Remifentanil is an ultra-short-acting phenylpiperidine opioid analgesic that is rapidly metabolized by nonspecific blood and tissue esterases. In clinical practice, remifentanil is now more commonly used during both cardiac and non-cardiac surgery than classic opioid agonists such as morphine, since it can be given in higher doses, is more titratable and enables fast recovery of patients in the postoperative period. Remifentanil preconditioning (RPC), achieved by intravenous remifentanil infusion interspersed with infusion-free periods before indexed ischaemia, attenuates cardiac ischaemia-reperfusion injury (IRI). This is experimentally manifested by reduced postischaemic myocardial infarct size (IS) and diminished markers of cardiac failure and apoptosis, and, clinically, by reduced release of biomarkers of myocardial cellular injury after cardiac surgery. However, the underlying mechanisms by which RPC has a cardioprotective effect need to be further explored. It’s generally considered that the Reperfusion Injury Salvage Kinase (RISK) pathway, triggering the expression of phosphatidylinositol 3-kinase (PI3K) as well as Akt, exerts a pivotal role in both classic ischaemic preconditioning (IPC) and pharmacological preconditioning induced cardioprotection. Moreover, recent studies show that the Survivor Activating Factor Enhancement (SAFE) signalling pathway, which involves signal transducers and activators of transcription-3 (STAT3) and janus activated kinase-2 (JAK2), also has an essential role in IPC. Although cross-talk has been found between the RISK and SAFE pathways, the SAFE pathway can function independently of the RISK to confer cardioprotection. However, the roles of JAK/STAT and PI3K/Akt signalling and, in particular, their relative importance in RPC-mediated cardioprotection have not been studied. I explored whether RPC confers cardioprotection via the JAK/STAT or PI3K/Akt pathway and its relationship with GSK3β inhibition. In first part of my study, I explored relative role of the JAK/STAT and PI3K/Akt which were involved in RPC cardioprotection using JAK2 and PI3K inhibition. Male Sprague-Dawley rats were either sham operated or randomly assigned to receive I/R alone or as well as RPC. Pretreatment with the JAK2 inhibitor AG490 or the PI3K inhibitor wortmannin was induced before ischaemia in rats. RPC reduced myocardial infarction and haemodynamic dysfunction induced by IRI accompanied with increased phosphorylation of STAT3 but not Akt or eNOS phosphorylation. AG490 but not wortmannin cancelled RPC’s cardioprotection. In addition, RPC attenuated hypoxia/reoxygenation induced cardiomyocyte apoptosis while STAT3 knock-out abolished the protective effects of RPC. These findings suggest that RPC confers cardioprotection primarily via activation of the JAK/STAT signalling but not the PI3K/Akt signalling pathway. The second study further investigated the role of GSK3β in RPC cardioprotection using the GSK3β inhibitor SB216763. I found that SB restored the ability of RPC to reduce the extent of myocardial infarction and CK-MB release despite the presence of AG490. The phosphorylation of GSK3β was increased by RPC. In addition, GSK3β gene knock-out with siRNA preserved RPC’s cardioprotection regardless of STAT3 abrogation indicating that GSK3β inhibition plays a critical role as a downstream effector in RPC mediated cardioprotection. Taken together with the evidence from this two part study, I conclude that RPC confers cardioprotection by activating the JAK/STAT and, subsequently, inhibiting GSK3β, a critical downstream effector of RPC cardioprotection. / published_or_final_version / Anaesthesiology / Master / Master of Philosophy

The undertreatment of chronic pain and the prevention of drug abuse and diversion of pain medications (i.e., opioids) have been identified as public health issues in the United States. In this domain, the Drug Enforcement Administration (D.E.A.) faces challenges when enforcing the Controlled Substance Act because it is tasked with regulating the dispensing of opioids by physicians in the treatment of chronic pain, while also attempting to prevent their abuse and diversion. Thus, the D.E.A. must use discretion in how it enforces the C.S.A. because intentional actions to prevent opioid abuse and diversion could also unintentionally affect the willingness of primary care physicians to prescribe them in the treatment of chronic pain. As an initial step in clarifying the boundaries between the D.E.A. and the medical profession, it was necessary to assess physician perceptions about the D.E.A. 's use of enforcement discretion. A total of 205 Oregon primary care physicians completed a web-based survey examining three domains: concern about D.E.A. enforcement discretion; autonomy related to use of opioids in the treatment of chronic pain; and prescribing of opioids in the treatment of chronic pain. Results indicated that some physicians perceive a concern about D.E.A. enforcement discretion, and those who have concern are more likely to perceive having reduced autonomy related to the use of opioids in the treatment of chronic pain. The results do not support previous research that showed that such concerns directly affects physician prescribing of opioids. Instead, results reveal that concern about D.E.A. enforcement discretion is associated with reduced perceived autonomy, and reduced perceived autonomy is associated with less willingness to prescribe opioids in the treatment of chronic pain. This research takes the study on this topic one step further in identifying physician perceptions about D.E.A. enforcement discretion, and how these perceptions were associated with physician autonomy and prescribing of opioids in the treatment of chronic pain. In doing so, this research provides important scholarly contributions to the enforcement discretion literature, specific to the D.E.A., and medical professionalism as it pertains to physician autonomy related to the use of opioids in the treatment of chronic pain.

This study examines the effects of gender and social bonds on the experience of prescription painkiller misuse for men and women. The theoretical framework for the project is Travis Hirschi's social control theory (1969), and the social bond elements of attachment, commitment, involvement, and belief, which emphasizes the importance of these bonds in creating a "stake in conformity" for the individual, leading to acceptance of social norms and desistence from deviance. This theory, however, is relatively silent with regard to gender differences and was developed to examine delinquency in an all male sample of adolescents. The elements of this theory were used to further test the effects of these social bonds and add to the literature gap on the gendered experience of the misuse of prescription painkillers. Data for this project comes from the 2011 National Survey on Drug Use and Health, an annual nationally representative, cross-sectional survey. Multivariate logistic regression analyses reveal that, being white, not being married, having less than a high school diploma, a having a job are all significant predictors of increased prescription painkiller misuse. Characteristics associated with a significant decrease in the odds of misusing prescription painkillers are being older, having a college degree, and placing importance on religious/spiritual beliefs. Multivariate logistic regression also reveals that female respondents are less likely to misuse prescription painkillers than are their male counterparts. Interaction effects are operationalized to measure the relationship between gender and the social bond elements of interest. Most of the interaction effects are not statistically significant, but some of the main effects remain significant, which indicates that the main effect has little impact on prescription painkiller misuse for women, but remains significant for men (marriage, education, work status). Significant interaction effects are found for gender (female) x income and gender (female) x religiosity, which indicates that for both men and women, increased income and higher levels of religiosity are significantly associated with decreased odds of prescription painkiller misuse, that the effect is stronger for women and that this difference between men and women is significant. These results provide further insight into the experiences of prescription painkiller misuse for men and women.