Studies of dynorphin and cholecystokinin release in the rat spinal cord: implications for opioid action

Although much is now known of the cellular actions of exogenous opiate drugs and of endogenous opioid peptides, how these compounds modify interconnecting neuronal systems in the CNS is still poorly understood. The studies described in this thesis have addressed the latter by employing the antibody microprobe technique (Duggan A.W. and Hendry I.A., 1986, Neurosci. Letts. 68, 134-140) to investigate (a) the release of dynorphin A(l-8) in the spinal cord of the rat as inflammation develops in peripheral tissues, and (b) the release of cholecystokinin, a putative 'anti-opioid' neuropeptide, in the rat spinal cord following the administration of morphine.(a) A dramatic increase in the spinal synthesis of prodynorphin derived peptides has been observed when inflammation develops in peripheral tissues. The functional significance of this increased synthesis is unclear and there have been no reports of the stimuli needed to produce dynorphin release in vivo nor of possible controls of such release. Microprobes bearing immobilised antibodies to the dynorphin A(l-8) derivative of prodynorphin, were inserted into the lumbar spinal cord of urethane anaesthetised normal rats and those with a peripheral inflammation, to determine whether dynorphins are being tonically released and how release is altered by manipulating the inflamed tissues. In the absence of any active peripheral stimulus the antibody microprobes detected minimal amounts of immunoreactive (ir)-dynorphin A(l-8) in two areas (lamina I and laminae IV-V) in the dorsal horn of the spinal cord of normal rats. With the development of unilateral ankle inflammation over 3 to 5 days, following subcutaneous injections of Freund's complete adjuvant, this was extended to the ventral horn of both sides of the spinal cord. Lateral compression of the ankles of the normal animals did not release ir-dynorphin A(l-8) during the period of stimulation, but this neuropeptide was detected in the ventral horn following the stimulus. By contrast, compression of inflamed ankles produced elevated levels of ir-dynorphin A( 1 -8) during the period of stimulus application at three major sites in the spinal grey matter. The largest peak was in the deep dorsal horn/ upper ventral horn (laminae VI -VII), with further sites of significant release in the mid dorsal horn (laminae II-V) and the lower ventral horn. These levels persisted for at least one hour after the period of stimulation. At a cellular level dynorphins reduce transmitter release from nerve terminals, and hence the observation that ir-dynorphin A( 1 -8) is released in the ventral and deep dorsal horn in addition to the superficial dorsal horn of the rat by manipulation of inflamed tissues, implies that wide-spread spinal inhibitory controls of spinal neuronal firing are evoked by such stimuli. This may ultimately affect the perception of pain, but release in the ventral horn suggests an involvement in reducing motor responses to peripheral noxious stimuli.(b) Of all possible candidates at the spinal cord level, the 'anti-opioid' activity of cholecystokinin (CCK) has been well characterised. This peptide has also been proposed to play a role in the development of tolerance to but not dependence on opiate drugs. Although the hypothesis that stimulation of opioid receptors may trigger a progressive compensatory increase in the activity of CCK containing neurones at the spinal cord level has received some indirect support, this has not been thoroughly investigated. Conflicting data have been obtained from experiments which have examined the spinal cord content of CCK and spinal release of CCK following the administration of opioids. Microprobes bearing immobilised antibodies to CCK-8, were inserted into the lumbar spinal cord of urethane anaesthetised normal rats under both basal conditions and following acute opiate administration. In the absence of any active peripheral stimulus an extensive presence of ir-CCK was detected in normal (drug naive) rats with three main zones. The largest peak was in the mid to deep dorsal horn/ upper ventral horn (laminae III -VII), with further major sites in the superficial dorsal horn (lamina I-II) and the mid/ lower ventral horn. Morphine administered intravenously over two hours (total dose 25mg/ kg) failed to alter this basal presence of irCCK. Enhanced release however, was observed in areas of the ventral horn of rats treated acutely with morphine following lmg/ kg injections of naloxone. It is proposed that the occupation of opioid receptors by morphine triggers the increased synthesis of CCK and predicted that following the development of tolerance to morphine, enhanced CCK release will be observed in the absence of naloxone administration

Exhibitionism: A Psycho-Legal Perspective

The criminalization of exhibitionism is indicative of our society\u27s unwillingness to deal rationally with sex offenses. As a result of this attitude, present treatment of exhibitionists is ineffective and even harmful. Ms. Riley argues that in order to encourage a more appropriate response to these men, their condition must be viewed from a psycho-legal perspective, which considers the presence of emotional disorders in individuals caught up in the penal system. Applying this perspective, the author proposes a diversion program that incorporates medical understanding of the disorder and therefore offers the possibility of curing exhibitionists and restoring them as productive members of society

Adoption and motivational factors for online grocery shopping in the UK

Following upon the results of previous qualitative research (Authors, 2005), the objective of this paper is to confirm the role of situational variables in the adoption process of online grocery shopping. Situational variables and life events in particular (e.g. having a baby, health problems) emerge as the trigger for starting online grocery shopping for two clusters. However, the adoption of e-grocery shopping seems to be re-evaluated frequently and consequently post-adoption evaluation appears crucial to the decision of whether to continue with or to drop internet grocery shopping

Theoretical analysis of seasonal changes in the phytoplankton of Husan Harbor, Korea

It has been shown (Riley, 1946, 1947) that seasonal changes in total phytoplankton populations can be depicted with a reasonable degree of accuracy by a simple theoretical construction in which the rate of change of the population is described in terms of physiological processes that increase or decrease its organic content (photosynthesis, respiration, grazing), and in which the rates of the individual processes are quantitatively predictable by reference to a few environmental factors...

