Abstract:
:An attractive alternative to the use of direct agonists at the cannabinoid receptor type 1 (CB1) in the control of neuropathic pain may be to potentiate the actions of endogenous cannabinoids. Thus, the effects of AM404, an inhibitor of anandamide uptake, were assessed in an experimental model of neuropathic pain in rats. Daily treatment with AM404 prevented, time- and dose-dependently, the development of thermal hyperalgesia and mechanical allodynia in neuropathic rats. Antagonists at cannabinoid CB1 or CB2 receptors, or at the transient receptor potential vanilloid type 1 receptor, each partially reversed effects induced by AM404. A complete reversal was obtained when the three antagonists were given together, suggesting that all three receptors are involved. AM404 treatment affected two pathways involved in the generation and maintenance of neuropathic pain, one mediated by nitric oxide (NO) and the other by cytokines. AM404 completely prevented the overproduction of NO and the overexpression of nNOS, inhibited the increase in tumour necrosis factor alpha (TNFalpha) and enhanced the production of interleukin-10. Both NO and TNFalpha are known to contribute to the apoptotic process, which plays an important role in the establishment of chronic pain states. AM404 treatment prevented the increase in the ratio between pro- and anti-apoptotic gene bax/bcl-2 expression observed in the spinal cord of neuropathic rats. Taken together, these findings suggest that inhibition of endocannabinoid uptake, by blocking the putative anandamide carrier, results in the relief of neuropathic pain and may represent a novel strategy for treating chronic pain.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Costa B,Siniscalco D,Trovato AE,Comelli F,Sotgiu ML,Colleoni M,Maione S,Rossi F,Giagnoni Gdoi
10.1038/sj.bjp.0706798subject
Has Abstractpub_date
2006-08-01 00:00:00pages
1022-32issue
7eissn
0007-1188issn
1476-5381pii
0706798journal_volume
148pub_type
杂志文章abstract::We have characterized the contribution of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX) and cytochrome P450 (CYP450) to the bradykinin (BK)- induced vasodilation in isolated hearts from wildtype (WT) and eNOS deficient mice (eNOS-/-). The endothelium-dependent vasodilation by bradykinin (BK, 1 microM...
journal_title:British journal of pharmacology
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doi:10.1038/sj.bjp.0704472
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abstract:BACKGROUND AND PURPOSE:The aim of this study was to determine whether the apelin/APJ system is altered in human cardiovascular disease by investigating whether the expression of apelin or its receptor is altered at the protein level. EXPERIMENTAL APPROACH:Radioligand binding studies were used to determine apelin recep...
journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1973.tb08238.x
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abstract:BACKGROUND AND PURPOSE:The effects of systemic treatment with indomethacin-loaded nanocapsules (IndOH-NC) were compared with those of free indomethacin (IndOH) in rat models of acute and chronic oedema. EXPERIMENTAL APPROACH:The following models of inflammation were employed: carrageenan-induced acute oedema (measured...
journal_title:British journal of pharmacology
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abstract::1. The responses of rat isolated aortae to vasoconstrictor and vasodilator agents have been studied in 14-day streptozotocin-diabetic rats. The effects of treatment with the aldose reductase inhibitor, ponalrestat, on these responses have also been investigated. 2. Maximum contractile responses and aortic sensitivity ...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1994.tb17028.x
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abstract::1 The fate of (15S)-15-methyl prostaglandin E(2) methyl ester and 16,16-dimethyl prostaglandin E(2) in the pulmonary circulation of rat isolated lungs was compared with that of prostaglandin E(2) by means of bioassay.2 Calculated on the basis of height of response of the assay tissues, the inactivation of prostaglandi...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1978.tb08456.x
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
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abstract::1. In order to assess the role of different ionic currents in hypoxia-induced action potential shortening, we investigated the effects of blockers of voltage-dependent and ATP-sensitive K(+)-channel on the membrane potential of hypoxic rabbit hearts and papillary muscles. The response to blocking of the inward rectifi...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1992.tb14436.x
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abstract:BACKGROUND AND PURPOSE:Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 cri...
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doi:10.1038/sj.bjp.0701891
更新日期:1998-06-01 00:00:00
abstract::1. The cyclic nucleotide phosphodiesterase (PDE) of guinea-pig eosinophils was partially characterized and the effects of selective inhibitors of PDE isoenzymes upon opsonized zymosan (OZ)-stimulated respiratory burst were studied. 2. PDE activity in eosinophil lysates appeared to be membrane-associated, displayed sub...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb09790.x
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journal_title:British journal of pharmacology
pub_type: 杂志文章
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更新日期:1997-10-01 00:00:00
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journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
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更新日期:2014-12-01 00:00:00
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doi:10.1111/j.1476-5381.1982.tb09177.x
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abstract::1. Histamine and carbachol produced concentration-related increases in the accumulation of 3H-inositol phosphates in slices of bovine tracheal smooth muscle. 2. Noradrenaline alone produced a small stimulation of 3H-inositol phosphate accumulation which was inhibited by the alpha-adrenoceptor antagonist phentolamine. ...
journal_title:British journal of pharmacology
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abstract:BACKGROUND AND PURPOSE:Rosiglitazone is an anti-diabetic drug improving insulin sensitivity and glucose uptake in skeletal muscle and adipose tissues. However, several recent clinical trials suggest that rosiglitazone can increase the risk of cardiovascular ischaemia, although other studies failed to show such risks. T...
journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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doi:10.1111/bph.12624
更新日期:2014-06-01 00:00:00
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journal_title:British journal of pharmacology
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journal_title:British journal of pharmacology
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更新日期:2010-09-01 00:00:00
abstract::Cannabinoid (CB1) receptor activation acts neuronally, reducing GI motility, diarrhoea, pain, transient lower oesophageal sphincter relaxations (TLESRs) and emesis, and promoting eating. CB2 receptor activation acts mostly via immune cells to reduce inflammation. What are the key questions which now need answering to ...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0707422
更新日期:2007-11-01 00:00:00