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IntroductionTimely, accurate and detailed information about traffic injuries are essential for managing national road safety programmes. However, there is considerable under-reporting in official statistics of many low and middle-income countries (LMICs) and large discrepancies between estimates from the Global Burden of Disease (GBD) study and WHO’s Global Health Estimates (GHE). We compared all sources of epidemiological information on traffic injuries in Cambodia to guide efforts to improve traffic injury statistics.MethodsWe estimated the incidence of traffic deaths and injuries and household ownership of motor vehicles in Cambodia from nationally representative surveys and censuses. We compared findings with GDB and GHE estimates.ResultsWe identified seven sources for estimating traffic deaths and three for non-fatal injuries that are not included as data sources in GBD and GHE models. These sources and models suggest a fairly consistent estimate of approximately 3100 deaths annually, about 50% higher than official statistics, likely because most hospital deaths are not recorded. Surveys strongly suggest that the vehicle fleet is dominated by motorcycles, which is not consistent with GBD estimates that suggest similar numbers of motorcyclist and vehicle occupant deaths. Estimates of non-fatal injuries from health surveys were about 7.5 times official statistics and 1.5 times GBD estimates.ConclusionIncluding local epidemiological data sources from LMICs can help reduce uncertainty in estimates from global statistical models and build trust in estimates among local stakeholders. Such analysis should be used as a benchmark to assess and strengthen the completeness of reporting of the national surveillance system.

BackgroundThere are large discrepancies between official statistics of traffic injuries in African countries and estimates from the Global Burden of Disease (GBD) study and WHO’s Global Status Reports on Road Safety (GSRRS). We sought to assess the magnitude of the discrepancy in Ethiopia, its implications and how it can be addressed.MethodsWe systematically searched for nationally representative epidemiological data sources for road traffic injuries and vehicle ownership in Ethiopia and compared estimates with those from GBD and GSRRS.FindingsGBD and GSRRS estimates vary substantially across revisions and across projects. GSRRS-2018 estimates of deaths (27 326 in 2016) are more than three times GBD-2019 estimates (8718), and these estimates have non-overlapping uncertainty ranges. GSRRS estimates align well with the 2016 Demographic and Health Survey (DHS-2016; 27 838 deaths, 95th CI: 15 938 to 39 738). Official statistics are much lower (5118 deaths in 2018) than all estimates. GBD-2019 estimates of serious non-fatal injuries are consistent with DHS-2016 estimates (106 050 injuries, 95th CI: 81 728 to 130 372) and older estimates from the 2003 World Health Survey. Data from five surveys confirm that vehicle ownership levels in Ethiopia are much lower than in other countries in the region.InterpretationInclusion of data from national health surveys in GBD and GSRRS can help reduce discrepancies in estimates of deaths and support their use in highlighting under-reporting in official statistics and advocating for better prioritisation of road safety in the national policy agenda. GBD methods for estimating serious non-fatal injuries should be strengthened to allow monitoring progress towards Sustainable Development Goal target 3.6.

IntroductionThe First UN Decade of Action for Road Safety (2011–2020) ended with most low/middle-income countries (LMICs) failing to reduce road traffic deaths. In contrast, Brazil reported a strong decline starting in 2012. However, comparisons with global health statistical estimates suggest that official statistics from Brazil under-report traffic deaths and overestimate declines. Therefore, we sought to assess the quality of official reporting in Brazil and explain discrepancies.MethodsWe obtained national death registration data and classified deaths to road traffic deaths and partially specified causes that could include traffic deaths. We adjusted data for completeness and reattributed partially specified causes proportionately over specified causes. We compared our estimates with reported statistics and estimates from the Global Burden of Disease (GBD)-2019 study and other sources.ResultsWe estimate that road traffic deaths in 2019 exceeded the official figure by 31%, similar to traffic insurance claims (27.5%) but less than GBD-2019 estimates (46%). We estimate that traffic deaths have declined by 25% since 2012, close to the decline estimated by official statistics (27%) but much more than estimated by GBD-2019 (10%). We show that GBD-2019 underestimates the extent of recent improvements because GBD models do not track the trends evident in the underlying data.ConclusionBrazil has made remarkable progress in reducing road traffic deaths in the last decade. A high-level evaluation of what has worked in Brazil could provide important guidance to other LMICs.

