Adverse challenges in the perinatal period may alter nociceptive sensitivity in later life

Chronic inflammatory and neuropathic pain states are poorly understood, and currently inadequately treated. Clinically, the symptoms of such pain states include allodynia (interpretation of innocuous stimuli as noxious), hyperalgesia (increased sensitivity to noxious stimuli) and spontaneous (non-evoked) pain. Additionally, chronic pain states are often associated with affective disorders such as anxiety and depression which can further reduce the individual’s quality of life. It is highly likely that neuropathic pain could occur in combination with chronic inflammation, for example as a result of post-surgical infection. When such injuries occur in early life, during the continuing development of the nervous system, it is possible that longterm adverse changes in sensory processing may occur. To investigate this, we have developed a rodent model of chronic pain with both a neuropathic and inflammatory component, designed to investigate the consequence of these to injuries coinciding. Furthermore, we are also investigating the effect of gestational stress, which has been shown to alter the stress responsiveness of the offspring and may also affect pain processing. To study the effect that prenatal stress may have on pain processing, we have utilised the rodent resident/intruder paradigm as a model of social stress to determine the outcomes of the combination of these adverse perinatal events. We find that a combined inflammatory and neuropathic injury in the adult rat increases sensitivity to both mechanical and thermal stimuli and also increases spontaneous pain, when compared to inflammation or nerve injury alone. We show that neuropathic pain can be induced in neonatal (P8) rats; however there is little response to inflammation at P8 and a combination of these two injuries does not have the additive effect on sensitivity that occurs in the adult. Upon recovery from neonatal nerve injury, we find that a subsequent noxious challenge (formalin) alters nocifensive behaviour, when compared to the formalin response of naïve (no prior injury) animals, indicating long-lasting changes to nociceptive processing. Interestingly, when nerve injury is carried out in adult animals, nocifensive behaviour in response to formalin is not altered compared to naïve controls. Calcium entry through the NMDA receptor and subsequent CaM Kinase IIα activation has been implicated as a crucial factor in long term potentiation (LTP) and the maintenance of sensitised states. In adult models of chronic pain, which may involve LTP mechanisms, we have shown an increased association of CaM Kinase IIα with NR2A/B spinal immunoprecipitates ipsilateral to injury. Furthermore, a different mechanism may be involved in neonatal pain states, as we have shown that spinal CaM Kinase IIα expression increases with development and is present at very low levels at the time of surgery in our pain models. Additionally, a number of other proteins associated with the NMDA receptor complex are developmentally regulated, and their involvement in the initiation and maintenance of chronic pain is likely to differ between the adult and the neonate. We further show that exposure to prenatal stress does not alter the thresholds to mechanical stimuli in adult or early life pain models, however the combination of prenatal stress and postnatal injury results in an enhanced response to formalin in later life, indicating that programming of stress and/or pain pathways has occurred as a result of these early life events. In addition to the development of a novel model of chronic pain, this study highlights the long-term impact that adverse perinatal events can have on offspring

FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation

The E3 ubiquitin ligase component FBXW7 modulates homeostasis and inhibits tumorigenesis in the murine intestine

Adverse challenges in the perinatal period may alter nociceptive sensitivity in later life

