sb-366791 and Inflammation

The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.

Topics: Activating Transcription Factor 3; Amidohydrolases; Anilides; Animals; Arachidonic Acids; Benzamides; Capsaicin; Carbamates; Cinnamates; Disease Models, Animal; Endocannabinoids; Ganglia, Spinal; Gene Expression; Hyperalgesia; Inflammation; Interleukin-6; Lumbar Vertebrae; Male; Osteoarthritis; Pain; Pain Management; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; TRPV Cation Channels

The aim of the present study was to investigate the participation of TRPV1 in an acute gout attack model.. Experiments were conducted to evaluate the participation of TRPV1 in the nociceptive and inflammatory responses (oedema, plasma extravasation, leucocyte infiltration and also IL-1β production) triggered by IA (ankle) administration of monosodium urate (MSU) in rats using selective antagonist TRPV1 receptor, defunctionalization of sensory fibres and increased immunoreactivity. We have also analysed the inflammatory response. The participation of mast cells in the MSU-induced nociception and inflammation was evaluated using a mast cell stabilizer and a mast cell degranulator compound.. We observed that MSU (1.25 mg/site) injected into the rat ankle joint elicited ongoing pain-like behaviour, hyperalgesia, allodynia and articular oedema as well as plasma extravasation, leucocyte infiltration and IL-1β production in lavage fluid. All of these events were inhibited by the co-administration of the selective TRPV1 receptor antagonist SB366791 (10 nmol/site). MSU crystals also increased the immunoreactivity of the TRPV1 receptor in the articular tissue of injected animals. Furthermore, the defunctionalization of TRPV1-positive sensory neurons also significantly reduced MSU-induced ongoing pain-like behaviour, hyperalgesia and oedema.. Thus we demonstrate that TRPV1 acts on sensory neurons and plays a relevant role in the nociception and inflammation induced by IA MSU, indicating it as a potential target to treat acute gout attacks.

Topics: Acute Disease; Anilides; Animals; Arthralgia; Cinnamates; Disease Models, Animal; Gout; Inflammation; Male; Rats; Rats, Wistar; TRPV Cation Channels; Uric Acid

Laparoscopic surgery induces a milder inflammatory response than open surgery, however, the precise mechanisms underlying this phenomenon remain to be elucidated. Our previous study demonstrated that stimulation of sensory neurons inhibited hepatic apoptosis and inflammatory responses in rats subjected to hepatic ischemia/reperfusion (I/R). Since carbon dioxide (CO2) has been demonstrated to stimulate sensory neurons, it was hypothesized that CO2‑pneumoperitoneum, as used in laparoscopic surgery, may attenuate inflammatory responses by stimulating sensory neurons. This hypothesis was examined using rats subjected to hepatic I/R. The rats were subjected to partial hepatic ischemia for 60 min followed by reperfusion. Abdominal insufflation with CO2 or air was performed for 30 min prior to hepatic I/R. Hepatic I/R‑induced hepatocellular apoptosis and expression of the neutrophil chemoattractant endothelial monocyte‑activated polypeptide‑II, were inhibited by CO2‑pneumoperitoneum, however, not by air‑pneumoperitoneum. Pretreatment with the transient receptor potential vanilloid 1 antagonist SB366791 reversed the protective effects of CO2‑pneumoperitoneum. The results from the present study demonstrated that CO2‑pneumoperitoneum attenuates hepatic apoptosis and inflammatory responses in rats subjected to hepatic I/R, possibly by stimulating sensory neurons. These findings suggested that CO2‑pneumoperitoneum contributed to the attenuated inflammatory response observed following laparoscopic surgery.

Topics: Anilides; Animals; Apoptosis; Carbon Dioxide; Cinnamates; Inflammation; Laparoscopy; Liver; Liver Diseases; Male; Pneumoperitoneum, Artificial; Rats; Rats, Wistar; Reperfusion Injury; Sensory Receptor Cells; TRPV Cation Channels

TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.

