RESUMEN
κ-Opioid receptors (κ-OR) are widely used to regulate the activity of the cardiovascular system. To explore the effect and mechanism of κ-OR on salt-sensitive hypertensive endothelial dysfunction, we used Dah1 rats to construct a rat model of salt-sensitive hypertension on a high-salt (HS) diet. Then, the rats were treated with κ-OR activators U50,488H (1.25 mg/kg) and inhibitor nor-BNI (2.0 mg/kg) for 4 weeks, respectively. The rat aortas were collected to detect the contents of NO, ET-1, AngII, NOS, T-AOC, SO, and NT. Protein expression was determined for NOS, Akt, and Caveolin-1. In addition, the vascular endothelial cells were extracted, and the levels of NO, TNF-α, IL-1, IL-6, IL-8, IL-10, p-Akt, and p-eNOS in cell supernatants were detected. In vivo results showed that compared with the HS group, treated with U50,488H promoted rats' vasodilation by increasing the NO content and decreasing ET-1 and AngII contents. U50,488H reduced endothelial cell apoptosis and attenuated vascular, smooth muscle cell and endothelial cell injury. U50,488H also enhanced the rats' response to oxidative stress by increasing the NOS and T-AOC contents. Moreover, U50,488H increased the eNOS, p-eNOS, Akt, and p-AKT expression and decreased the iNOS and Caveolin-1 expression. In vitro results showed that U50,488H promoted NO, IL-10, p-Akt, and p-eNOS levels in endothelial cell supernatants versus the HS group. And U50,488H reduced the adhesion of peripheral blood mononuclear cells and polymorphonuclear neutrophils to endothelial cells and the migration function of polymorphonuclear neutrophils. Our study suggested that κ-OR activation may improve vascular endothelial dysfunction in salt-sensitive hypertensive rats through the PI3K/Akt/eNOS signaling pathway. This may be a potential therapeutic approach in the treatment of hypertension.
Asunto(s)
Caveolina 1 , Endotelio Vascular , Hipertensión , Receptores Opioides kappa , Animales , Ratas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Células Endoteliales , Hipertensión/tratamiento farmacológico , Interleucina-10 , Leucocitos Mononucleares , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Cloruro de Sodio Dietético , Receptores Opioides kappa/metabolismo , Endotelio Vascular/fisiopatologíaRESUMEN
OBJECTIVES: We aimed to observe the protective effect of κ opioid receptor (κ-OR) agonist on myocardial injury in heart failure (HF) rats and its effect on Ca2+-SERCA2a and to explore the regulatory mechanism with the Nrf2/HO-1 signaling pathway. METHODS: 50 Sprague-Dawley rats were randomly divided into the following groups: the sham operation group (sham group), HF model group (HF group), HF+κ-OR agonist U50488 group (HU group), HF+U50488H+novel calmodulin-dependent protein kinase II (CaMKII) agonist (oleic acid) (HUO group), and HF+U50488H+Nrf2 inhibitor (HUM group). The HF rat's model was established through surgical ligation of the left anterior descending coronary artery and the exhausting swimming exercise. After that, rat's cardiac function was monitored by echocardiography. HE and MASSON staining was used to detect the myocardial injury, and TUNEL staining was used to detect the myocardial apoptosis. ELISA was performed to detect the biomarkers of oxidative stress. Moreover, the distribution of reactive oxygen species (ROS) and Nrf2 was detected under immunofluorescence. The expression of sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA) 2a, calmodulin, endoplasmic reticulum stress- (ERS-) related proteins, and Nrf2/HO-1 signaling pathway-related proteins were detected by Western Blotting. RESULTS: κ-OR agonist U50488H can significantly enhance rat's cardiac function, reduce the injury and apoptosis of myocardial cells, and alleviate endoplasmic reticulum stress injury in HF rats via upregulating the SERCA2a expression and inhibiting the Ca2+ influx. Furthermore, U50488H could also inhibit the phosphorylation of CaMKII and cAMP-response element binding protein (CREB). Additionally, administration of CaMKII-specific agonist could partially block the therapeutic effect of κ-OR agonist on the myocardium of HF rats. Interestingly, the antagonist of Nrf2 could also significantly reverse the therapeutic effect of κ-OR agonist. Therefore, these results suggested that the effect of U50488H on HF rats is dependent on regulating CaMKII phosphorylation and activating the Nrf2/HO-1 pathway. CONCLUSION: κ-OR agonists U50488H can improve ERS in cardiomyocytes and relieve myocardial injury in HF rats through activating the Nrf2/HO-1 pathway and regulating Ca2+-SERCA2a to inhibit Ca2+ influx.