IntroductionThere is considerable uncertainty in estimates of traffic deaths in many sub-Saharan African countries, with the Global Burden of Disease (GBD) and the Global Status Report on Road Safety (GSRRS) reporting widely differing estimates. As a case study, we reviewed and compared estimates for Tanzania.MethodsWe estimated the incidence of traffic deaths and vehicle ownership in Tanzania from nationally representative surveys. We compared findings with GBD and GSRRS estimates.ResultsTraffic death estimates based on the 2012 census (9382 deaths; 95% CI: 7565 to 11 199) and the 2011–2014 Sample Vital Registration with Verbal Autopsy (8778; 95% CI: 7631 to 9925) were consistent with each other and were about halfway between GBD (5 608; 95% UI: 4506 to 7014) and WHO (16 252; 95% CI: 13 130 to 19 374) estimates and more than twice official statistics (3885 deaths in 2013). Surveys and vehicle registrations data show that motorcycles have increased rapidly since 2007 and now comprise 66% of vehicles. However, these trends are not reflected in GBD estimates of motorcycles in the country, likely resulting in an underestimation of motorcyclist deaths.ConclusionReducing discrepancies between GBD and GSRRS estimates and demonstrating consistency with local epidemiological data will increase the legitimacy of such estimates among national stakeholders. GBD, which is the only project that models the road-user distribution of traffic deaths in all countries, likely severely underestimates motorcycle deaths in countries where there has been a recent increase in motorcycles. Addressing police under-reporting and strengthening surveillance capacity in Tanzania will allow a better understanding of the road safety problem and better targeting of interventions.

BackgroundInjury is a leading contributor to the global disease burden in children and places children at risk for adverse and lasting impacts on their health-related quality of life (HRQoL) and development. This study aimed to identify key predictors of HRQoL following injury in childhood and adolescence.MethodsData from 2259 injury survivors (ResultsMean PedsQL total score increased with higher socioeconomic status and decreased with increasing age. It was lower for transport-related incidents, ≥1 comorbidities, intentional injuries, spinal cord injury, vertebral column fracture, moderate/severe traumatic brain injury and fracture of patella/tibia/fibula/ankle. Mean PedsQL physical score was lower for females, fracture of femur, fracture of pelvis and burns. Mean PedsQL psychosocial score was lower for asphyxiation/non-fatal submersion and muscle/tendon/dislocation injuries.ConclusionsPostinjury HRQoL was associated with survivors’ socioeconomic status, intent, mechanism of injury and comorbidity status. Patterns of physical and psychosocial functioning postinjury differed according to sex and nature of injury sustained. The findings improve understanding of the long-term individual and societal impacts of injury in the early part of life and guide the prioritisation of prevention efforts, inform health and social service planning to help reduce injury burden, and help guide future Global Burden of Disease estimates.

Background and purpose: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.

Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.

Background and purpose: Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB2)-selective aminoalkylindole with antinociceptive efficacy in animal pain models. The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo. Experimental approach: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB2 receptors. Inhibition of cAMP was assayed using intact CB2-expressing cells. A mouse model of visceral pain (para-phenylquinone, PPQ) and a rat model of acute inflammatory pain (carrageenan) were employed to characterize the compounds in vivo. Key results: In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB2, but an inverse agonist at rat and mouse CB2 receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB2 receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB2 receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB2 receptors. Conclusions and implications: These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB2 receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB2 agonist enantiomer of AM1241, is consistent with previous observations that CB2 agonists are effective in relief of pain. British Journal of Pharmacology (2007) 151, 1061–1070; doi:10.1038/sj.bjp.0707303

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 > celecoxib > etoricoxib > 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.