Topics: Anilides; Animals; Calcium; Calcium Channels; Calcium Signaling; Capsaicin; CD4-Positive T-Lymphocytes; Cells, Cultured; Cinnamates; Colitis; Humans; Inflammation; Interleukin-10; Intestines; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Antigen, T-Cell; Sensory System Agents; TRPV Cation Channels

The activation of C-fibers in the airways induces coughing, mucus production and bronchoconstriction, which are also symptoms of airway diseases. In this study, we evaluated the role of the C-fibers and the TRPV1 (transient receptor potential vanilloid 1) receptor in an experimental mouse model of allergic airway inflammation. To study the role of C-fibers, we either degenerated the C-fibers persistently (capsaicin administration in neonate mice) or transiently (capsaicin administration in adult mice). No alteration was observed in eosinophil recruitment to the bronchoalveolar lavage fluid in animals treated with capsaicin in the neonatal period. However, in adult animals, capsaicin treatment after the first ovalbumin challenge (in the establishment of the inflammatory process) decreased the eosinophil numbers. This effect was more pronounced in adult animals treated with capsaicin before beginning the ovalbumin immunization (in the development of the inflammatory process). In addition, interleukin (IL)-5 and chemokine ligand 11 (CCL11) levels in the bronchoalveolar lavage fluid, as well as P-selectin expression and p65 nuclear factor κB (NF-κB) activation in the lung were also decreased. No alterations were observed in the IL-10 and IL-13 levels. Next we determined the effect of TRPV1 receptor blockade on allergic airway inflammation. SB366791 administrated in mice by intraperitoneal (500μg/kg) or intranasal (0.1, 1 or 10nmol/site) route failed to decrease eosinophil recruitment to the bronchoalveolar lavage fluid or alter any other metrics cited above. Thus, the present results confirm and extend previous data supporting the involvement of C-fibers, but not the TRPV1 receptor, in allergic airway inflammation.

Topics: Allergens; Anilides; Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Capsaicin; Cell Count; Cinnamates; Cytokines; Female; Gene Expression Regulation; Hypersensitivity; Immunization; Inflammation; Leukocytes; Lung; Mice; Mice, Inbred BALB C; Nerve Fibers, Unmyelinated; NF-kappa B; Ovalbumin; P-Selectin; Respiratory System; TRPV Cation Channels

The anti-hyperalgesic effects of TRPV1 receptor antagonists are well documented in animal models of pain, however, the precise site of their action is not known. Here we have examined the effects of the selective TRPV1 antagonist SB-366791 on glutamatergic synaptic transmission in substantia gelatinosa using spinal cord slices from either control rats or animals that had undergone a peripheral inflammation induced by intraplantar injection of Freund's complete adjuvant (FCA). In control animals, SB-366791 (30 microM) had no effect on spontaneous excitatory post-synaptic currents (sEPSC) or evoked EPSCs. In slices from FCA-inflamed animals, SB-366791 decreased sEPSC frequency to 66+/-8% of control in 5/10 neurones, and decreased miniature glutamatergic EPSCs (mEPSC) frequency to 63+/-4% of control, in 6/7 neurones; with no significant effect on sEPSC or mEPSC amplitude. Dorsal root evoked EPSCs at C-fibre intensity were reduced to 72+/-6% of control by SB-366791 (30 microM) in 3/4 neurones from FCA-treated animals. In conclusion, SB-366791 inhibited glutamatergic transmission in a subset of neurones via a pre-synaptic mechanism following peripheral inflammation. We hypothesise that during peripheral inflammation spinal TRPV1 becomes tonically active, promoting the synaptic release of glutamate. These results provide evidence for a mechanism by which TRPV1 contributes to inflammatory pain and provides a basis for the understanding of the efficacy of TRPV1 antagonists.

Topics: Anilides; Animals; Cinnamates; Excitatory Postsynaptic Potentials; Freund's Adjuvant; Glutamates; Inflammation; Models, Biological; Posterior Horn Cells; Rats; Synaptic Transmission; Time Factors; TRPV Cation Channels