BACKGROUND AND PURPOSEAcute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile. EXPERIMENTAL APPROACHWe evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists. KEY RESULTSMesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT. CONCLUSIONS AND IMPLICATIONSSalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects. LINKED ARTICLESThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx

Background Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse. Methods We evaluated SalA and the novel analogue β-tetrahydropyran Salvinorin B (β-THP SalB) for the ability to modulate pain and inflammation in vivo. The hot water tail-withdrawal assay, intradermal formalin-induced inflammatory pain and paclitaxel-induced neuropathic pain models were used to evaluate analgesic properties in mice. Tissue infiltration of inflammatory cells was measured by histology and flow cytometry. Results β-THP SalB produced a longer duration of action in the tail-withdrawal assay compared to the parent compound SalA, and, like SalA and U50,488, β-THP SalB is a full agonist at the KOPr. In the formalin-induced inflammatory pain model, β-THP SalB and SalA significantly reduced pain score, paw oedema and limited the infiltration of neutrophils into the inflamed tissue. β-THP SalB and SalA supressed both mechanical and cold allodynia in the paclitaxel-induced neuropathic pain model, in a dose-dependent manner. Conclusions Structural modification of SalA at the C-2 position alters its analgesic potency and efficacy in vivo. Substitution with a tetrahydropyran group at C-2 produced potent analgesic and anti-inflammatory effects, including a reduction in paclitaxel-induced neuropathic pain. This study highlights the potential for KOPr agonists as analgesics with anti-inflammatory action and little risk of abuse.

ObjectiveThere is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout.MethodsA content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions.ResultsThe content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: ‘asymptomatic hyperuricaemia’, ‘asymptomatic monosodium urate crystal deposition’, ‘asymptomatic hyperuricaemia with monosodium urate crystal deposition’, ‘gout’, ‘tophaceous gout’, ‘erosive gout’, ‘first gout flare’ and ‘recurrent gout flares’. There was consensus agreement that the label ‘gout’ should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus).ConclusionConsensus agreement has been established for the labels and definitions of eight gout disease states, including ‘gout’ itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

AimsDiagnosis of heart failure in older people in long-term care is challenging because of co-morbidities, cognitive deficit, polypharmacy, immobility, and poor access to services. This study aimed to ascertain heart failure prevalence and clinical management in this population.Methods and resultsA total of 405 residents, aged 65–100 years, in 33 UK care facilities were prospectively enrolled between April 2009 and June 2010. The presence of heart failure was determined using European Society of Cardiology guidelines, modified where necessary for immobility. Evaluation of symptoms and signs, functional capacity, and quality of life, portable on-site echocardiography, and medical record review were completed in 399 cases. The point prevalence of heart failure was 22.8% [n = 91, 95% confidence interval (CI) 18.8–27.2%]; of these, 62.7% (n = 57, 95% CI 59.6–66.5%) had heart failure with preserved ejection fraction and 37.3% had left ventricular systolic dysfunction (n = 34, 95% CI 34.8–40.5%). A total of 76% (n = 61) of previous diagnoses of heart failure were not confirmed, and up to 90% (n = 82) of study cases were new. No symptoms or signs were reliable predictors of heart failure.ConclusionHeart failure was diagnosed in almost a quarter of residents: the prevalence was substantially higher than in other populations. The majority of heart failure cases were undiagnosed, while three-quarters of previously recorded cases were misdiagnosed. Common symptoms and signs appear to have little clinical utility in this population. Early, accurate differential diagnosis is key to the effective management of heart failure; this may be failing in long-term care facilities.Trial registrationISRCTN19781227

The anti-inflammatory peptide Ac-SDKP is released from thymosin-␤4 by renal meprin-␣ and prolyl oligopeptidase. Am J Physiol Renal Physiol 310: F1026 -F1034, 2016. First published March 9, 2016 doi:10.1152/ajprenal.00562.2015.-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with antiinflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-␤4 (T␤4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and T␤4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, T␤4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-␣ metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, T␤4 is hydrolyzed by meprin-␣. In vitro, we found that the incubation of T␤4 with both meprin-␣ and POP released Ac-SDKP, whereas no Ac-SDKP was released when T␤4 was incubated with either meprin-␣ or POP alone. Incubation of T␤4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-␣ inhibitor actinonin. In addition, kidneys from meprin-␣ knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-␣ KO mice failed to release Ac-SDKP from T␤4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 Ϯ 0.2 nmol/l; captopril, 15.1 Ϯ 0.7 nmol/l; captopril ϩ actinonin, 6.1 Ϯ 0.3 nmol/l; P Ͻ 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from T␤4 is mediated by successive hydrolysis involving meprin-␣ and POP.N-acetyl-seryl-aspartyl-lysyl-proline; thymosin-␤4; meprin-␣; prolyl oligopeptidase; angiotensin-converting enzyme THE ANTI-INFLAMMATORY PEPTIDE N-acetyl-seryl-aspartyl-lysylproline (Ac-SDKP) was identified originally in the bone marrow (24). It has also been widely distributed in mammalian organs, plasma, urine, and circulating mononuclear cells (23,39,46). In animal diseases with hypertension, as well as cardiovascular and kidney disease, Ac-SDKP reduces inflammatory cell infiltration and collagen deposition in the heart, kidney, lung, and liver (14,15,33,34,37,44). Ac-SDKP is hydrolyzed by angiotensin-converting enzyme (ACE) and has a short half-life of 4.5 min in the circulation (16). Treatment with ACE inhibitors significantly increased plasma concentration of Ac-SDKP (2), and some of the ACE inhibitors protective effects were reported to be mediated by the increases in Ac-SDKP concentrations (34, 35).Thymosin-␤4 (T␤4) is a major G-actin-sequestering peptide that consists of 43 amino acids. Since it contains the Ac-SDKP sequence in its NH 2 -terminal, T␤4 is considered to be the precursor of 39). Our group has shown p...