Asunto(s)
3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero , Cardiotónicos , Insuficiencia Cardíaca , Hemo Oxigenasa (Desciclizante) , Receptores Opioides kappa , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Animales , Masculino , Ratas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Factor 2 Relacionado con NF-E2RESUMEN
The kappa opioid receptor is a constituent of the endogenous opioid analgesia system widely expressed in somatosensory nervous pathways and also in endometrial tissues. This work investigates the possible involvement of kappa opioid receptor on the nociceptive, behavioral and histopathological manifestations of endometriosis in a murine model. Female mice receiving endometrial implants develop a persistent mechanical hypersensitivity in the pelvic area that is stronger during the estrus phase of the estrous cycle. The kappa opioid receptor agonist U50,488H produces a dose-dependent relief of this mechanical hypersensitivity, regardless of the cycle phase. Repeated exposure to a low dose of U50,488H (1 mg/kg/day s.c. for one month) provides sustained relief of mechanical hypersensitivity, without tolerance development or sedative side effects. Interestingly, this treatment also inhibits a decreased rearing behavior associated with spontaneous pain or discomfort in endometriosis mice. This KOR-mediated pain relief does not prevent the anxiety-like behavior or the cognitive impairment exhibited by endometriosis mice, and the growth of endometriotic cysts is also unaltered. These data provide evidence of strong pain-relieving properties of kappa opioid receptor stimulation in female mice with endometriosis pain. The persistence of affective and cognitive manifestations suggests that these comorbidities are independent of pelvic pain and simultaneous treatment of these comorbidities may be necessary for successful management of endometriosis.
Asunto(s)
3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgésicos Opioides/uso terapéutico , Endometriosis/tratamiento farmacológico , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos Opioides/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Nocicepción/efectos de los fármacosRESUMEN
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.
Asunto(s)
Colestasis/complicaciones , Modelos Animales de Enfermedad , Prurito/etiología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Animales , Antipruriginosos/uso terapéutico , Conductos Biliares/patología , Conductos Biliares/cirugía , Colestasis/tratamiento farmacológico , Colestasis/patología , Clonidina/uso terapéutico , Ligadura , Hígado/patología , Masculino , Ratones Endogámicos ICR , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Prurito/tratamiento farmacológico , Prurito/patología , Receptores Opioides kappa/agonistasRESUMEN
Olfactory bulbectomized (OBX) mice are characterized by impaired performance in the passive avoidance test and decreased number of cholinergic neurons in the hippocampus. Several studies have reported that κ-opioid receptor agonists improve cognitive function in mice. However, their influence on OBX-induced cognitive dysfunction remains unclear. To address this question, we evaluated the effects of the endogenous κ-opioid receptor agonist dynorphin A (Dyn A) and the selective agonist trans-(-)-U-50488 on the behavior of OBX mice in the passive avoidance test. The cognitive dysfunction of OBX mice was significantly recovered by the intracerebroventricular administration of Dyn A or trans-(-)-U-50488. The effects of these two agonists were counteracted by the selective κ-opioid receptor antagonist nor-binaltorphimine or the inhibitor of acetylcholine release ß-bungarotoxin. These findings suggest that κ-opioid receptor agonists produce anti-dementia effects through activation of cholinergic neurons in OBX mice.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Animales , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/fisiología , Disfunción Cognitiva/fisiopatología , Dinorfinas/farmacología , Dinorfinas/uso terapéutico , Hipocampo/fisiología , Masculino , Trastornos de la Memoria/fisiopatología , Ratones , Bulbo Olfatorio/cirugía , Receptores Opioides kappa/fisiologíaRESUMEN