Propoxyphene, Norpropoxyphene, and Proadifen (SKF-525A) Are Mechanism Based Inhibitors of CYP3A4, CYP3A5, and CYP3A in Human Liver Microsomes

Indiana University-Purdue University Indianapolis (IUPUI)The purpose of this study is to determine if propoxyphene and norpropoxyphene are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanismbased inhibition is a type of irreversible inhibition that results from an inhibitor or its metabolite binding to an enzyme during drug metabolism, which renders the enzyme nonfunctional. Propoxyphene is an analgesic that is frequently prescribed in the United States and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes. Time-dependent and concentration-dependent loss of activity of CYP3A was measured by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5), and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with vi CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver microsomes fall within the range of reported therapeutic blood levels of propoxyphene, with reversible inhibition constants (Ki values) above therapeutic blood concentrations for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels, except for blood levels after repeated dosing of propoxyphene at high concentrations. The predicted change in the area under the plasma concentration versus time curve of an orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times higher with co-administration of propoxyphene based on in vitro kinetic parameters. Propoxyphene and norpropoxyphene may cause adverse events when chronically administered at high doses and/or when co-administered with other CYP3A substrates

The Impact of Race and Gender-Related Discrimination on the Psychological Distress Experienced by Junior Doctors in the UK:A Qualitative Secondary Data Analysis

Almost half of NHS doctors are junior doctors, while high proportions are women and/or Black, Asian, and Minority Ethnic (BAME) individuals. Discrimination against this population is associated with poorer career-related outcomes and unequal representation. We aimed to qualitatively explore junior doctors' experience of workplace racial and gender-based discrimination, and its impact on their psychological distress (PD). In this study, we carried out a secondary analysis of data from a UK-based parent study about junior doctors' working cultures and conditions. Interview data was examined using thematic analysis. Transcripts (n = 14) documenting experiences of race and/or gender-based discrimination were sampled and analysed from 21 in-depth interviews conducted with UK junior doctors. Four themes were generated about the experiences and perpetrators of discrimination, the psychological impact of discrimination, and organisational interventions that tackle discrimination. Discrimination in various forms was reported, from racially charged threats to subtle microaggressions. Participants experienced profoundly elevated levels of PD, feeling fearful, undermined, and under-confident. Discrimination is associated with elevated levels of PD, whilst negatively impacting workforce sustainability and retention. This reduces the opportunity for more diversity in NHS medical leadership. We encourage NHS hospitals to review their policies about discrimination and develop in-person workshops that focus on recognising, challenging, and reporting workplace discrimination.</p

Mental health and help seeking among trauma-exposed emergency service staff:a qualitative evidence synthesis

OBJECTIVES: To identify factors and contexts that may contribute to mental health and recovery from psychological difficulties for emergency service workers (ESWs) exposed to occupational trauma, and barriers and facilitators to help-seeking behaviour among trauma-exposed ESWs. BACKGROUND: ESWs are at greater risk of stressor-related psychopathology than the general population. Exposure to occupational stressors and trauma contribute to the observed rates of post-trauma psychopathology in this occupational group with implications for workforce sustainability. Types of organisational interventions offered to trauma-exposed ESWs are inconsistent across the UK, with uncertainty around how to engage staff. DESIGN: Four databases (OVID MEDLINE, EMBASE, PsycINFO and SCOPUS) were systematically searched from 1 January 1980 to March 2020, with citation tracking and reference chaining. A modified Critical Appraisal Skills Programme tool and quality appraisal prompts were used to identify fatally flawed studies. Qualitative studies of trauma-exposure in front-line ESWs were included, and data were extracted using a customised extraction table. Included studies were analysed using thematic synthesis. RESULTS: A qualitative evidence synthesis was conducted with 24 qualitative studies meeting inclusion criteria, as defined by the PerSPEcTiF framework. Fourteen descriptive themes emerged from this review, categorised into two overarching constructs: (1) factors contributing to mental health (such as the need for downtime, peer support and reassurance) and (2) factors influencing help-seeking behaviour (such as stigma, the content/form/mandatory nature of interventions, and mental health literacy issues including emotional awareness and education). CONCLUSION: ESWs reported disconnect between the organisations’ cultural positioning on trauma-related mental health, the reality of undertaking the role and the perceived applicability and usefulness of trauma interventions. Following traumatic exposure, ESWs identify benefitting from recovery time and informal support from trusted colleagues. A culture which encourages help seeking and open dialogue around mental health may reduce stigma and improve recovery from mental ill health associated with trauma exposure