TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception

Background: Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular overthe- counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen. Methodology/Principal Findings: Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E-2 (PGE(2)) and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test. Conclusions: This study shows that TRPV1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV1 in the brain

Business is key: a sustainable supply chain management checklist could hold the solution to environmental preservation

Thesis (MPA)--Stellenbosch University, 2017.ENGLISH SUMMARY : Sustainability is key for global survival, but the problem is raised as to how the world can achieve sustainability. Businesses hold the potential to have a massive impact regarding how products are produced, raw materials are purchased and product waste is handled. This raises the question as to how businesses can actually implement sustainability throughout their operations. This study aims to assess the use of companies’ supply chains to address this question. This paper will look into both academic theories of supply chain sustainability and practical commitments made by companies, and assess where the overlays exist. Secondary research was conducted by means of a literature review, looking into many theoretical concepts including but not limited to: sustainable supply chain management, the triple bottom line, reverse logistics, sustainable sourcing and sustainable development. Furthermore, case studies were developed for the fast moving consumer goods industry by looking into six companies (four international and two South African). These case studies were developed by using sustainability reports, newspaper articles and articles published by NGOs. It was determined by the findings of this paper that there are three key areas of sustainable sourcing, which are: (1) Supplier relationships, looking into using a firm’s influence over suppliers, improving small-scale farming practice, forming partnerships with suppliers, as well as developing a supplier code of conduct; (2) Holistic Purchasing Strategy, whereby firms no longer look merely at price but take the externalities which impact sustainability into account when purchasing for their supply chain; (3) Partnerships with NGOs, whereby companies form relationships with NGOs in the areas in which they wish to improve and benefit from shared expertise. The findings for reverse logistics revealed two key areas, these are: (1) Product design, whereby businesses focus their product design on different principles to increase sustainability, like design for environment, design for sustainability, design for disassembly, design for recycling, and design for remanufacture; (2) Product Recovery, whereby companies look both in-house to recycle and reduce waste that goes to landfills and end-user/consumer recycling of waste their products create. These findings from sustainable sourcing and reverse logistics form the foundation for the development of the checklist which businesses can use to assess their sustainability efforts and then make the appropriate changes. Future research that can be addressed includes studies that replicate this study but make use of different industries like technology or high-end beauty products. Another area could be a replica study of the companies discussed in this study to assess at a future point their progress and current commitments. Alternative research could focus on the other aspects of supply chain management which were not covered in this paper, namely warehousing, production and distribution.AFRIKAANSE OPSOMMING : Volhoubaarheid is die sleutel tot globale oorlewing, maar die vraag is hoe die wereld by volhoubaarheid kan uitkom. Sake-ondernemings het die potensiaal om ’n groot invloed te he op hoe produkte vervaardig word, rou material aangekoop word en hoe afvalmateriaal hanteer word. Die vraag ontstaan hoe besighede volhoubaarheid tasbaar kan implementeer regdeur hul ondernemings. Hierdie studie wil die gebruik van maatskappye se voorsieningsketting bepaal om die vraag te beantwoord. In die verhandeling sal gekyk word na akademiese teoriee van voorsieningskettingvolhoubaarheid en die praktiese toepassings waartoe maatskappye hulle verbind het, en waar die twee oorvleuel. Sekondere navorsing is gedoen deur middel van ’n kritiese oorsig van publikasies, met die klem op teoretiese konsepte (maar nie beperk daartoe nie) van: volhoubare voorsienings kettingsbestuur, drievoudige verslagdoening, terugwaartse logistiek, volhoubare verkryging en volhoubare ontwikkeling. Voorts is gevallestudies ontwikkel vir die hoeomset-verbruiksgoedere-industrie deur ondersoek in te stel na ses maatskappye (vier internasionaal en twee plaaslik). Hierdie gevallestudies is saamgestel met behulp van volhoubaarheidsverslae, koerantartikels en artikels wat deur Nie-regeringsorganisasies (NRO’s) gepubliseer is. Die bevindinge van hierdie verhandeling is dat daar drie sleutel-areas is vir volhoubare bronverskaffing, naamlik: (1) Betrekkinge met bronverskaffers – die studie van ’n firma se invloed op verskaffers; die verbetering van kleinskaalse boerdery-praktyke; die opbou van vennootskappe met verskaffers, sowel as die ontwikkeling van ’n verskaffers-gedragskode. (2) Holistiese Aankoopstrategie, waar firmas nie langer slegs na prys kyk nie, maar buitefaktore in ag neem wat volhoubaarheid beinvloed wanneer hulle aankope doen by hul verskaffers. (3) Vennootskappe met Nie-regeringsorganisasies: Besighede kan vennootskappe met NRO’s aangaan in areas waarin praktyke kan verbeter en kundighede en vaardighede gedeel kan word. Die bevindinge oor terugwaartse logistiek het twee sleutelareas uitgewys: 1. Produkontwerp: Dit is wanneer maatskappye hul produkontwerp fokus op ander beginsels om volhoubaarheid te verbeter, soos Ontwerp vir Omgewing, Ontwerp vir Volhoubaarheid, Ontwerp vir Demontasie, Ontwerp vir Herwinning en Ontwerp vir Hervervaardiging. 2. Produk-verhaling: Maatskappye poog om gedurende die vervaardigingsproses afvalstowwe te verminder of om te sien hoe dit herbruik kan word, sodat minder afval by stortingsterreine beland. Sodoende word minder rommel ook deur die verbruiker van hierdie produkte geskep. Hierdie bevindinge van die gebruik van volhoubare bronmateriaal en terugwaartse logistiek, vorm die basis waardeur ’n vervaardiger ’n kontrolelys met bepaalde volhoubaarheids-doelwitte kan opstel. Hiermee kan hulle gereeld meet of die doelwitte bereik word en aanpassings maak om te verbeter. Toekomstige navorsing kan gedoen word met soortgelyke studiemetodes, maar in verskillende industriee, soos byvoorbeeld die vervaardiging van tegnologiese produkte en/of eksklusiewe skoonheidsmiddels. Verder kan hierdie studie herhaal word, maar oor ’n paar jaar om te bepaal of die maatskappye wel hul doelwitte ten opsigte van volhoubaarheid bereik het. Alternatiewe navorsing kan fokus op ander aspekte van die voorsieningsketting wat nie in hierdie studie gedek is nie, naamlik opgaring, produksie en verspreiding