International audience; BACKGROUND: Measurement of the global burden of disease with disability-adjusted life-years (DALYs) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury. There has been extensive debate about a range of conceptual and methodological issues concerning the definition and measurement of these weights. Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach. METHODS: We surveyed respondents in two ways: household surveys of adults aged 18 years or older (face-to-face interviews in Bangladesh, Indonesia, Peru, and Tanzania; telephone interviews in the USA) between Oct 28, 2009, and June 23, 2010; and an open-access web-based survey between July 26, 2010, and May 16, 2011. The surveys used paired comparison questions, in which respondents considered two hypothetical individuals with different, randomly selected health states and indicated which person they regarded as healthier. The web survey added questions about population health equivalence, which compared the overall health benefits of different life-saving or disease-prevention programmes. We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study. We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 (implying no loss of health) to 1 (implying a health loss equivalent to death). Additionally, we compared new disability weights with those used in WHO's most recent update of the Global Burden of Disease Study for 2004. FINDINGS: 13,902 individuals participated in household surveys and 16,328 in the web survey. Analysis of paired comparison responses indicated a high degree of consistency across surveys: correlations between individual survey results and results from analysis of the pooled dataset were 0*9 or higher in all surveys except in Bangladesh (r=0*75). Most of the 220 disability weights were located on the mild end of the severity scale, with 58 (26%) having weights below 0*05. Five (11%) states had weights below 0*01, such as mild anaemia, mild hearing or vision loss, and secondary infertility. The health states with the highest disability weights were acute schizophrenia (0*76) and severe multiple sclerosis (0*71). We identified a broad pattern of agreement between the old and new weights (r=0*70), particularly in the moderate-to-severe range. However, in the mild range below 0*2, many states had significantly lower weights in our study than previously. INTERPRETATION: This study represents the most extensive empirical effort as yet to measure disability weights. By contrast with the popular hypothesis that disability assessments vary widely across samples with different cultural environments, we have reported strong evidence of highly consistent results. FUNDING: Bill & Melinda Gates Foundation.

The International Classification of Diseases Injury Severity Score (ICISS) has been proposed as an International Classification of Diseases (ICD)-10-based alternative to mortality prediction tools that use Abbreviated Injury Scale (AIS) data, including the Trauma and Injury Severity Score (TRISS). To date, studies have not examined the performance of ICISS using Australian trauma registry data. This study aimed to compare the performance of ICISS with other mortality prediction tools in an Australian trauma registry.This was a retrospective review of prospectively collected data from the Victorian State Trauma Registry. A training dataset was created for model development and a validation dataset for evaluation. The multiplicative ICISS model was compared with a worst injury ICISS approach, Victorian TRISS (V-TRISS, using local coefficients), maximum AIS severity and a multivariable model including ICD-10-AM codes as predictors. Models were investigated for discrimination (C-statistic) and calibration (Hosmer-Lemeshow statistic).The multivariable approach had the highest level of discrimination (C-statistic 0.90) and calibration (H-L 7.65, P= 0.468). Worst injury ICISS, V-TRISS and maximum AIS had similar performance. The multiplicative ICISS produced the lowest level of discrimination (C-statistic 0.80) and poorest calibration (H-L 50.23, P0.001).The performance of ICISS may be affected by the data used to develop estimates, the ICD version employed, the methods for deriving estimates and the inclusion of covariates. In this analysis, a multivariable approach using ICD-10-AM codes was the best-performing method. A multivariable ICISS approach may therefore be a useful alternative to AIS-based methods and may have comparable predictive performance to locally derived TRISS models.

Corticotropin-releasing factor (CRF) plays a major role in controlling the body's response to stress. Because painful conditions are inherently stressful, we hypothesize that CRF may act via CRF-1 receptors to contribute to the pain experience. Studies were designed to investigate whether blocking CRF-1 receptors with selective antagonists or reducing their expression with CRF-Saporin, would attenuate ulcer, inflammatory- and neuropathic-like pain. Five experimental designs were undertaken. In experiment 1, ulcer pain was induced in mice following oral administration of indomethacin, while in experiments 2 and 3, inflammatory pain was induced in rats with either carrageenan or FCA, respectively. For these studies, animals were dosed with CP-154,526 (3, 10, 30 mg/kg) and NBI 27914 (1-30 mg/kg) 1 h prior to the assessment of tactile, thermal or mechanical hypersensitivity, respectively. In experiment 4, neuropathic pain was induced. Twenty-one days following spinal nerve ligation (SNL), animals received CRF-Saporin or control. Three weeks later tactile allodynia was assessed. Similarly, in experiment 5, a separate set of rats received CRF-Saporin or control. Twenty-one days later, mechanical hyperalgesia was assessed following intraplantar carrageenan. Results from the antagonist studies showed that CP-154,526 and NBI 27914 either fully or partially reversed the referred ulcer pain with minimal effective doses (MED) equal to 3 and 10 mg/kg, respectively. Similarly, both NBI 27914 and CP-154,526 reversed the thermal and mechanical hypersensitivity elicited by carrageenan and FCA with MEDs

