Mark Rae - Academia.edu (original) (raw)
Papers by Mark Rae
SCIREA Journal of Education
Physiology News
We welcome feedback on our membership magazine, or letters and suggestions for articles for publi... more We welcome feedback on our membership magazine, or letters and suggestions for articles for publication, including book reviews, from our Members.
Advances in Physiology Education
Medical students increasingly utilize social media platforms to supplement their preclinical lear... more Medical students increasingly utilize social media platforms to supplement their preclinical learning; however, the prevalence of social media use for physiology learning in medical education remains unclear. The aim of the present study was to determine how first-year medical students from both direct entry medicine and graduate entry medicine interacted with social media as a learning tool by assessing its prevalence, perceived benefits, favored platforms, and reason(s) for its use. Seventy-one percent of surveyed students (out of 139 participants) stated that they interacted with social media in general more than 12 times per week. However, 98% had previously used internet platforms to source physiology information, with 89.2% doing so at least once per week during term. YouTube was the primary source of learning for 76% of students. Significantly, 94% of students indicated that they would first search for answers online if they did not understand something in physiology rather t...
Advances in Physiology Education
Respiratory physiology & neurobiology, Jan 30, 2018
Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain ... more Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain networks, including those pivotal to the motor control of breathing. The aim of this study was to examine respiratory control in the TgF344-AD transgenic rat model of AD. At 8-11 months of age, basal minute ventilation and ventilatory responsiveness to chemostimulation were equivalent in conscious wild-type (WT) and TgF344-AD rats. Under urethane anesthesia, basal diaphragm and genioglossus EMG activities were similar in WT and TgF344-AD rats. The duration of phenylbiguanide-induced apnoea was significantly shorter in TgF344-AD rats compared with WT. Following bilateral cervical vagotomy, diaphragm and genioglossus EMG responsiveness to chemostimulation were intact in TgF344-AD rats. Amyloid precursor protein C-terminal fragments were elevated in the TgF344-AD brainstem, in the absence of amyloid-β accumulation or alterations in tau phosphorylation. Brainstem pro-inflammatory cytokine co...
Journal of the Scholarship of Teaching and Learning
The current study sought to determine the effectiveness of video-on-demand podcasts (vodcasts) as... more The current study sought to determine the effectiveness of video-on-demand podcasts (vodcasts) as a tool for facilitating the understanding of Physiology by first year undergraduate Graduate Entry to Medicine (GEM 1) students. Seventy three GEM 1 students were provided with full length vodcasts of lecture material in advance of each of nine Physiology lectures. Exam performance, using identical sample questions, was assessed against performance of the 2012-2013 GEM 1 class, which did not have access to the vodcasts. Qualitative information on students' perceptions of the vodcasts was also gathered and analysed. Analysis revealed that the study group of 2013-2014 GEM 1 students achieved significantly higher grades in various examination formats in comparison to the control 2012-2013 GEM 1 cohort. Qualitative analysis of responses to the attitudinal survey revealed that the majority of students liked the vodcasts and that previewing them before lectures did indeed facilitate understanding of the lecture material. However, only 15% of the class was able to view all nine of the prepared vodcasts prior to lectures. Notably, the majority of students indicated that they also considered the vodcasts to be valuable revision tools. This study is the first to show that the use of vodcasts can provide clear, quantifiable benefits for GEM student learning over and above lecture notes and/or lecture slides alone. Our analysis suggests that this improvement was due both to their use as a preview tool as well as facility for later revision of lecture content.
MedEdPublish
This article was migrated. The article was not marked as recommended. Technologies such as audien... more This article was migrated. The article was not marked as recommended. Technologies such as audience response units ('clickers') have been used to facilitate greater student engagement within a variety of educational settings, but numerous technical issues have limited their more widespread use. More recently, flexible, cloud-based student response systems (SRSs), which are designed for use with student mobile devices and overcome most of the limitations of clicker systems, have become widely available. However, the suitability of use for such systems in accelerated degree programmes such as graduate entry to medicine (GEM) has yet to be assessed. Therefore, we utilised Socrative, a freely available SRS, in a physiology component of a first year GEM module to ascertain, a) its ease of deployment, b) its popularity with students and, c) if they felt it improved their learning. There were no technical problems using Socrative. Further, 93% of respondents to an attitudinal surve...
Journal of Physiology and Biochemistry
Vasoconstriction within the renal medulla contributes to the development of hypertension. This st... more Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 ± 7%, P < 0.001) and Wistar rats (by 17 ± 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 ± 6%, P < 0.001) and Wistar rats (by 33 ± 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals.
Experimental Physiology, 2016
Access to the full text of the published version may require a subscription.
