European journal of pharmacology
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Cancer cachexia is a multifactorial, critical illness syndrome characterized by an ongoing loss of skeletal muscle and adipose tissue. The reductions in body weight and skeletal muscle mass are important prognostic indicators for cancer patients that are refractory to current therapies. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced in the stomach, stimulates food intake and growth hormone secretion, suppresses inflammation, and prevents muscle catabolism. ⋯ We also demonstrated that skeletal muscle mass and muscle contraction force in both fast-twitch muscle and slow-twitch muscle were retained in ghrelin-treated mice in conjunction with an upregulation of local insulin-like growth factor 1/Akt signaling. In addition, ghrelin administration reduced the expressions of phosphorylated-p38 mitogen-activated protein kinase, phosphorylated-nuclear factor-kappa B, Forkhead box protein O1, muscle RING-finger protein-1, and F-Box protein 32 in the lysates of skeletal muscle in the tumor-bearing state. Our results indicate that ghrelin administration exerts a protective effect against cancer cachexia by ameliorating skeletal muscle wasting and regulating systemic inflammation.
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Ultra-low doses of non-selective α2-adrenoceptor antagonists augment acute spinal morphine antinociception and block morphine tolerance; however, the receptor involved in mediating these effects is currently unknown. Here, we used tail flick and paw pressure tests on the rat to investigate the acute analgesic and tolerance-inducing effects of spinal morphine and norepinephrine alone or in combination with an ultra-low dose of the α2A-adrenoceptor antagonist, BRL44408. We also assessed the potential antinociceptive effects of BRL44408 alone following spinal administration. ⋯ This implicates the spinal α2A-adrenoceptor subtype in the action of ultra-low dose α2-adrenoceptor antagonists on morphine and norepinephrine tolerance. The BRL44408-induced analgesia is partially dependent on its interaction with the α2-adrenoceptors. Thus, this agent class may be useful in pain therapy.
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Comparative Study
Intrathecal orphenadrine elicits spinal block in the rat.
The purpose of this study was to estimate the local anesthetic effect of orphenadrine, an anti-muscarinic agent, in spinal anesthesia and its comparison with the local anesthetic lidocaine. After the rat was injected intrathecally, the spinal block of orphenadrine and lidocaine was constructed in a dosage-dependent fashion. The potency and duration of spinal anesthesia with orphenadrine were compared with that of lidocaine. ⋯ Orphenadrine, but not lidocaine, exhibited longer duration of nociceptive/sensory blockade than that of motor blockade at equipotent doses. Ineffective-dose orphenadrine as adjuvant did not enhance spinal anesthesia with lidocaine. The preclinical data revealed that orphenadrine with a more sensory-selective action over motor block exhibited more potent and longer spinal anesthesia when compared to lidocaine.
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This study assessed the effect of stimulation of CB2 receptors or CB1 blockade on fibrosis and apoptosis in rats subjected to bile duct ligation (BDL). It was performed in sham and BDL rats for four weeks. Fibrosis-induced rats received a CB2 receptor agonist β-caryophyllene, CB1 receptor antagonist, hemopressin, combination of β-caryophyllene and CB2 antagonist, AM630 or vehicle daily during the last 2 weeks of the BDL ligation. ⋯ CB2 receptor blockade by AM630 prevents the effects of β-caryophyllene on CB1 receptor and MMP-1 genes expression. This study points out that either stimulation of CB2 receptors or CB1 blockade can attenuate hepatic fibrosis in bile duct ligated rats. The mechanisms underlying these incidents may open new avenues for attenuating fibrosis and apoptosis of cholestasis- induced liver diseases.