This study aims to investigate the effect of κ-opioid receptor activation on myocardial ischemia and reperfusion(I/R) injury and elucidate the underlying mechanisms. Myocardial I/R rat model and simulated I/R cardiomyocytes model were established. In vivo study showed that U50,488â¯H improved cardiac function, reduced myocardial infarct size and serum cTnT significantly. The effect of U50,488â¯H was abolished by nor-BNI(a κ-opioid receptor antagonist), Compound C(an AMPK inhibitor), Akt inhibitor and L-NAME(an eNOS inhibitor). AICAR, an AMPK activator, mimicked the effect of U50,488â¯H. U50,488â¯H up-regulated p-AMPK, p-Akt, and p-eNOS, which were abolished by nor-BNI. AICAR increased p-Akt and p-eNOS, which was abolished by Compound C. In vitro study showed that U50,488â¯H increased p-AMPK, p-Akt, and p-eNOS via κ-OR activation. The effect of U50,488â¯H on p-AMPK was abolished by compound C, but not Akt inhibitor and L-NAME. The effect of U50,488â¯H on p-Akt was abolished by compound C and Akt inhibitor, but not L-NAME. AICAR increased p-Akt and p-eNOS, which was abolished by Akt inhibitor, but not L-NAME. U50,488â¯H and AICAR also increased the viability of cardiomyocytes subjected to simulated I/R, the effects of U50,488â¯H and AICAR were blocked by nor-BNI, Compound C, Akt inhibitor, and L-NAME, respectively. In conclusion, κ-OR activation confers cardioprotection via AMPK/Akt/eNOS signaling.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Opioides kappa/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Aminoimidazol Carboxamida/uso terapéutico , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Masculino , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Ribonucleótidos/farmacología , Ribonucleótidos/uso terapéutico , Transducción de Señal , Troponina T/sangreRESUMEN
Renal ischemia-reperfusion injury (IRI) is regarded as a leading cause of acute kidney failure and renal dysfunction. Previous studies show that kappa opioid receptor (KOR) agonists can attenuate IRI in cardiomycytes and neuronal cells. In this study we explored the effects of a KOR agonist on renal IRI and the underlying mechanisms in vivo and in vitro. An IRI model was established in SD rats, which were intravenously pretreated with a KOR agonist U50448H (1 mg/kg), a KOR antagonist Nor-BNI (2 mg/kg) followed by U50448H (1 mg/kg), or the PI3K inhibitor wortmannin (1.4 mg/kg) followed by U50448H (1 mg/kg). U50448H pretreatment significantly decreased the serum levels of creatinine (Cr) and BUN, the renal tubular injury scores and the apoptotic index (AI) in IRI model rats. Furthermore, U50448H significantly increased SOD activity and NO levels, and reduced the MDA levels in the kidney tissues of IRI model rats. Moreover, U50448H significantly increased the phosphorylation of Akt, eNOS and PI3K in the kidney tissues of IRI model rats. All the beneficial effects of U50448H were blocked by Nor-BNI or wortmannin pre-administered. Similar results were observed in vitro in renal tubular epithelial NRK-52E cells subjected to a hypoxia-reoxygenation (HR) procedure. Our results demonstrate that the KOR agonist U50448H protects against renal IRI via activating the PI3K/Akt signaling pathway.