Journal of Neurophysiology, 2016
Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive ... more Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility, and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein that connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit nonprogressing cognitive dysfunction, with deficits in verbal, short-term, and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient, and specific deficits in synaptogenesis and channel clustering at synapses has been noted. L...
Biochemical Society Transactions, 2015
Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as ... more Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as specific membrane currents and neurotransmitter release linked to their ability to mobilize calcium from intracellular calcium stores. As such, most I-mGluR research to date has focused on the coupling of these receptors to phospholipase C (PLC)-dependent and inositol (1,4,5) trisphosphate (IP3)-mediated calcium release via activation of IP3 receptors located upon the sarco/endoplasmic reticulum. However, there are now numerous examples of PLC- and IP3-independent I-mGluR-evoked signals, which may instead be mediated by activation of ryanodine receptors (RyRs). A prime candidate for mediating this coupling between I-mGluR activation and RyR opening is cyclic ADP ribose (cADPR) and, indeed, several of these PLC-/IP3-independent I-mGluR-evoked calcium signals have now been shown to be mediated wholly or partly by cADPR-evoked activation of RyRs. The contribution of cADPR signalling to I-mG...
Group 1 metabotropic glutamate receptors (I-mGluRs) are proposed to mediate their effects through... more Group 1 metabotropic glutamate receptors (I-mGluRs) are proposed to mediate their effects through phospholipase Cβ dependent formation of the second messenger inositol-1,4,5-trisphosphate (IP3). Subsequent activation of IP3Rs releases calcium from the endoplasmic reticulum (ER) into the cytosol. Recently however, it has been suggested that I-mGluR - mediated intracellular calcium signals are dependent on activation of ryanodine receptors (RYRs) by cyclic ADP ribose (cADPR) in acutely dissociated rat hippocampal neurons. The current study therefore sought to determine if I-mGluR - mediated calcium signals in cultured rat hippocampal neurons (obtained from Sprague Dawley rats, P3-P5) were also dependent on cADPR activation of RYRs. Intracellular somatic calcium signals were recorded from these neurons following loading with the calcium sensitive dye, fluo-2 AM (150μM). Experiments were carried out at room temperature with neurons continuously perfused (2ml/min) with a standard saline ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investi... more The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investigated in cultured hippocampal cells using Ca(2+) imaging techniques and whole-cell voltage-clamp recording. In neurons, but not glia, global supralinear Ca(2+) release from intracellular stores was observed when the mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was combined with elevated extracellular K(+) levels (10.8 mm), moderate depolarization (15-30 mV), or NMDA (3 micrometer). There was a delay (2-8 min) before the stores were fully charged, and the enhancement persisted for a short period (up to 10 min) after removal of the store-loading stimulus. Studies with the mGlu receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine demonstrated that these effects were mediated by activation of the mGlu(5) receptor subtype. The L-type voltage-gated Ca(2+) channel antagonist nifedipine (10 micrometer) substantially reduced responses to DHPG obtained in the presence of elevate...
The Scientific World JOURNAL, 2002
Cannabis has a long history of consumption both for recreational and medicinal uses. Recently the... more Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids) affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1and CB2, with CB1receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS) regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid) system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor...
The Journal of Physiology, 2014
Hyperactivity of the stress system and low-grade immune activation characterize the functional bo... more Hyperactivity of the stress system and low-grade immune activation characterize the functional bowel disorder irritable bowel syndrome (IBS). r These studies show that interleukin (IL)-6 and IL-8 and the stress hormone corticotropin-releasing factor (CRF), present in IBS plasma, have functional effects on gastrointestinal activity by stimulating myenteric neurons and colonic contractions. r Moreover, in the Wistar Kyoto rat model of IBS, which exhibits altered gastrointestinal motility and visceral pain sensitivity, blocking IL-6 and/or CRF1 receptors alleviates these IBS-like symptoms. r Underlying these effects are altered colonic protein expression of tight junction proteins which regulate gut barrier function and the T-type calcium channel Ca V 3.2, which has been linked to visceral pain. r These findings demonstrate the importance of the enteric nervous system and intestinal physiology in bowel dysfunction.
Neuropharmacology, 2011
After injury GABA A receptor positive allosteric modulators (PAMs) mediate robust analgesia in an... more After injury GABA A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABA A-a2 and-a3 receptor function within the spinal cord. GABA can also act at GABA A receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABA A receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1e10 mg/kg) and TPA023 (3e30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenaninflamed and nerve-injured rats. The non-selective PAM diazepam (1e5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3e30 mg/kg) and the a5-selective NAM a5IA-II (10e60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenaninflamed rats a5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of NS11394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABA A receptors might be more complex than previously anticipated, and is worthy of further exploration.
