal administration of NP-1815-PX produced an anti-allodynic effect in mice with traumatic nerve damage without affecting acute nociceptive pain and motor function (although its oral administration did not produce the effect). Furthermore, in a mouse model of herpetic pain, P2X4R upregulation in the spinal cord exclusively occurred in microglia, and intrathecal NP-1815-PX suppressed induction of mechanical allodynia. This model also showed K(+)/Cl(-) cotransporter 2 (KCC2) downregulation, which is implicated in dorsal horn neuron hyperexcitability; this downregulation was restored by intrathecal treatment with NP-1815-PX or by interfering with brain-derived neurotrophic factor (BDNF) signaling, a P2X4R-activated microglial factor implicated in KCC2 downregulation. Taken together, the newly developed P2X4R antagonist NP-1815-PX produces anti-allodynic effects in chronic pain models without altering acute pain sensitivity, suggesting that microglial P2X4R could be an attractive target for treating chronic pain.
Assuntos
Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Receptores Purinérgicos P2X4/genética , Animais , Azepinas , Modelos Animais de Doenças , Humanos , Hiperalgesia/genética , Hiperalgesia/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/patologia , Oxidiazóis , Dor/genética , Dor/patologia , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologiaRESUMO
Oxaliplatin causes peripheral neuropathy as a major dose-limiting side effect, and the control of this neuropathy is difficult. This study was designed to investigate whether prophylactic repetitive administration of 5-HT1A receptor agonists inhibits oxaliplatin-induced mechanical allodynia in mice. Repetitive administration of 5-HT1A receptor agonists (xaliproden and tandospirone) inhibited mechanical allodynia induced by a single intraperitoneal injection of oxaliplatin. These agonists also inhibited oxaliplatin-induced mast cell migration, which is involved in the induction of mechanical allodynia. These results suggest that the prophylactic repetitive administration of 5-HT1A receptor agonists attenuates oxaliplatin-induced mechanical allodynia by inhibiting the cutaneous mast cell migration.
Assuntos
Movimento Celular/efeitos dos fármacos , Hiperalgesia/imunologia , Hiperalgesia/prevenção & controle , Isoindóis/farmacologia , Mastócitos/efeitos dos fármacos , Naftalenos/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Hiperalgesia/induzido quimicamente , Masculino , Mastócitos/citologia , Camundongos , Compostos Organoplatínicos , Oxaliplatina , Pele/imunologiaRESUMO
Transient ischemia-reperfusion in the hand and foot elicits spontaneous dysesthesia. However, the mechanisms by which this occurs are not completely understood. The objectives of this study were to examine peripheral neural activity related to spontaneous dysesthesia in a mouse model of hind-paw transient ischemic-reperfusion and to investigate the involvement of oxidative stress in this neural activity. The femoral artery and vein were interrupted for 10min using tourniquet pressure, before the tourniquet was removed to allow reperfusion of the hind paw. Neural activity in the saphenous nerve was recorded during both ischemia and reperfusion. In both the ischemic phase and the reperfusion phase, the frequency of saphenous nerve firing was significantly increased compared to baseline. The antioxidant agent N-acetyl-l-cysteine inhibited significantly the firing of the saphenous nerve in both the maximum and minimum activity periods during ischemia, and in the maximum activity state after reperfusion percentage inhibition being approximately 68%, 60%, and 58%, respectively. In the reperfusion phase, the production of 4-hydroxy-2-noneal, a major product of endogenous lipid peroxidation, was significantly increased in the plantar skin, and this was inhibited by N-acetyl-l-cysteine. In the ischemic phase, a similar trend was observed. These results suggest that an increase in peripheral nerve activity related to oxidative stress may be involved in the spontaneous dysesthesia induced by transient ischemia-reperfusion.