Asunto(s)
3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Riñón/efectos de los fármacos , Receptores Opioides kappa/agonistas , Daño por Reperfusión/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Riñón/patología , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Superóxido DismutasaRESUMEN
BACKGROUND/AIMS: In a previous study, we showed that κ-opioid receptor stimulation with the selective agonist U50,488H ameliorated hypoxic pulmonary hypertension (HPH). However, the roles that pulmonary arterial smooth muscle cell (PASMC) proliferation, apoptosis, and autophagy play in κ-opioid receptor-mediated protection against HPH are still unknown. The goal of the present study was to investigate the role of autophagy in U50,488H-induced HPH protection and the underlying mechanisms. METHODS: Rats were exposed to 10% oxygen for three weeks to induce HPH. After hypoxia, the mean pulmonary arterial pressure (mPAP) and the right ventricular pressure (RVP) were measured. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected by flow cytometry and Western blot. Autophagy was assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay and by Western blot. RESULTS: Inhibition of autophagy by the administration of chloroquine prevented the development of HPH in the rat model, as evidenced by significantly reduced mPAP and RVP, as well as decreased autophagy. U50,488H mimicked the effects of chloroquine, and the effects of U50,488H were blocked by nor-BNI, a selective κ-opioid receptor antagonist. In vitro experiments showed that the inhibition of autophagy by chloroquine was associated with decreased proliferation and increased apoptosis of PASMCs. Under hypoxia, U50,488H also significantly inhibited autophagy, reduced proliferation and increased apoptosis of PASMCs. These effects of U50,488H were blocked by nor-BNI. Moreover, exposure to hypoxic conditions significantly increased AMPK phosphorylation and reduced mTOR phosphorylation, and these effects were abrogated by U50,488H. The effects of U50,488H on PASMC autophagy were inhibited by AICAR, a selective AMPK agonist, or by rapamycin, a selective mTOR inhibitor. CONCLUSION: Our data provide evidence for the first time that κ-opioid receptor stimulation protects against HPH by inhibiting PASMCs autophagy via the AMPK-mTOR pathway.
Asunto(s)
3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/efectos de los fármacos , Receptores Opioides kappa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Proteínas Quinasas Activadas por AMP/química , Animales , Antihipertensivos/farmacología , Apoptosis/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cloroquina/farmacología , Modelos Animales de Enfermedad , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Masculino , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Naltrexona/análogos & derivados , Naltrexona/farmacología , Arteria Pulmonar/citología , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
BACKGROUNDS/AIMS: The selective κ-opioid agonist U50,488H protects heart from myocardial ischemia-reperfusion (MI/R) injury. We examined whether U50,488H is also beneficial for MI/R induced heart failure. METHODS: Anesthetized male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia via left anterior descending coronary artery (LAD) occlusion, followed by 4 weeks of reperfusion. Infarct size was examined by Evans blue/triphenyl tetrazolium chloride (TTC) staining. Cardiac function and remodeling were examined by echocardiography and histology. HO-1 gene transcription and expression were measured by RT-PCR and western blot. RESULTS: Compared to vehicle-treated MI/R rats, rats administered a single dose of U50,488H at the beginning of reperfusion exhibited reduced myocardial infarct size, oxidative stress, hypertrophy, and fibrosis, improved mechanical function, and greater neovascularization. U50,488H also increased myocardial heme oxygenase (HO)-1 gene transcription and expression, while pharmacological HO-1 inhibition reversed all protective effects of U50,488H. Furthermore, U50,488H protected control cultured cardiomyoctes against simulated I/R-induced apoptosis but not cultures subjected to shRNA-mediated HO-1 knockdown. Inhibition of HO-1 in the subacute phase of reperfusion reversed the U50,488H-induced increase in neovascularization and suppression of oxidative stress. Finally, U50,488H increased Akt phosphorylation and nuclear translocation of Nrf2, a key HO-1 transcription activator, while inhibition of PI3K-Akt signaling abolished U50,488H-induced Nrf2 nuclear translocation, HO-1 upregulation, and cardioprotection. CONCLUSION: Activation of HO-1 expression through the PI3K-Akt-Nrf2 pathway may mediate the acute and long-term protective effects of U50,488H against heart failure by enhancing cardiomyocyte survival and neoangiogenesis and by reducing oxidative stress.