SCIREA Journal of Education
Physiology News
We welcome feedback on our membership magazine, or letters and suggestions for articles for publi... more We welcome feedback on our membership magazine, or letters and suggestions for articles for publication, including book reviews, from our Members.
Advances in Physiology Education
Medical students increasingly utilize social media platforms to supplement their preclinical lear... more Medical students increasingly utilize social media platforms to supplement their preclinical learning; however, the prevalence of social media use for physiology learning in medical education remains unclear. The aim of the present study was to determine how first-year medical students from both direct entry medicine and graduate entry medicine interacted with social media as a learning tool by assessing its prevalence, perceived benefits, favored platforms, and reason(s) for its use. Seventy-one percent of surveyed students (out of 139 participants) stated that they interacted with social media in general more than 12 times per week. However, 98% had previously used internet platforms to source physiology information, with 89.2% doing so at least once per week during term. YouTube was the primary source of learning for 76% of students. Significantly, 94% of students indicated that they would first search for answers online if they did not understand something in physiology rather t...
Advances in Physiology Education
Respiratory physiology & neurobiology, Jan 30, 2018
Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain ... more Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain networks, including those pivotal to the motor control of breathing. The aim of this study was to examine respiratory control in the TgF344-AD transgenic rat model of AD. At 8-11 months of age, basal minute ventilation and ventilatory responsiveness to chemostimulation were equivalent in conscious wild-type (WT) and TgF344-AD rats. Under urethane anesthesia, basal diaphragm and genioglossus EMG activities were similar in WT and TgF344-AD rats. The duration of phenylbiguanide-induced apnoea was significantly shorter in TgF344-AD rats compared with WT. Following bilateral cervical vagotomy, diaphragm and genioglossus EMG responsiveness to chemostimulation were intact in TgF344-AD rats. Amyloid precursor protein C-terminal fragments were elevated in the TgF344-AD brainstem, in the absence of amyloid-β accumulation or alterations in tau phosphorylation. Brainstem pro-inflammatory cytokine co...
Journal of the Scholarship of Teaching and Learning
The current study sought to determine the effectiveness of video-on-demand podcasts (vodcasts) as... more The current study sought to determine the effectiveness of video-on-demand podcasts (vodcasts) as a tool for facilitating the understanding of Physiology by first year undergraduate Graduate Entry to Medicine (GEM 1) students. Seventy three GEM 1 students were provided with full length vodcasts of lecture material in advance of each of nine Physiology lectures. Exam performance, using identical sample questions, was assessed against performance of the 2012-2013 GEM 1 class, which did not have access to the vodcasts. Qualitative information on students' perceptions of the vodcasts was also gathered and analysed. Analysis revealed that the study group of 2013-2014 GEM 1 students achieved significantly higher grades in various examination formats in comparison to the control 2012-2013 GEM 1 cohort. Qualitative analysis of responses to the attitudinal survey revealed that the majority of students liked the vodcasts and that previewing them before lectures did indeed facilitate understanding of the lecture material. However, only 15% of the class was able to view all nine of the prepared vodcasts prior to lectures. Notably, the majority of students indicated that they also considered the vodcasts to be valuable revision tools. This study is the first to show that the use of vodcasts can provide clear, quantifiable benefits for GEM student learning over and above lecture notes and/or lecture slides alone. Our analysis suggests that this improvement was due both to their use as a preview tool as well as facility for later revision of lecture content.
MedEdPublish
This article was migrated. The article was not marked as recommended. Technologies such as audien... more This article was migrated. The article was not marked as recommended. Technologies such as audience response units ('clickers') have been used to facilitate greater student engagement within a variety of educational settings, but numerous technical issues have limited their more widespread use. More recently, flexible, cloud-based student response systems (SRSs), which are designed for use with student mobile devices and overcome most of the limitations of clicker systems, have become widely available. However, the suitability of use for such systems in accelerated degree programmes such as graduate entry to medicine (GEM) has yet to be assessed. Therefore, we utilised Socrative, a freely available SRS, in a physiology component of a first year GEM module to ascertain, a) its ease of deployment, b) its popularity with students and, c) if they felt it improved their learning. There were no technical problems using Socrative. Further, 93% of respondents to an attitudinal surve...
Journal of Physiology and Biochemistry
Vasoconstriction within the renal medulla contributes to the development of hypertension. This st... more Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 ± 7%, P < 0.001) and Wistar rats (by 17 ± 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 ± 6%, P < 0.001) and Wistar rats (by 33 ± 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals.
Experimental Physiology, 2016
Access to the full text of the published version may require a subscription.