Selective suppression of inhibitory synaptic transmission by nocistatin in the rat spinal cord dorsal horn

Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters l-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profound hyperalgesia after intrathecal application. Similar to glycine and GABA(A) receptor antagonists, NST had no significant effects in the rat tail-flick test, a model of acute thermal pain. Our results provide a cellular basis for the antagonism of N/OFQ and NST and suggest the existence of a so far unidentified membrane receptor for NST. In addition, they support a role of NST as an endogenous inhibitor of glycinergic and GABAergic neurotransmission in the sensory part of the spinal cord and as a mediator of spinal hyperalgesia

The cannabinoids R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU-210), 2-O-arachidonoylglycerylether (HU-310) and arachidonyl-2-chloroethylamide (ACEA) increase isoflurane provoked sleep duration by activation of cannabinoids 1 (CB1)-receptors in mice

Cannabinoids produce antinociception via specific cannabinoid receptor activation, but there are also non-receptor mediated effects like for example the activation of the arachidonic acid cascade. Here we investigate the influence of cannabinoids (CB) on sleep duration after isoflurane anesthesia. We found that the CB receptor agonists R(-)-7-hydroxydelta-6-tetra-hydrocannabinol-dimethylheptyl (HU-210) (0.1 mg/kg), 2-O-arachidonoylglycerylether (30 mg/kg) and arachidonyl-2-chloroethylamide (3 mg/kg) significantly prolong the duration of isoflurane induced sleep in mice (P < 0.05). This effect was absent when co-injecting the selective CB, antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (1 mg/kg). Furthermore, HU-210 was ineffective in CB, receptor knockout mice (CB1 -/-). Our behavioral tests (tail flick, rotarod) indicate that the sleep latency can be prolonged even at low drug dosages which do not influence thermal nociception. In the chosen dosages thimerosal (20 mg/kg), 2-AG (10 mg/kg), R-1-methanandamide (R-1-MAEA) (10 mg/kg) and flurbiprofen (27 mg/kg) were ineffective to increase sleep duration. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Flurbiprofen inhibits capsaicin induced calcitonin gene related peptide release from rat spinal cord via an endocannabinoid dependent mechanism