Asunto(s)
3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Cardiotónicos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Hemo-Oxigenasa 1/metabolismo , Daño por Reperfusión Miocárdica/complicaciones , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Animales , Cardiotónicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Vectores Genéticos/metabolismo , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/genética , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/genética , Lentivirus/metabolismo , Masculino , Modelos Biológicos , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/genética , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas Sprague-Dawley , Receptores Opioides kappa/metabolismo , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
The systemic administration of opioids can be used for their strong analgesic effect. However, extensive activation of opioid receptors (ORs) beyond the targeted tissue can cause dysphoria, pruritus, and constipation. Therefore, selective activation of peripheral ORs present in the afferent fibers of the targeted tissue can be considered a superior strategy in opioid analgesia to avoid potential adverse effects. The purpose of this study was to clarify the role of peripheral kappa opioid receptors (kORs) in arthritic pain for the possible use of peripheral ORs as a target in anti-nociceptive therapy. We administered U50488 or nor-BNI/DIPPA, a selective agonist or antagonist of kOR, respectively into arthritic rat knee joints induced using 1% carrageenan. After the injection of U50488 or U50488 with nor-BNI or DIPPA into the inflamed knee joint, we evaluated nociceptive behavior as indicated by reduced weight-bearing on the ipsilateral limbs of the rat and recorded the activity of mechanosensitive afferents (MSA). In the inflamed knee joint, the intra-articular application of 1µM, 10nM, or 0.1nM U50488 resulted in a significant reduction in nociceptive behavior. In addition, 1µM and 10nM U50488 decreased MSA activity. However, in a non-inflamed knee joint, 1µM U50488 had no effect on MSA activity. Additionally, intra-articular pretreatment with 20µM nor-BNI or 10µM DIPPA significantly blocked the inhibitory effects of 1µM U50488 on nociceptive behavior and MSA activity in the inflamed knee joint. These results implicate that peripheral kORs can contribute to anti-nociceptive processing in an inflamed knee joint.
Asunto(s)
Articulación de la Rodilla/metabolismo , Receptores Opioides kappa/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgésicos Opioides/farmacología , Animales , Inflamación , Articulación de la Rodilla/fisiopatología , Masculino , Nocicepción/efectos de los fármacos , Nociceptores/efectos de los fármacos , Dolor , Ratas , Ratas Sprague-Dawley , Receptores Opioides , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides kappa/fisiologíaRESUMEN
Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Vaina de Mielina/metabolismo , Oligodendroglía/efectos de los fármacos , Receptores Opioides kappa/fisiología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Acetamidas/uso terapéutico , Animales , Diferenciación Celular , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Eliminación de Gen , Ratones Endogámicos C57BL , Ratones Noqueados , Oligodendroglía/citología , Oligodendroglía/metabolismo , Pirrolidinas/uso terapéutico , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismoRESUMEN
We studied the ability of the agonist of κ1-opioid receptors U-50,488 in doses of 0.1 and 1 mg/kg to simulate ischemic pre- and postconditioning of the heart and κ-opioid receptors ICI 199,441 in a dose of 0.1 mg/kg to simulate the antiarrhythmic effect of heart preconditioning. The duration of ischemia was 10 or 45 min and the duration of reperfusion was 10 min or 2 h. Administration of 1 mg/kg U-50,488 both before ischemia and 5 min before reperfusion produced a pronounced antiarrhythmic effect. U-50,488 injected 5 min before reperfusion 2-fold reduced the ratio of infarction to risk area. Administration of ICI 199,441 in a dose of 0.1 mg/kg 15 min before ischemia produced a potent antiarrhythmic effect. Antiarrhythmic effect of κ-opioid receptor agonists depended on activation of κ-opioid receptors.
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3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Cardiotónicos/farmacología , Precondicionamiento Isquémico Miocárdico/métodos , Daño por Reperfusión Miocárdica/prevención & control , Pirrolidinas/farmacología , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Animales , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Cardiotónicos/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/patología , Pirrolidinas/uso terapéutico , Ratas , Ratas WistarRESUMEN
Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach.
