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Thesis (Ph.D)--Tufts University, 2000. / Adviser: Robin B. Kanarek. Submitted to the Dept. of Psychology. Includes bibliographical references (leaves 109-134). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph. D.)--Case Western Reserve University, 2008. / [School of Medicine] Department of Biochemistry. Includes bibliographical references.

Thesis (Ph. D.)--University of Michigan, 1997. / Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xiii, 172 p.; also includes graphics (some col.). Includes bibliographical references (p. 131-172 ). Available online via OhioLINK's ETD Center

Thesis (Ph.D.)--University of Michigan, 1997. / Includes bibliographical references.

The metabolism of the opioid peptide [3H]dynorphin 1-8 by slices of central nervous system (c.n.s.) and peripheral tissues, from the rat and guinea-pig has been studied. Rat spinal cord rapidly degraded [3H]dynorphin 1-8, the N-terminal tyrosine residue being most susceptible to hydrolysis and therefore forming the major metabolite. Pre-treatment of the metabolizing tissue with a standard cocktail of enzyme inhibitors decreased the degradation of [3H]dynorphin 1-8 at both the N- and C-termini. However, inclusion of this enzyme inhibitor cocktail revealed the activity of a further enzyme, an endopeptidase, capable of cleaving the leucine5–arginine6 bond within the octapeptide liberating the opioid pentapeptide [Leu]enkephalin. This pattern of metabolism was observed across all rat brain regions and periphery.

Opioid users are an at-risk community. Risk of opioid overdose among substance users has increased tremendously in the last decade. Many factors, including adulterated drugs and hesitation in calling emergency response services, have led to many individuals not receiving the required harm reduction treatment, during an overdose incident. The problem is further compounded by the fact that many users are using alone in private residences and hence, no support mechanisms are available for them to assist them in case of an overdose situation. To circumvent this scenario, citizen training in Naloxone, an overdose harm reduction drug, has been promoted. However, there lies an essential communication gap between the citizens who have the training and the Naloxone kit and an active overdose event. Many at-risk communities may face the same challenge, especially if they are at risk of social isolation and voluntary/involuntary self-harm. Through our work, we wish to mobilize change in such at-risk communities, by studying the backend infrastructure of a crowdsourced emergency response system, called as a Peer Alerting Lifeline. The system would be responsible, for connecting peer responders, to an actual emergency event. Specifically, in the case of substance overdose, this would allow Naloxone kit holders to be informed of an overdose event in their vicinity and respond to the same. We aim to study the design infrastructure of such a system. / Graduate