Assuntos
Potenciais de Ação , Membro Posterior/fisiopatologia , Estresse Oxidativo , Parestesia/fisiopatologia , Nervos Periféricos/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Aldeídos/metabolismo , Animais , Modelos Animais de Doenças , Membro Posterior/irrigação sanguínea , Membro Posterior/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parestesia/complicações , Parestesia/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Pele/irrigação sanguínea , Pele/metabolismoRESUMO
The chemotherapeutic agent paclitaxel (PTX) causes peripheral neuropathy as a major dose-limiting side effect, and this peripheral neuropathy is difficult to control. Our previous report showed that prophylactic repetitive administration of goshajinkigan ( niú che shèn qì wán), but not hachimijiogan ( ba wèi dì huáng wán), which lacks two of the constituents of goshajinkigan, inhibited PTX-induced mechanical allodynia in mice. Thus, the herbal medicines Plantaginis Semen ( che qián zÇ) or Achyranthis Radix ( niú xi) may contribute to the inhibitory action of goshajinkigan on the exacerbation of PTX-induced mechanical allodynia [Andoh et al, J. Tradit. Complement. Med. 2014; 4: 293-297]. Therefore, in this study, we examined whether an extract of Plantaginis Semen (EPS) or Achyranthis Radix (EAR) would relieve PTX-induced mechanical allodynia in mice. A single intraperitoneal injection of PTX caused mechanical allodynia, which peaked on day 14 after injection. Repetitive oral administration of EPS, but not EAR, starting from the day after PTX injection significantly inhibited the exacerbation of PTX-induced mechanical allodynia. Repetitive intraperitoneal injection of aucubin, one of the main components of EPS, starting from the day after PTX injection also significantly reduced PTX-induced mechanical allodynia. However, repetitive intraperitoneal injection of geniposide acid (a precursor of aucubin) or catalpol (a metabolite of aucubin) did not prevent the exacerbation of mechanical allodynia. These results suggest that prophylactic administration of EPS is effective for preventing the exacerbation of PTX-induced allodynia. Aucubin may contribute to the inhibitory action of EPS on the exacerbation of PTX-induced allodynia.
RESUMO
To investigate the mechanisms underlying itching in atopic dermatitis, we examined whether thromboxane (TX) A2, an arachidonic acid metabolite, is involved in spontaneous scratching, an itch-related response, in NC mice with atopic dermatitis-like skin lesions. The TXA2 receptor (TP) antagonist ONO-3708 inhibited the spontaneous scratching. The mRNA expression of TX synthase (TXSyn) distributed mainly in epidermis and the concentration of TXB2, a metabolite of TXA2, were increased in lesional skin. Scratching caused by the PAR2 agonist SLIGRL-NH2 was suppressed by ONO-3708. SLIGRL-NH2-induced scratching decreased approximately 75% in TP-deficient mice, compared to wild-type mice. In primary cultures of mouse keratinocytes, SLIGRL-NH2 induced the production of TXA2, as evidenced by the increased TXB2, which was inhibited by the TXSyn inhibitor sodium ozagrel and a PAR2-neutralizing antibody. Taken together, these results suggest that epidermal TXA2, which may be produced via PAR2 activation, is involved in itching in atopic dermatitis.
Assuntos
Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Prurido/tratamento farmacológico , Prurido/metabolismo , Tromboxano A2/análogos & derivados , Tromboxano A2/metabolismo , Animais , Queratinócitos/metabolismo , Masculino , Metacrilatos/farmacologia , Camundongos , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacologia , RNA Mensageiro/metabolismo , Receptor PAR-2/antagonistas & inibidores , Tromboxano A2/farmacologiaRESUMO
BACKGROUND: Oxaliplatin, a platinum-based chemotherapeutic agent, induces acute cold allodynia and dysesthesia. Cold-sensitive transient receptor potential channels (TRPM8 and TRPA1) have been implicated as candidates to mediate oxaliplatin-induced cold allodynia and hyperalgesia, but precise roles of these channels remain unclear. In this study, we investigated the role of TRPM8 in oxaliplatin-induced cold allodynia. METHODS: Oxaliplatin was injected intraperitoneally in mice. Cold allodynia was evaluated by the acetone test. Expression levels of TRPM8 mRNA and protein were measured using reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: Oxaliplatin-induced cold allodynia was alleviated by the TRPM8 blockers N-(2-aminoethyl)-N-[4-(benzyloxy)-3-methoxybenzyl]-N'-(1S)-1-(phenyl) ethyl] urea and TC-I 2014. Oxaliplatin increased the expression levels of TRPM8 mRNA and protein in the dorsal root ganglia and plantar skin, respectively. Prophylactic administration of the c-Myc inhibitor 10058-F4 prevented cold allodynia and the increase of TRPM8 mRNA after oxaliplatin injection. CONCLUSION: These results suggest that oxaliplatin induces cold allodynia through the increase of c-Myc-mediated TRPM8 expression in primary sensory neurons.