The transient potential vanilloid 1 receptor (TRPV1) is a calcium-permeable channel responsible for the transduction and modulation of acute and chronic pain signaling. As such, this receptor is a potential target for the treatment of a number of pain disorders. However, AMG517, a TRPV1 antagonist, presents several clinical limitations that include the induction of severe hyperthermia. The aim of this study was to investigate the possible interaction of the flavonoid eriodictyol with the TRPV1 receptor and to determine its putative antinociceptive and hyperthermic effects. Eriodictyol was able to displace [(3)H]-resiniferatoxin binding (IC(50)=47; 21-119nM) and to inhibit calcium influx mediated by capsaicin (IC(50)=44; 16-125nM), suggesting that eriodictyol acts as a TRPV1 antagonist. Moreover, eriodictyol induced antinociception in the intraplantar capsaicin test, with maximal inhibition of 49±10 and 64±4% for oral (ID(50)=2.3; 1.1-5.7mg/kg) and intrathecal (ID(50)=2.2; 1.7-2.9nmol/site) administration, respectively. Eriodictyol did not induce any change in body temperature or locomotor activity. Orally administered eriodictyol (4.5mg/kg) prevented the nociception induced by intrathecal injections of capsaicin, as well as the non-protein thiol loss and 3-nitrotyrosine (3-NT) formation induced by capsaicin in spinal cord. Eriodictyol also reduced the thermal hyperalgesia and mechanical allodynia elicited by complete Freund's adjuvant (CFA) paw injection. In conclusion, eriodictyol acts as an antagonist of the TRPV1 receptor and as an antioxidant; it induces antinociception without some of the side effects and limitations such as hyperthermia that are expected for TRPV1 antagonists.

The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic extract produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compounds isolated from the dichloromethane fraction, only ␣-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, ␣-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. ␣-Spinasterol was able to displace [ 3 H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and ␣-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mechanical threshold of naive mice. The treatment with ␣-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addition, ␣-spinasterol and the dichloromethane fraction reduced the edema, mechanical, and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and ␣-spinasterol did not affect body temperature or locomotor activity. In conclusion, ␣-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect.

Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

In a previous work based on popular belief, Campomanesia xanthocarpa Berg., popularly known as “guavirova”, showed to have a potential effect in the control of a number of conditions associated with cardiovascular diseases. The aim of the present work was to investigate the effects of C. xanthocarpa extract (CXE) on antiplatelet, antithrombotic and fibrinolytic activities in mice and in human blood. Mice were treated orally for 5 days with CXE or acetylsalicylic acid and at the end of the treatment period animals were challenged for bleeding, acute thromboembolism and ulcerogenic activity. In addition, we have assessed the prothrombin time and activated partial thromboplastin time (aPTT) after oral administration. In in vitro assays, antiplatelet effects of CXE was evaluated on platelet aggregation, and fibrinolytic activity of the extract was observed by mice or human artificial blood clot degradation. Platelet citotoxicity of the extract was also determined by the LDH assay. Results demonstrated that CXE has a significant protective effect on thrombosis. It also inhibits platelet aggregation without demonstrating cytotoxicity on platelets. CXE slightly prolonged aPTT and showed no ulcerogenic activity after oral administration. In addition, CXE showed a fibrinolytic activity. Thus, C. xanthocarpa showed antiplatelet, antithrombotic and fibrinolytic activities in mice.