An investigation of the mechanisms by which opiates affect the motility of the gut

(1) The object of this study was to investigate the effect and mechanisms by which morphine and the opioid peptides affect gut motility. Emphasis was placed on the examination of the neuronal basis of these effects, particularly the involvement of a tonic non-adrenergic, non-cholinergic inhibitory mechanism postulated to be responsible for the suppression of myogenic activity and the release of 5-hydroxytryptamine (5-HT) and acetylcholine (ACh) by these drugs. Alternative explanations of these effects were also sought. (2) The preparation chosen for this study was the rat isolated colon, which permits demonstration of the responses to opioids and other drugs in vitro. (3) The isolated colon of the rat contracts rhythmically to morphine and other opioid peptides. These rhythmic contractions could be divided into the initial contraction and the subsequent waves of contractions. The 5-HT antagonist, methysergide, non-competitively antagonised the initial response but had no effect on the waves of rhythmic contractions. In contrast, the specific opioid antagonist, naloxone, competitively antagonised the initial contraction and abolished the rhythmic contractile activity. (4) The rhythmic waves of contractions were unaffected by pretreatment with parachlorophenylalanine (PCPA) which depleted the intestinal 5-HT as measured spectrofluorometrically. Contractions were still produced in tissues made subsensitive to 5-HT by a process of autodesensitisation and were not abolished by atropine, casting doubt on the 5-HT/ACh hypothesis. The ineffectiveness of reserpine in depleting the 5-HT content of the colon was also confirmed in the study. (5) Several other drugs having in common the ability to block conductance in neural pathways or neuro-effector transmission, i. e. tetrodotoxin (TTX), apamin, tolazoline, phentolamine, oxprenolol and clonidine, produced similar patterns of rhythmic contractile activity in the rat colon. This suggested that the inherent myogenic activity of the colonic muscle might normally be suppressed by nervous influence. (6) Electrical field stimulation of the colon provided evidence about the innervation of this tissue. It was demonstrated that there is a motor cholinergic response to nerve stimulation which was reduced or abolished by atropine or morphine and potentiated by 6-hydroxydopamine pretreatment or apamin. Indirect evidence for the presence of an inhibitory adrenergic influence was provided. The inability of adrenergic and cholinergic antagonists to block inhibitory responses of the colon to nerve stimulation provided evidence for the existence of non-adrenergic, non-cholinergic (NANC) inhibitory nerves in the colon. In addition, the optimum frequency of stimulation of the inhibitory response was less than that characteristic of either an adrenergic or cholinergic mechanism. (7) The observation that this NANC inhibitory, nerve-mediated response to electrical field stimulation could still be elicited in the presence of drugs producing rhythmic waves of contractions, made it unlikely that the removal of a non-adrenergic, non-cholinergic inhibitory mechanism was responsible for producing the. rhythmic contractile activity in the colon. (8) The similarity between the effects of the opioids, the adrenergic neurone blocker and adrenoceptor antagonists, clonidine and apamin, raised the possibility that the actions of these drugs might be mediated through adrenergic neurones. This possibility was examined using the techniques of High Performance Liquid Chromatography (HPLC) with electrochemical detection and also in tritium efflux studies. (9) Preliminary experiments with the HPLC were concerned with the optimisation of the conditions necessary for chromatographic separation. It was demonstrated that changes in the electrode potential voltage, mobile phase composition and flow rate affected the detection and separation of catecholamines. The catecholamine content of the rat colon, mouse, guinea-pig and rat vasa deferentia were also measured. Transmitter overflow from the mouse and guinea-pig vasa deferentia occurring spontaneously and in response to electrical field stimulation were measured. No spontaneous release of noradrenaline or its metabolites was demonstrated in the rat colon. (10) Morphine, clonidine and TTX did not affect tritium efflux at concentrations at which they produce rhythmic waves of contractions in the colon. (11) The implications of these results for the hypothesis previously postulated and the one suggested in this study to explain the rhythmic contractions are discussed

Protease-activated receptor-2 (PAR2) in cardiovascular system.

Vascular system is constituted by a complex and articulate network, e.g. arteries, arterioles, venules and veins, that requires a high degree of coordination between different elemental cell types. Proteinase-activated receptors (PARs) constitute a recent described family of 7-transmembrane G protein-coupled receptors that are activated by proteolysis. In recent years several evidence have been accumulated for an involvement of this receptor in the response to endothelial injury in vitro and in vivo experimental settings suggesting a role for PAR2 in the pathophysiology of cardiovascular system. This review will deal with the role of PAR2 receptor in the cardiovascular system analyzing both in vivo and in vitro published data. In particular this review will deal with the role of this receptor in vascular reactivity, ischemia/reperfusion injury, coronary atherosclerotic lesions and angiogenesis

Substance P Induces Rapid and Transient Membrane Blebbing in U373MG Cells in a p21-Activated Kinase-Dependent Manner

U373MG astrocytoma cells endogenously express the full-length neurokinin 1 receptor (NK1R). Substance P (SP), the natural ligand for NK1R, triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293-NK1R cells. In both cell lines, the SP-induced morphological changes are Gq-independent, and they require the Rho, Rho-associated coiled-coil kinase (ROCK) signaling pathway. Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs. Colchicine, a tubulin polymerization inhibitor, blocked SP-induced blebbing in U373MG but not in HEK293-NK1R cells. Although p21-activated kinase (PAK) is expressed in both cell lines, SP induced rapid phosphorylation of PAK in U373MG, but failed to phosphorylate PAK in HEK293-NK1R cells. The cell-permeable Rho inhibitor C3 transferase inhibited SP-induced PAK phosphorylation, but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation, suggesting that Rho activates PAK in a ROCK-independent manner. Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293-NK1R cells

