Targeting the Endocannabinoid System to Reduce Inflammatory Pain

The endogenous cannabinoids (endocannabinoids) anandamide (AEA) and 2-arachidonylglycerol (2-AG) exert their effects predominantly through cannabinoid CB1 and CB2 receptors, but these actions are short-lived because of rapid hydrolysis by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective inhibition of either enzyme elevates CNS levels of the appropriate endocannabinoid and produces analgesic effects with fewer psychomimetic side effects than Δ9-tetrahydrocannabinol (THC), the primary active constituent of marijuana. While cannabinoid receptor agonists and FAAH inhibitors reliably produce anti-inflammatory and anti-hyperalgesic effects in the carrageenan test and other inflammatory pain models, much less is known about the consequences of inhibiting MAGL in these assays. Here, we tested whether the selective MAGL inhibitor JZL184 would reduce nociceptive behavior in the carrageenan test. JZL184 significantly attenuated carrageenan-induced paw edema and mechanical allodynia, whether administered before or after carrageenan. Complementary genetic and pharmacological approaches revealed that JZL184’s anti-allodynic effects required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Importantly, the anti-edematous and anti-allodynic effects of JZL184 underwent tolerance following repeated injections of high dose JZL184 (16 or 40 mg/kg), but repeated administration of low dose JZL184 (4 mg/kg) retained efficacy. Interestingly, the anti-allodynic effects of the combination of low dose of JZL184 (4mg/kg) and high dose of the selective and long-acting FAAH inhibitor PF-3845 (10 mg/kg) was augmented compared with each drug alone. On the contrary, the combination treatment did not reduce edema more than either JZL184 or PR-3845 given alone. These results suggest that low doses of MAGL inhibitors alone or in combination with FAAH inhibitors, reduce inflammatory nociception through the activation of both CB1 and CB2 receptors with no evidence of tolerance following repeated administration