Calcitonin gene related peptide (CGRP) is involved in nociceptive transmission and modulation at the spinal level. In the spinal superperfusion model, Delta(9) tetrahydrocannabinol inhibited capsaicin induced CGRP release in a concentration dependent manner. Similarly, flurbiprofen (3 muM) inhibited spinal CGRP release. This inhibition was reversed by the CB1 antagonist AM-251 (1 muM), but not by co-administration of prostaglandin E-2 (PGE(2); 285 nM). AM-251 had no modulatory effect on flurbiprofen-induced cyclooxygenase (COX) inhibiting capacity as shown by PGE2 levels. Furthermore, the phospholipase A(2) inhibitor palmityl trifluromethyl ketone (15 muM) reversed flurbiprofen's inhibitory effect. In conclusion the present work provides evidence on the shift of arachidonic acid metabolism towards endocannabinoids formation in response to COX inhibition as a mechanism for flurbiprofen inhibitory effect on spinal CGRP release. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Ketoprofen-induced cyclooxygenase inhibition in renal medulla and platelets of rats treated with caffeine

It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs), The aim of the present study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dose-dependent (estimated ID50 0.3 mg/kg p.o.) reduction of PGE(2) biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-induced inhibition of PGE(2) biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect of caffeine on ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B-2 biosynthesis. Additional experiments showed increased COX-2 mRNA expression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX-2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE(2) biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported for in vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE(2) biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are not related to interference with renal COX inhibition. Copyright (C) 2001 S.Karger AG, Basel

HU-210 shows higher efficacy and potency than morphine after intrathecal administration in the mouse formalin test

The discovery of endocannabinoids opens up new perspectives in experimental pain research. Here we present data for the excellent antinociceptive properties of the synthetic caanabinoid, R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl(HU-210), after intrathecal and oral administration in mice. It is known that cannabinoids depress motor activity. Therefore, these compounds are suspected of influencing antinociceptive tests. Our behavioural tests (RotaRod, tail flick) clearly show that HU-210 affects nociceptive behaviour even at dosages which do not yet influence motor activity. Moreover, spinal microdialysis (5 mul/min) in the dorsal horn of freely moving mice showed an enhancement of prostaglandin production during the formalin test. HU-210 applied via artificial cerebral spinal fluid during microdialysis perfusion increases prostaglandin concentrations under both baseline and formalin test conditions. Indomethacin reduces the HU-210 effect on pronociceptive prostaglandin production but does not reinforce the antinociceptive properties of HU-210. Thus, HU-210 shows antinociceptive properties that are independent of its influence on the prostaglandin pathway. (C) 2001 Elsevier Science B.V. All rights reserved

Defining the clinical characteristics of Peyronie\u27s disease in young men.

INTRODUCTION: Peyronie\u27s disease (PD) is usually seen in men in their fifth decade of life. AIM: In this study, we investigated the characteristics of the disease in young men. MAIN OUTCOME MEASURES: The demographics, clinical features, and associated comorbidities of the patients with PD were retrospectively reviewed. METHODS: The findings were compared between men with the disease who were under 40 years of age with those over 40 years. Statistical analyses were conducted to define differentiating features between these two groups. RESULTS: Of the 296 patients, 32 were under the age of 40 years and 264 over 40 years. The mean duration of the disease was 2 +/- 4 and 6 +/- 8 months in the respective age groups. Fifty-six percent of the patients under the age of 40 years and 75% of the patients over this age presented with curvature (P \u3c 0.01). Thirty-seven percent under 40 years and 12% men over 40 years had more than one plaque at presentation (P \u3c 0.01). Dupuytren\u27s contracture was seen only in patients over 40 years of age. Pain at presentation was found in 75% under the age of 40 years and in 65% over 40 years (P = 0.03). Trauma history was found in 18% under 40 years and in 5% over this age (P \u3c 0.01). Statistical significant differences were found between the groups under and over the age of 40 years for hypertension (P \u3c 0.01) and dyslipidemia (P \u3c 0.01). Diabetes was noted in 50% of the patients under the age of 40 years and in 18% of the patients over this age (P \u3c 0.001). Multivariate analysis of conditions associated in men with PD under 40 years of age showed statistical significant differences for diabetes (P = 0.015), presentation within 6 months (P = 0.004), and having multiple plaques (P = 0.008). CONCLUSIONS: Young men with PD are more likely to present at an earlier stage of the disease, to have diabetes, and to have more than one plaque at the time of presentation