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Terminaciones Nerviosas/metabolismo , Dolor/patología , Péptidos/uso terapéutico , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Piel/inervación , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgésicos/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Animales , Carragenina/toxicidad , Cisplatino/toxicidad , Modelos Animales de Enfermedad , Adyuvante de Freund/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Inflamación/inducido químicamente , Inflamación/complicaciones , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Naloxona/farmacología , Naloxona/uso terapéutico , Terminaciones Nerviosas/efectos de los fármacos , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dimensión del Dolor , Péptidos/farmacología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ratas , Ratas WistarRESUMEN
BACKGROUND: Evidence suggests that activation of κ-opioid receptor (KOR) by U50,488H exhibits potential cardiovascular protective properties. However, the effects of U50,488H on vascular dysfunction in diabetes mellitus (DM) are still not clear. The present study was designed to investigate the effects of U50,488H on vascular dysfunction in diabetic rats and explore the underlying mechanisms involved. METHODS: Rats were randomly divided into control, DM, DM + vehicle, DM + U50,488H and DM + nor-binaltorphimine (nor-BNI) groups. Streptozotocin injection was used to induce DM. Weight, blood glucose, blood pressure and plasma insulin for each group were measured. Arterial functions were assessed with isolated vessels mounted for isometric tension recordings. Angiotensin II (ANG II), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin (IL)-6 and IL-8 levels were measured by ELISA, and endothelial nitric oxide synthase (eNOS) phosphorylation and NF-κB p65 translocation were measured by Western blot. RESULTS: Activation of KOR by U50,488H reduced the enhanced contractility of aortas to KCl and noradrenaline and increased acetylcholine-induced vascular relaxation, which could also protect the aortal ultrastructure in DM. U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment. Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment. CONCLUSIONS: Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.
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3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Antihipertensivos/farmacología , Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/prevención & control , Endotelio Vascular/efectos de los fármacos , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Animales , Antihipertensivos/uso terapéutico , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiopatología , Diabetes Mellitus Experimental/tratamiento farmacológico , Angiopatías Diabéticas/fisiopatología , Endotelio Vascular/fisiopatología , Masculino , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Estreptozocina , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the µ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH: We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS: Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ). CONCLUSIONS AND IMPLICATIONS: Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
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Analgésicos Opioides/farmacología , Nocicepción/fisiología , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgesia , Analgésicos no Narcóticos/farmacología , Analgésicos no Narcóticos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Benzamidas/farmacología , Diazepam/farmacología , Etorfina/farmacología , Etorfina/uso terapéutico , Femenino , Calor , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Naltrexona/análogos & derivados , Naltrexona/farmacología , Piperazinas/farmacología , Receptores Opioides/genética , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/genética , Estrés Psicológico , Receptor de NociceptinaRESUMEN
The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10-20 µg), DAMGO (1-2 µg) and U50,488H (25-50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg), deltorphin II (1.5-15 µg) and SNC80 (10-20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.
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Analgésicos Opioides/uso terapéutico , Microglía/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/administración & dosificación , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Analgésicos Opioides/administración & dosificación , Animales , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Células Cultivadas , Encefalina Ala(2)-MeFe(4)-Gli(5)/administración & dosificación , Encefalina Ala(2)-MeFe(4)-Gli(5)/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Microglía/citología , Microglía/metabolismo , Minociclina/administración & dosificación , Minociclina/uso terapéutico , Morfina/administración & dosificación , Morfina/uso terapéutico , Ratas Wistar , Receptores Opioides delta/genéticaRESUMEN
RATIONALE: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. OBJECTIVE: The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). RESULTS: Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. CONCLUSION: Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.
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Dolor Agudo/tratamiento farmacológico , Analgésicos Opioides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Inflamación/tratamiento farmacológico , Dolor Nociceptivo/tratamiento farmacológico , Receptores Opioides/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Dolor Agudo/complicaciones , Animales , Benzamidas/uso terapéutico , Carragenina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fentanilo/uso terapéutico , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Imidazoles/uso terapéutico , Inflamación/complicaciones , Macaca , Masculino , Dimensión del Dolor/efectos de los fármacos , Piperazinas/uso terapéutico , Compuestos de Espiro/uso terapéuticoRESUMEN
The present study was designed to investigate the effect of κ-opioid receptor stimulation with U50,488H on endothelial function and underlying mechanism in rats with hypoxic pulmonary hypertension (HPH). Chronic hypoxia-induced HPH was simulated by exposing the rats to 10% oxygen for 2 wk. After hypoxia, mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI) were measured. Relaxation of pulmonary artery in response to acetylcholine (ACh) was determined. Expression and activity of endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) with NO production, total antioxidant capacity (T-AOC), gp91(phox) expression and nitrotyrosine content were measured. The effect of U50,488H administration during chronic hypoxia was investigated. Administration of U50,488H significantly decreased mPAP and right ventricular hypertrophy as evidenced by reduction in RVP and RVHI. These effects were mediated by κ-opioid receptor. In the meantime, treatment with U50,488H significantly improved endothelial function as evidenced by enhanced relaxation in response to ACh. Moreover, U50,488H resulted in a significant increase in eNOS phosphorylation, NO content in serum, and T-AOC in pulmonary artery of HPH rats. In addition, the activity of eNOS was enhanced, but the activity of iNOS was attenuated in the pulmonary artery of chronic hypoxic rats treated with U50,488H. On the other hand, U50,488H markedly blunted HPH-induced elevation of gp91(phox) expression and nitrotyrosine content in pulmonary artery, and these effects were blocked by nor-BNI, a selective κ-opioid receptor antagonist. These data suggest that κ-opioid receptor stimulation with U50,488H improves endothelial function in rats with HPH. The mechanism of action might be attributed to the preservation of eNOS activity, enhancement of eNOS phosphorylation, downregulation of iNOS activity and its antioxidative/nitrative effect.