Targeting the Endocannabinoid Metabolic Enzymes to Reduce Inflammatory Pain

Pain is a debilitating condition that presents a problem of clinical relevance. Common analgesics include opioids and non-steroidal anti-inflammatory drugs (NSIADs). Despite different degrees of effectiveness, a major drawback of these analgesic classes is their side effects. For example, side effects associated with opioids include pruritus, respiratory depression, hyperalgesia, constipation, dependence. In addition, chronic use of NSAIDs can cause gastric ulcers. Delta-9 tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, produces antinociception in various preclinical models of pain. Similarly, many synthetic cannabinoid receptor agonists produce antinociception in preclinical models of pain. However, their psychomimetic effects dampen interest for their therapeutic development. THC and these cannabinoids act upon the endocannabinoid system, which is comprised of the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors, endogenous ligands arachidonoylethanolamide (anandamide; AEA), 2-arachidonoyolglycerol (2-AG), and endocannabinoid biosynthetic and catabolic enzymes. In the present study, we evaluated the impact of inhibiting one of the major biosynthetic enzymes of 2-AG, diacylglycerol lipase-b (DAGL-b), and two primary endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL), and fatty acid amide hydrolase (FAAH). MAGL is responsible for degrading 2-AG and FAAH is the principal degradative enzyme for anandamide. We hypothesized that inhibiting these enzymes will produce anti-edematous and anti-allodynic effects in preclinical models of inflammatory pain. In Chapter 2, we tested whether the selective MAGL inhibitor JZL184 and FAAH inhibitor PF-3845 would reduce nociceptive behavior in the carrageenan test. JZL184 and PF-3845 significantly attenuated carrageenan-induced paw edema and mechanical allodynia (a nociceptive response to normally non-noxious stimuli), whether administered before or after carrageenan. Complementary genetic and pharmacological approaches revealed that JZL184’s anti-allodynic effects required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Anti-edematous effects of PF-3845 were mediated through CB2 receptors. Importantly, the anti-edematous and anti-allodynic effects of JZL184 underwent tolerance following repeated injections of high dose JZL184 (16 or 40 mg/kg), but repeated administration of low dose JZL184 (4 mg/kg) retained efficacy. Although the data in the first set of studies demonstrate that inhibition of MAGL or FAAH reduces inflammatory pain, JZL184 and PF-3845 only produced partial effects. In an attempt to increase efficacy, Chapter 3 tested whether combined blockade of FAAH and MAGL would produce enhanced anti-edematous and anti-allodynic effects in the carrageenan model of inflammatory pain. Partial blockade of MAGL, with a low dose of JZL184 (4 mg/kg), and full blockade of FAAH, with a high dose of PF-3845 (10 mg/kg), enhanced the anti-allodynic effects, but no further increases in the anti-edematous effects were found. Importantly, repeated administration of this combination did not result in tolerance. A novel FAAH-MAGL dual inhibitor SA-57, which is far more potent in inhibiting FAAH than MAGL, reversed carrageenan-induced allodynia. Taken together, these findings suggest that dual MAGL and FAAH inhibition represents a promising avenue for the treatment of inflammatory pain. Chapter 4 of this dissertation tested whether inhibition of DAGL-b, a major biosynthetic enzyme of 2-AG, would reverse inflammatory pain. Two DAGL-b inhibitors, KT109, and KT172, which have been previously shown to reduce arachidonic acid, prostaglandins, and TNF-a levels in lipopolysaccharide (LPS)-stimulated murine macrophages, were used to test whether these compounds would elicit antinociceptive effects in the LPS model of inflammatory pain model. Because these drugs also inhibit ABHD6, we assessed KT195, a selective ABHD6 inhibitor that is inactive against DAGL-b. KT109, but not KT172 or KT195, significantly reversed LPS-induced allodynia. Importantly, we found that DAGL-b knockout mice possess an anti-allodynic phenotype, but KT109 did not elicit any further decrease in allodynia in these animals. The anti-allodynic effects of KT-109 did not require cannabinoid receptors. Additionally, the anti-allodynic effects of KT-109 did not undergo tolerance following repeated administration. KT-109 did not produce any gastric hemorrhagic effects when compared to the NSAID diclofenac, which significantly produced gastric hemorrhages. These results suggest that blockade of DAGL-b leads to antinociceptive effects through a cannabinoid receptor independent mechanism of action, with absence of notable side effects. Collectively, the research presented in this dissertation suggests that the endocannabinoid catabolic enzymes MAGL and FAAH, and the endocannabinoid biosynthetic enzyme DAGL-b, represent promising targets to treat inflammatory pain

"Learning by dining": informal networks and productivity in Mexican industry

The authors analyze the determinants of firm productivity in a group of Mexican firms. In particular, they test the contribution of external factors such as trade and knowledge diffusion, the availability of infrastructure, informal knowledge exchange, competitive environment, and business regulatory climate. The authors find that one factor consistently emerges as an important proximate source of productivity-access to informal networks. Interaction in the form of"business lunches"with local buyers and suppliers, competitors, government officials, and other professionals have a significant and positive effect on a firm's productivity. Access to regulators and agents of backward and forward linkages are important in settings where information on business practices and regulations is not publicly disclosed. The results complement predictions of traditional growth theory-in addition to technology and learning being the driving force of firm productivity, proximity to influential individuals who can grant favors or provide information advantage on business and trade practices have significant productivity impacts.Economic Theory&Research,Labor Policies,Banks&Banking Reform,Environmental Economics&Policies,Decentralization,Environmental Economics&Policies,Economic Theory&Research,Banks&Banking Reform,Municipal Financial Management,ICT Policy and Strategies

