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The vanilloid receptor 1 (VR1) is a cation channel expressed predominantly by nociceptive sensory neurons and is activated by a wide array of pain-producing stimuli, including capsaicin, noxious heat, and low pH. Although the behavioral effects of injected capsaicin and the VR1 antagonist capsazepine have indicated a potential role for VR1 in the generation and maintenance of persistent pain states, species differences in the molecular pharmacology of VR1 and a limited number of selective ligands have made VR1 difficult to study in vivo. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbox-amide (BCTC) is a recently described inhibitor of capsaicin-and acidmediated currents at rat VR1. Here, we report the effects of BCTC on acute, inflammatory, and neuropathic pain in rats. Administration of BCTC (30 mg/kg p.o.) significantly reduced both mechanical and thermal hyperalgesia induced by intraplantar injection of 30 g of capsaicin. In rats with Freund's complete adjuvantinduced inflammation, BCTC significantly reduced the accompanying thermal and mechanical hyperalgesia (3 mg/kg and 10 mg/kg p.o., respectively). BCTC also reduced mechanical hyperalgesia and tactile allodynia 2 weeks after partial sciatic nerve injury (10 and 30 mg/kg p.o.). BCTC did not affect motor performance on the rotarod after administration of doses up to 50 mg/kg p.o. These data suggest a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.The vanilloid receptor type 1 (VR1) is a pivotal molecular integrator of noxious stimuli that is expressed on somatic and autonomic primary afferent neurons. VR1 has been confirmed as a ligand-gated ion channel after its cloning from rat and human tissues, and has been shown to be highly expressed in small-diameter primary afferent neurons (Caterina et al., 1997;Hayes et al., 2000;McIntyre et al., 2001). In vitro studies have shown that, like the native vanilloid receptor, recombinant VR1 can be activated by a variety of chemical as well as physical stimuli. In vitro, VR1 responds to plant-derived compounds, including capsaicin, a pungent component of chili peppers, lipid mediators such as anandamide , the lipoxygenase product 12-(S)-hydroperoxyeicosatetraenoic acid (Hwang et al., 2000), as well as noxious heat (Caterina et al., 1997) and low pH (Tominaga et al., 1998).A potential role for VR1 in nociception has been evident for some time because injection of the VR1 agonist capsaicin induces nocifensive and hyperalgesic behaviors in rodents and pain in humans (Szolcsanyi, 1977;Carpenter and Lynn, 1981;Simone et al., 1987Simone et al., , 1989Gilchrist et al., 1996). Further support for VR1 as a therapeutic target arose from experiments involving capsazepine. Capsazepine is a VR1 antagonist that has been shown to competitively inhibit capsaicin-mediated responses in isolated dorsal root ganglion (DRG) neurons (Bevan et al., 1992a) and tissues from rat (Bevan et al., 1992b;Cholewinski et al., 1993;Maggi et al., 1993;Santicioli et al., 19...

Objective-The goal of this study was to assess the role of B-cell activating factor (BAFF) receptor in B-cell regulation of atherosclerosis. Methods and Results-Male LDL receptor-deficient mice (Ldlr −/− ) were lethally irradiated and reconstituted with either wild type or BAFF receptor (BAFF-R)-deficient bone marrow. After 4 weeks of recovery, mice were put on a high-fat diet for 6 or 8 weeks. BAFF-R deficiency in bone marrow cells led to a marked reduction of conventional mature B2 cells but did not affect the B1a cell subtype. This was associated with a significant reduction of dendritic cell activation and Tcell proliferation along with a reduction of IgG antibodies against malondialdehyde-modified low-density lipoprotein. In contrast, serum IgM type antibodies were preserved. Interestingly, BAFF-R deficiency was associated with a significant reduction in atherosclerotic lesion development and reduced numbers of plaque T cells. Selective BAFF-R deficiency on B cells led to a similar reduction in lesion size and T-cell infiltration but in contrast did not affect dendritic cell activation. Conclusion-BAFF-

1 Both clinical and preclinical models of postsurgical pain are being used more frequently in the early evaluation of new chemical entities. In order to assess the validity and reliability of a rat model of postincisional pain, the effects of different classes of clinically effective analgesic drugs were evaluated against multiple behavioural end points. 2 Following surgical incision, under general anaesthesia, of the plantar surface of the rat hind paw, we determined the time course of mechanical hyperalgesia, tactile allodynia and hind limb weight bearing using the Randall -Selitto (paw pressure) assay, electronic von Frey and dual channel weight averager, respectively. Behavioural evaluations began 24 h following surgery, and were continued for 9 -14 days. 3 Mechanical hyperalgesia, tactile allodynia and a decrease in weight bearing were present on the affected limb within 1 day of surgery with maximum sensitivity 1 -3 days postsurgery. Accordingly, we examined the effect of nonsteroidal antiinflammatory drugs (NSAIDs), morphine and gabapentin, on established hyperalgesia and allodynia, 1 day following plantar incision. 4 In accordance with previous reports, both systemic morphine and gabapentin administration reversed mechanical hyperalgesia and tactile allodynia in the incised rat hind paw. Both drugs were more potent against mechanical hyperalgesia than tactile allodynia.5 All of the NSAIDs tested, including cyclooxygenase 2 selective inhibitors, reversed mechanical hyperalgesia and tactile allodynia in the incised rat hind paw. The rank order of potency for both hyperalgesia and allodynia was indomethacin 4 celecoxib 4 etoricoxib 4 naproxen. 6 We have investigated the potency and efficacy of different classes of analgesic drugs in a rat model of postincisional pain. The rank order of potency for these drugs reflects their utility in treating postoperative pain in the clinic. As these compounds showed reliable efficacy across two different behavioural end points, the Randall -Selitto (paw pressure) assay and electronic von Frey, these methods may prove useful in the study of postsurgical pain and the assessment of novel treatments.