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3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/patología , Hipoxia/complicaciones , Receptores Opioides kappa/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Acetilcolina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Endotelio Vascular/patología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/complicaciones , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Masculino , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ácido Peroxinitroso/biosíntesis , Fosforilación/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Superóxidos/metabolismo , Vasodilatación/efectos de los fármacos , Presión Ventricular/efectos de los fármacosRESUMEN
Activation of peripheral κ opioid receptors (KOR) effectively relieves pain and hyperalgesia in preclinical and clinical models of pain. Although centrally located KOR activation results in sexually dimorphic effects, it is unclear whether peripheral KOR also produces sex dependent effects in persistent inflammatory pain conditions. In this study, we investigated whether local administration of a specific KOR agonist, U50, 488 relieve mechanical hyperalgesia induced by the injection of complete Freund's adjuvant (CFA) in the rat hindpaw, and whether there are sex differences. The effects of U50, 488 were assessed three days after the induction of CFA-induced inflammation, a time point at which mechanical hyperalgesia was most prominent. There were no sex differences in baseline and CFA-induced changes in mechanical thresholds between male and female rats. Local treatment of U50, 488 produced moderate, but significant, anti-hyperalgesia in both male and female rats. However, U50, 488 was significantly more effective in male rats at the highest dose of U50, 488. We confirmed that the highest dose of U50, 488 used in this study did not produce systemic effects, and that the drug effect is receptor specific. On the basis of these results, we suggest that local KOR agonists are effective in mitigating mechanical hyperalgesia under a persistent inflammatory pain condition and that sex differences in anti-hyperalgesic effects become more evident at high doses.
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Hiperalgesia/tratamiento farmacológico , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/uso terapéutico , Adyuvantes Inmunológicos , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Femenino , Adyuvante de Freund , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/fisiopatología , Masculino , Umbral del Dolor , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
Withdrawal is one of the defining characteristics of alcohol dependence, and is often characterized by impaired physiological function and enhanced negative affect. Recent evidence suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the negative affect often associated with drugs of abuse. The objective of the present experiments was to determine the role of the DYN/KOR system in the regulation of anxiety-related behavior during acute withdrawal from ethanol. Rats were fed an ethanol liquid diet and following removal, the ability of the KOR antagonist nor-BNI to attenuate the increased anxiogenic-like response characteristic of ethanol withdrawal was investigated using the elevated plus maze. A comparison study was also conducted examining anxiety-related behavior following direct activation of KORs via injections of the KOR agonist U50,488. Rats experiencing ethanol withdrawal showed a significant decrease in open arm exploration compared to controls, an effect that was blocked by nor-BNI. Similar decreases in open arm exploration were observed following injections with the KOR agonist, U50,488, an effect also reversed by pretreatment with nor-BNI. These results suggest that similar mechanisms are involved in the regulation of ethanol withdrawal- and KOR agonist-induced changes in behavior. Given the potential role of enhanced negative affect in persistent ethanol drinking, understanding the role of the DYN/KOR system in regulating anxiety associated with withdrawal may be critical in understanding the factors associated with the nature of alcohol dependence.