South Asian Countries : Economic Growth and Fertility

Analysis of data sets on contraceptive use is important to assess the effectiveness of policy decisions towards meeting the Millennium Development Goal that endeavours to ensure universal access to contraceptive use. The paper therefore attempts to estimate the trends in the contraceptive use and unmet need in India and her major neighbouring countries during the recent past based on the data base provided by the United Nations, Department of Economic, and Social Affairs, Population Division (2017). The study estimated the trends in the percentage of women who want to avoid pregnancy, by using modern contraceptives or used traditional methods or no methods. The paper concludes that for healthy upbringing of children birth spacing is important for women and the family. To meet the unmet need for use of modern contraceptives, the south Asian countries need to improve availability of resources for timely delivery of contraceptive services. The paper finally develops a statistical model to explore the causal relation between economic growth, fertility behaviour and contraceptive use in these set of countries. A long run relation is found to exist among the concerned variables in all the countries except Pakistan. Such, findings call for systematic intervention in terms of policy prescription

Academic Involvement in Children’s Education: An Investigation into the Lives of Domestic Worker Parents of Kolkata

Parenting holds tremendous significance in today’s world as quality parenting facilitates the development of social and emotional competence in a child. The present study explores the dual role of domestic workers as workers and parents. Domestic Workers work from dawn to dusk to take care of their employees’ families. The obvious question arises: who takes care of their children, back home? As a parent, Domestic workers with their odd working hours and low or no literacy rate are nowadays trying to overcome the socio-economic challenges as well as handicaps of the profession by getting involved in their children’s academics. This paper investigates the effects of the length of working hours and education levels of domestic worker parents on their academic involvement with the children. The present study uses a descriptive survey research design to find out the relationship between academic involvement and work hours. The data was subjected to appropriate descriptive and inferential statistics. The results indicate a negative relationship between work hours and academicinvolvement. It is also revealed that higher education level to be associated with better academic involvement. The study thus calls for further intervention by schools and the government to motivate parents. Parent-teacher meetings may be of help in this respect along with workshops and government-sponsored programs to educate the parents to support them to climb up the socio-economic ladder through their children

Teacher Attitude towards Emergency Remote teaching: challenges in Indian academe

The present study intends to explore the challenges of teachers’ attitudes during Emergency Remote Teaching (ERT) in higher educational institutions (HEIs) during the COVID-19 pandemic. It also investigates whether teacher age is in any way a mediating factor for teacher attitude. The transformative sequential research design of mixed methods was employed on a random sample of 90 participants pooled ever since the lockdown had been announced in India (March 23, 2020). The qualitative data (text), thus obtained, has been categorized into six challenges, sorted into categories, and transformed into quantitative data (code) for the Chi-square test and interpretation. The Chi-square test confirms no significant association between challenges in ERT identified by teachers’ attitudes and teachers’ ages. The study discusses the challenges felt by teachers and the probable ways of mitigation them for running remote teaching during this pandemic

Growth and physical property study of single nanowire (diameter ~ 45nm) of half doped Manganite

We report here the growth and characterization of functional oxide nanowire of hole doped manganite of La0.5Sr0.5MnO3 (LSMO). We also report four probe electrical resistance measurement of single nanowire of LSMO (diameter ~ 45nm) using FIB fabricated electrodes. The wires were fabricated by hydrothermal method using autoclave at a temperature of 270 oC. The elemental analysis and physical property like electrical resistivity were studied at individual nanowire level. The quantitative determination of Mn valency and elemental mapping of constituent elements was done by using Electron Energy Loss Spectroscopy (EELS) in the Scanning Transmission Electron Microscopy (STEM) mode. We addressed the important issue of whether as a result of size reduction the nanowires can retain the desired composition, structure and physical properties. The nanowires used were found to have a ferromagnetic transition (TC) at around 325 K which is very close to the bulk value of around 330 K found in single crystal of the same composition confirming that the functional behavior is likely to be retained even after size reduction of the nanowires to a diameter of 45 nm. The electrical resistivity shows insulating behavior within the temperature range measured, which is very much similar to the bulk system.Comment: 11 pages, 7 figures, accepted in Journal of Nanomaterial