Replication Data for: The Political Consequences of Policing: Evidence from New York City

Replication data and code for, "The Political Consequences of Policing: Evidence from New York City" forthcoming in Political Behavio

Coffee Shops, Beat Cops, and the Ballot Box: A Study of Gentrification, Urban Policing, and Political Behavior

This dissertation explores the causes and consequences of contemporary policing practices, focusing particular attention on the high volume, aggressive, and racially discriminatory policing strategies that police departments throughout the United States began to adopt in the 1970s and 1980s. In a series of empirical analyses, it makes three principle claims. First, this dissertation argues that the adoption of these punitive policing practices can be attributed in no small part to municipal strategies of gentrification and revitalization. In doing so, it advances research on the post-industrial policing hypothesis, which argues that as cities pursue growth strategies designed to appeal to members of the so-called "creative classes'' or businesses in the post-industrial sector, they will increasingly adopt punitive policing practices to harass, displace, or control groups (including racial and ethnic minorities) that are deemed incompatible with these strategies. Mobilizing data on order maintenance policing (OMP) in New York City and the Stop, Question, and Frisk (SQF) police stops that OMP generated, this dissertation finds that gentrification in New York City is associated with significantly higher rates of SQF police stops, mostly in neighborhoods that lie adjacent to or near gentrifying tracts. In a second analysis, this dissertation argues that these aggressive policing strategies have the potential to impact political behavior, and explores how OMP practices in New York City affected voter turnout and candidate choice in that city. In a series of national and local elections, it finds that while concentrated policing can negatively affect political participation in the form of voter turnout, heavily policed communities can and do mobilize to counteract these harmful and discriminatory policing policies. Specifically, it finds that while SQF policing was associated with lower rates of turnout in the 2010 and 2006 national elections, it was also associated with higher rates of turnout in the 2008 national election and the 2013 mayoral election and Democratic primary. While the positive association between turnout and policing in the 2008 national election was likely do to the unique mobilizing affect that Barack Obama's campaign had on marginalized communities, this dissertation argues that the higher rates of turnout in the 2013 general and Democratic primary are attributable to the mobilization of communities in New York City to end SQF policing. In support of this claim, this chapter presents additional evidence that higher rates of SQF policing was associated with more support for the Democratic primary candidate (John Liu) who promised to end SQF policing and significantly less support for the candidate (William Thompson) who promised to keep it. In its third and final analysis, this dissertation explores the extent to which aggressive and discriminatory policing affects political behavior in other national contexts, specifically the United Kingdom. Characterizing contemporary policing practices in Britain which: 1) were adopted specifically following their successful implementation in American cities such as New York City and 2) which exhibit similar levels of racial and ethnic disparity, this chapter argues that like gentrification, post-industrial policing and its political consequences are global in scope. Mobilizing data from police stops of citizens in Greater London, Manchester, and the West-Midlands this analysis similarly finds that as the intensity of police-citizen contact increases, political participation decreases. Unlike in New York City, however, this analysis does not uncover instances or contexts where higher levels of policing were associated with higher rates of turnout, which it tentatively attributes to differences in political opportunity structure in the two contexts

Spatial Processes and the Relationship between Gentrification and Disparate Policing: An Analysis of New York City and Los Angeles

Current literature debates the desirability of urban revitalization and gentrification for cities. While municipal revitalization of central cities --- and the influx of well-educated and higher income individuals typically associated with it --- can revive moribund and marginalized communities, both processes are associated with heightening inequality and adverse outcomes for the poor and for racial or ethnic minorities. This thesis explores one such negative outcome: the extent to which the gentrification is associated with discriminatory policing practices. Specifically, it tests whether gentrification is associated with more order maintenance policing (OMP) --- a policing strategy that targets low-level, highly discretionary offenses such as disorderly behavior and disturbing the peace, and which historically has targeted the poor and minority groups. Pushing the limitations of the extant literature, this thesis tests whether the relationship between gentrification and OMP ought to be understood as a fundamentally spatial process, and considers a suite of spatial models for the relationship between gentrification and policing as the consequence of endogenous and exogenous spatial interactions, as well as test for omitted spatial variables. Data from both New York City and Los Angeles are collected and analyzed. Results and implications are discussed

Measuring disparities in police use of force and injury among persons with serious mental illness

Abstract Objectives To measure disparities in experience of police use of force and injury among persons with serious mental illnesses. Methods We gathered novel police use of force and suspect injury data from 2011 to 2017 from a nonrandom sample of nine police departments in the United States and used synthetic methods to estimate the share of the local population with serious mental illness. We estimate disparities using multi-level models estimated in a Bayesian framework. Results Persons with serious mental illness constitute 17.0% of use of force cases (SD = 5.8) and 20.2% of suspects injured in police interaction (SD = 9.0) in sample cities. The risk that persons with serious mental illness will experience police use of force is 11.6 times higher (95% CI, 10.7–12.6) than persons without serious mental illness. Persons with serious mental illness are also at a higher risk of experiencing injury, 10.7 times (95% CI, 9.6–11.8), relative to persons without serious mental illness. These relative risk ratios are several times larger than racial and ethnic disparities estimated in the same cities. Conclusion Persons with serious mental are at a significantly elevated risk of experiencing police use of force and injury in police encounters than the general public. The disparities we estimate are several times higher than racial/ethnic disparities in force and injury. Efforts to reform police practices and reimagine public safety in the United States should address significant disparities in police use of force against those with serious mental illness