Journal of Neurophysiology, 2016
Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive ... more Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility, and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein that connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit nonprogressing cognitive dysfunction, with deficits in verbal, short-term, and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient, and specific deficits in synaptogenesis and channel clustering at synapses has been noted. L...
Biochemical Society Transactions, 2015
Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as ... more Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as specific membrane currents and neurotransmitter release linked to their ability to mobilize calcium from intracellular calcium stores. As such, most I-mGluR research to date has focused on the coupling of these receptors to phospholipase C (PLC)-dependent and inositol (1,4,5) trisphosphate (IP3)-mediated calcium release via activation of IP3 receptors located upon the sarco/endoplasmic reticulum. However, there are now numerous examples of PLC- and IP3-independent I-mGluR-evoked signals, which may instead be mediated by activation of ryanodine receptors (RyRs). A prime candidate for mediating this coupling between I-mGluR activation and RyR opening is cyclic ADP ribose (cADPR) and, indeed, several of these PLC-/IP3-independent I-mGluR-evoked calcium signals have now been shown to be mediated wholly or partly by cADPR-evoked activation of RyRs. The contribution of cADPR signalling to I-mG...
Group 1 metabotropic glutamate receptors (I-mGluRs) are proposed to mediate their effects through... more Group 1 metabotropic glutamate receptors (I-mGluRs) are proposed to mediate their effects through phospholipase Cβ dependent formation of the second messenger inositol-1,4,5-trisphosphate (IP3). Subsequent activation of IP3Rs releases calcium from the endoplasmic reticulum (ER) into the cytosol. Recently however, it has been suggested that I-mGluR - mediated intracellular calcium signals are dependent on activation of ryanodine receptors (RYRs) by cyclic ADP ribose (cADPR) in acutely dissociated rat hippocampal neurons. The current study therefore sought to determine if I-mGluR - mediated calcium signals in cultured rat hippocampal neurons (obtained from Sprague Dawley rats, P3-P5) were also dependent on cADPR activation of RYRs. Intracellular somatic calcium signals were recorded from these neurons following loading with the calcium sensitive dye, fluo-2 AM (150μM). Experiments were carried out at room temperature with neurons continuously perfused (2ml/min) with a standard saline ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investi... more The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investigated in cultured hippocampal cells using Ca(2+) imaging techniques and whole-cell voltage-clamp recording. In neurons, but not glia, global supralinear Ca(2+) release from intracellular stores was observed when the mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was combined with elevated extracellular K(+) levels (10.8 mm), moderate depolarization (15-30 mV), or NMDA (3 micrometer). There was a delay (2-8 min) before the stores were fully charged, and the enhancement persisted for a short period (up to 10 min) after removal of the store-loading stimulus. Studies with the mGlu receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine demonstrated that these effects were mediated by activation of the mGlu(5) receptor subtype. The L-type voltage-gated Ca(2+) channel antagonist nifedipine (10 micrometer) substantially reduced responses to DHPG obtained in the presence of elevate...
The Scientific World JOURNAL, 2002
Cannabis has a long history of consumption both for recreational and medicinal uses. Recently the... more Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids) affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1and CB2, with CB1receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS) regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid) system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor...
The Journal of Physiology, 2014
Hyperactivity of the stress system and low-grade immune activation characterize the functional bo... more Hyperactivity of the stress system and low-grade immune activation characterize the functional bowel disorder irritable bowel syndrome (IBS). r These studies show that interleukin (IL)-6 and IL-8 and the stress hormone corticotropin-releasing factor (CRF), present in IBS plasma, have functional effects on gastrointestinal activity by stimulating myenteric neurons and colonic contractions. r Moreover, in the Wistar Kyoto rat model of IBS, which exhibits altered gastrointestinal motility and visceral pain sensitivity, blocking IL-6 and/or CRF1 receptors alleviates these IBS-like symptoms. r Underlying these effects are altered colonic protein expression of tight junction proteins which regulate gut barrier function and the T-type calcium channel Ca V 3.2, which has been linked to visceral pain. r These findings demonstrate the importance of the enteric nervous system and intestinal physiology in bowel dysfunction.
Neuropharmacology, 2011
After injury GABA A receptor positive allosteric modulators (PAMs) mediate robust analgesia in an... more After injury GABA A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABA A-a2 and-a3 receptor function within the spinal cord. GABA can also act at GABA A receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABA A receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1e10 mg/kg) and TPA023 (3e30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenaninflamed and nerve-injured rats. The non-selective PAM diazepam (1e5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3e30 mg/kg) and the a5-selective NAM a5IA-II (10e60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenaninflamed rats a5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of NS11394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABA A receptors might be more complex than previously anticipated, and is worthy of further exploration.