1. The biology and chemistry of the endogenous opioid peptide precursors and the distribution, release and metabolism of the products of proenkephalin are summarised, together with a review of the in vitro and in vivo cardiovascular effects of endogenous opioid peptides. 2. The four major products of proenkephalin, [Met] enkephalin, [Leu] enkephalin, [Met] enkephalyl-arg[6]-phe[7] and [Met] enkephalyl-arg[6]- gly[7] -leu[8] , were studied for their direct effects on isolated rat atria and perfused mesentery in vitro and for their indirect effects on responses of the tissues to exogenous noradrenaline. The effects of the proenkephalin products upon atrial responses to noradrenergic and cholinergic nerve stimulation were also investigated. [Met] Enkephalin, [Leu] enkephalin, [Met] enkephalyl-arg6-phe7 and [Met] enkephalyl-arg[6]-gly[7]-leu[8] (10[-9]-10[-6]M) had no direct effects upon isolated atria or the perfused mesentery and did not produce any modulatory effects upon responses to exogenous noradrenaline or on atrial responses to noradrenergic and cholinergic nerve stimulation. 3. The cardiovascular responses to proenkephalin products were investigated in the urethane-anaesthetised rat. Blood pressure and integrated heart rate were measured using a pressure transducer connected to a carotid artery cannula. Intravenous administration of proenkephalin products (30-300?g/kg) produced a dose-related decrease in mean arterial pressure and heart rate. This was of a similar magnitude for the four opioid peptides. The response was abolished by naloxone (1 mg/kg) demonstrating that it was opioid-receptor mediated, and was qualitatively similar to that produced by the p-opioid receptor selective agonist DAGO. The involvement of u -receptors in the response is further supported by the lack of effect of the ?-receptor selective agonist DPDPE and k-receptor selective agonist U-50, 488H. This militates against an involvement of ?- and k-receptors in the cardiovascular response to proenkephalin products. 4. An "atypical response" to [Met] enkephalyl-arg[6]-phe[7] was exhibited in 25% of preparations studied. This consisted of an initial bradycardia and decrease in mean arterial pressure followed by a tachycardia and increase in mean arterial pressure. The tachycardia and pressor response were mimicked by the dipeptide arg-phe and antagonised by propranolol and phentolamine respectively. Both components of the response were abolished by hexamethonium which suggests that the response may have been due to the stimulation of sympathetic ganglia. The "atypical response" was produced in litter mates and may reflect genetically controlled differential capabilities to enzymatically degrade the heptapeptide and generate the pharmacologically active dipeptide. 5. The cardiovascular responses to proenkephalin products were potentiated following pre-treatment with captopril, the angiotensin converting enzyme inhibitor, or bestatin, the aminopeptidase inhibitor, although to a lesser extent. The effects of captopril on the duration of the responses, especially to the heptapeptide and octapeptide, were most marked indicating that the activity of a captopril-sensitive enzyme may be responsible for the relatively short duration of the observed responses. 6. Pharmacological manipulations, such as the use of atropine and the quaternary opioid antagonist N-methyl levallorphan, and surgical procedures, including bilateral vagotomy and pithing, were employed to examine the mechanisms involved in the cardiovascular response to proenkephalin products. Through these techniques it was demonstrated that the response was vagally dependent, mediated by peripheral opioid receptors and dependent on the central nervous sytem functioning. The cardiovascular response to proenkephalin products therefore arises from the stimulation of peripheral opioid receptors. This is then transmitted to the central nervous system by the vagus nerve and results in the production of a centrally mediated decrease in mean arterial pressure and an atropine-sensitive bradycardia. 6a. Non-opioid effects of N-methyl levallorphan (initial nicotinic agonist activity followed by ganglion blocking effects) were observed at doses only two-fold higher than those required to block cardiovascular responses to Met enkephalin. The narrow selectivity of this compound makes it inappropriate for opioid antagonist studies where nicotinic receptors may be involved. 7. Manipulations of the hypothalamus-pituitary-adrenal axis, through adrenalectomy and suppression of pituitary function by dexamethasone administration, had significant effects upon the cardiovascular responses to proenkephalin products. This indicates that the activity of the hypothalamus-pituitary-adrenal axis and/or changes in the levels of circulating opioids has a considerable influence on the magnitude of the evoked response. 8. The respiratory effects of proenkephalin products and cardiovascular responses in artificially ventilated rats were studied. The results confirmed that the cardiovascular responses to proenkephalin products in the urethane-anaesthetised rat were not secondary to respiratory effects.

Intro: Opioids and their role in medicine, their use and abuse, have become a topic of intense scrutiny and interest over the last several years. Since 1999, the number of opioid overdose deaths has quadrupled, while the amount of prescription opioids sold in the U.S has increased by the same factor. Federal lawmakers, law enforcement, pharmaceutical companies, and investigative journalists have all become involved in what is often called “the opioid epidemic”, a stage where the issues of pain management, drug abuse, regulation, and autonomy are in seeming opposition. Physicians are uniquely positioned on this stage, both as healers and healthcare providers, professionals tasked with managing pain, preventing and treating addiction and overdose, and advocating for the needs of the population they serve. Paradoxically, issues related to pain management, addiction, and abuse are widely underrepresented in the educational curricula of most physicians’ formal training. This study aims to assess the attitudes and knowledge related to opioids in family medicine residents in a rural Appalachian residency program; as well as measure how these attitudes and knowledge change in the cohort after a limited course of education in issues surrounding opioid use, prescription, and abuse. It is our hope that this intervention will edify the residents, and they will feel more prepared to confront issues surrounding opioids as they move forward in their careers. Methods: Residents were given a ten-item questionnaire that assessed their knowledge of current Tennessee and Virginia state laws with regards to the prescription of opioids: The questionnaire also included an open-ended question where residents were asked to express how they felt about prescribing opioids: opinions they had formed, things they learned, things that they wished were different. Responses were uniquely identified by a paired code that abstracted the identity of the respondent from subsequent analysis. After anonymous collection of the completed questionnaire and open-ended response, a 30 minute didactic session was administered by the authors outlining common issues with opioid prescriptions, an overview of current TN and VA state law regarding opioid prescription, clinic policy, and discussion with residents of current thinking regarding best practices. The questionnaire was then administered again, responses were anonymously gathered and paired with their pre-didactic identification number. The responses were then analyzed to assess the impact of the didactic on understanding of current opioid prescribing law, and the open ended responses were examined for common themes in residents’ perception of prescribing opioids while in residency. - Conclusions: In general, short and focused didactic education regarding current state laws regarding opioid prescription appears to benefit residents understanding of how to prescribe opioids appropriately. Residents generally find the processes surrounding opioid prescription challenging, medically and emotionally, and are interested in more education about the topic.