European journal of pharmacology
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The Ruta graveolens L. plant is used in traditional medicine to treat a large number of diseases. The methanol (50%) extract of the whole plant was observed to inhibit the expression of inducible nitric oxide synthase (iNOS) and the cycloxygenase-2 (COX-2) gene in lipopolysaccharide (LPS)-induced macrophage cells (J774A.1, [Raghav, S. K., Gupta, B., Agrawal, C., Goswami, K., Das, H. ⋯ The active compound at a dose of 40 mg/kg body weight was observed to inhibit the iNOS and IL-1beta gene expression significantly in endotoxin-induced inflammatory model of BALB/c mice. The low level of nitric oxide production was also observed in the sera of compound treated mice. The normal behavioral condition in LPS challenged BALB/c mice was noticed when these were treated with active compound.
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The present study evaluated some of the mechanisms through which alpha-amyrin, a pentacyclic triterpene isolated from Protium Kleinii and other plants, exerts its effects against 12-O-tetradecanoylphorbol-acetate (TPA)-induced skin inflammation in mice. Topical application of alpha-amyrin (0.1-1 mg/ear) dose-dependently inhibited TPA-induced increase of prostaglandin E2 (PGE2) levels. In contrast with the selective cyclooxygenase (COX)-1 SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or COX-2 rofecoxib inhibitors, alpha-amyrin failed to alter either COX-1 or COX-2 activities in vitro. ⋯ Collectively, present results suggest that topical skin application of alpha-amyrin exerts a strong and rapid onset inhibition of TPA-induced inflammation. These effects seem to be associated with the suppression of skin PGE2 levels by mechanisms involving the suppression of COX-2 expression, via inhibition of upstream protein kinases--namely ERK, p38 MAPK and PKCalpha--and blocking of NF-kappaB activation. These results indicate that alpha-amyrin-derivative could be potentially relevant for the development of a topical agent for the management of inflammatory diseases.
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[Arg8]-vasopressin (AVP) is an essential hormone for maintaining osmotic homeostasis and is known to be a potent vasoconstrictor that regulates the cardiovascular system. In the present study, cardiomyocytes were isolated from neonatal mice and used to investigate the effects of AVP on cardiac hypertrophy. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that vasopressin V1A receptor mRNA, but not V1B or V2 receptor mRNA, was expressed in primary cultured neonatal mouse cardiomyocytes. ⋯ The effects of AVP on these parameters were significantly inhibited by a selective vasopressin V1A receptor antagonist, OPC-21268, and were not observed in cardiomyocytes from mice lacking the vasopressin V1A receptor. In vivo cardiac hypertrophy in response to pressure overload was attenuated in vasopressin V1A receptor-deficient (V1AR-KO) mice. Taken together, our data suggest that AVP promotes cardiomyocyte hypertrophy via the vasopressin V1A receptor, which is in part regulated by the pathway of ERK1/2 signaling.
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Antinociception achieved after peripheral administration of opioids has opened a new approach to the treatment of severe and chronic pain. Additionally, opioid analgesics with restricted access to the central nervous system could improve safety of opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and neuropathic pain. ⋯ Moreover, the local opioid antinociceptive effects were significantly attenuated by naloxone methiodide, a peripherally acting opioid receptor antagonist, demonstrating that the effect was mediated by peripheral opioid receptors. The present data indicate that the peripherally restricted 6-amino acid conjugates of 14-O-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in neuropathic pain. Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting pain.
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Patients with cancer frequently report pain that can be difficult to manage. This study examined the antihyperalgesic effects of a cannabinoid receptor agonist, CP 55,940, in a murine model of cancer pain. Implantation of fibrosarcoma cells into and around the calcaneous bone in mice produced mechanical hyperalgesia (decreased paw withdrawal thresholds and increased frequency of paw withdrawals). ⋯ The antihyperalgesic effect of CP 55,940 was mediated via the cannabinoid CB1 but not CB2 receptor. Finally, repeated administration of CP 55,940 produced a short-term and a longer-term attenuation of tumor-evoked hyperalgesia. These results suggest that cannabinoids may be a useful alternative or adjunct therapy for treating cancer pain.