Validation of gait analysis has the potential to bridge the gap between data from animal pain models and clinical observations. The goal of these studies was to compare alterations in gait due to inflammation or nerve injury to traditional pain measurements in animals. Pharmacological experiments determined whether gait alterations were related to enhanced nociception, edema, or motor nerve dysfunction. Gait was analyzed using an automated system (DigiGait) after injection of an inflammatory agent (carrageenan; CARR or FCA; Freund's complete adjuvant) or nerve injury (axotomy; AXO, partial sciatic nerve ligation; PSNL, spinal nerve ligation; SNL or chronic constriction injury; CCI). All models caused significant alterations in gait and thermal (inflammatory) or mechanical (nerve injury) hyperalgesia. Both indomethacin and morphine were able to block or reverse thermal hyperalgesia and normalize gait in the CARR model. Indomethacin partially blocked and did not reverse paw edema, suggesting that gait alterations must be primarily driven by enhanced nociception. In nerve injury models, AXO, PSNL, CCI, and SNL caused changes to the largest number of gait indices with the rank order being AXO > PSNL = CCI > > SNL. Gabapentin and duloxetine reversed mechanical hyperalgesia but did not normalize gait in any nerve injury model. Collectively, these data suggest that pain is the primary driver of abnormal gait in models of inflammatory but not nerve injury-related pain and suggests that, in the latter, disruption in gait is due to perturbation to the motor system. Gait may therefore constitute an alternative and potentially clinically relevant measure of pain due to inflammation.

Objectives: Population modelling holds considerable promise for identifying the most efficient and cost-effective falls prevention measures, but the outcomes need to be in a readily useable form. This paper describes an iterative, collaborative process undertaken by researchers and falls prevention policy officers to develop such a format for falls prevention intervention evidence. Methods: The researchers developed a draft template that underwent several iterations and improvements, through three collaborative consultations with policy officers. Results: Although the researchers initially identified many key information needs, active engagement with policy officers ensured that policy requirements were met and that the value of the reporting formats for policy decision-making was maximised. Importantly, they highlighted the need to articulate underlying modelling assumptions clearly. The resulting formats, with complete data, were given to policy officers to inform their local jurisdictional policy decisions. Conclusions: There is strong benefit in researchers and policy officers collaborating to develop optimal formats for presenting scientific evidence to inform policy decisions. Such a process can reduce concerns of researchers that evidence is not incorporated into policy decisions. They also meet policy officers' needs for evidence to be provided in a way that can directly inform their decision-making processes. Refereed/Peer-reviewed

Voltage-gated Na(+) channels may play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na(+) channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain; however, their therapeutic utility is compromised by central nervous system side effects. We reasoned that it may be possible to gain superior control over pain states and, in particular, a better therapeutic index, by designing broad-spectrum Na(+) channel blockers with higher potency, faster onset kinetics, and greater levels of state dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analog of the state-dependent Na(+) channel blocker V102862 [4-(4-fluorophenoxy)benzaldehyde semicarbazone]. Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1 to 3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and postincisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating Rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high-potency, broad-spectrum, state-dependent Na(+) channel blockers will have clinical utility for treating neuropathic, inflammatory, and postsurgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na(+) channel blockers may lead to improved pain therapeutics.

Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658–672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.

To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.

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(2 H )-carbox-amide (BCTC) is a recently described inhibitor of capsaicin- and acid-mediated 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 μg of capsaicin. In rats with Freund9s 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.