Chronic inflammatory and neuropathic pain states are poorly understood, and currently inadequately treated. Clinically, the symptoms of such pain states include allodynia (interpretation of innocuous stimuli as noxious), hyperalgesia (increased sensitivity to noxious stimuli) and spontaneous (non-evoked) pain. Additionally, chronic pain states are often associated with affective disorders such as anxiety and depression which can further reduce the individual’s quality of life. It is highly likely that neuropathic pain could occur in combination with chronic inflammation, for example as a result of post-surgical infection. When such injuries occur in early life, during the continuing development of the nervous system, it is possible that longterm adverse changes in sensory processing may occur. To investigate this, we have developed a rodent model of chronic pain with both a neuropathic and inflammatory component, designed to investigate the consequence of these to injuries coinciding. Furthermore, we are also investigating the effect of gestational stress, which has been shown to alter the stress responsiveness of the offspring and may also affect pain processing. To study the effect that prenatal stress may have on pain processing, we have utilised the rodent resident/intruder paradigm as a model of social stress to determine the outcomes of the combination of these adverse perinatal events. We find that a combined inflammatory and neuropathic injury in the adult rat increases sensitivity to both mechanical and thermal stimuli and also increases spontaneous pain, when compared to inflammation or nerve injury alone. We show that neuropathic pain can be induced in neonatal (P8) rats; however there is little response to inflammation at P8 and a combination of these two injuries does not have the additive effect on sensitivity that occurs in the adult. Upon recovery from neonatal nerve injury, we find that a subsequent noxious challenge (formalin) alters nocifensive behaviour, when compared to the formalin response of naïve (no prior injury) animals, indicating long-lasting changes to nociceptive processing. Interestingly, when nerve injury is carried out in adult animals, nocifensive behaviour in response to formalin is not altered compared to naïve controls. Calcium entry through the NMDA receptor and subsequent CaM Kinase IIα activation has been implicated as a crucial factor in long term potentiation (LTP) and the maintenance of sensitised states. In adult models of chronic pain, which may involve LTP mechanisms, we have shown an increased association of CaM Kinase IIα with NR2A/B spinal immunoprecipitates ipsilateral to injury. Furthermore, a different mechanism may be involved in neonatal pain states, as we have shown that spinal CaM Kinase IIα expression increases with development and is present at very low levels at the time of surgery in our pain models. Additionally, a number of other proteins associated with the NMDA receptor complex are developmentally regulated, and their involvement in the initiation and maintenance of chronic pain is likely to differ between the adult and the neonate. We further show that exposure to prenatal stress does not alter the thresholds to mechanical stimuli in adult or early life pain models, however the combination of prenatal stress and postnatal injury results in an enhanced response to formalin in later life, indicating that programming of stress and/or pain pathways has occurred as a result of these early life events. In addition to the development of a novel model of chronic pain, this study highlights the long-term impact that adverse perinatal events can have on offspring.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Current and potential contributions of community pharmacy teams to self-harm and suicide prevention: A qualitative interview study

BACKGROUND:Suicide prevention is a global priority. Despite the focus on primary care in suicide prevention, little is known about the contributory role of community pharmacists and nothing about the role of the wider community pharmacy team in this area. We aimed to explore the current and potential role of community pharmacy teams in self-harm and suicide prevention. METHODS:We conducted one-to-one semi-structured qualitative interviews with community pharmacy staff (pharmacists, pre-registration pharmacists, pharmacy technicians, dispensing/pharmacy assistants, delivery drivers) in the North West of England, UK. We identified themes from the interview transcripts through an iterative process of inductive thematic analysis. RESULTS:We conducted twenty-five interviews with community pharmacy staff. Many described examples of helping those who were contemplating suicide or self-harm. No participants had received suicide prevention training. We identified six themes. The first two themes (i) Relationship with Patient and (ii) Pharmacy environment were seen as facilitators, which, if supported by (iii) Training, could underpin the final three themes: (iv) Opportunities for contact, (v) Facilitated referral pathway and (v) Restricting access to means. The distinct lack of training should be overcome with evidence-informed training. Referral pathways should be clear and enable direct and accessible referral by community pharmacy teams. There are opportunities for existing pharmacy services and schemes to be adapted to maximise suicide and self-harm prevention activities. Pharmacy teams did not identify themselves to have a clear role in restricting access to medication. CONCLUSIONS:Pharmacy teams already support patients in relation to self-harm and suicide, often relying on their personal experience in the absence of formal training. With the implementation of evidence-informed training and clear referral pathways, this could be done in a more effectively