ORCID Profile
0000-0003-2068-3868
Current Organisation
University of Adelaide
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Publisher: Elsevier BV
Date: 06-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-10-2022
DOI: 10.1097/J.PAIN.0000000000002795
Abstract: The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Sensory signals, generated in response to distension, are relayed to the spinal cord and brain to evoke physiological and painful sensations and regulate urine storage and voiding. Hyperexcitability of these sensory pathways is a key component in the development of chronic bladder hypersensitivity disorders including interstitial cystitis/bladder pain syndrome and overactive bladder syndrome. Despite this, the full array of ion channels that regulate bladder afferent responses to mechanical stimuli have yet to be determined. Here, we investigated the role of low-voltage-activated T-type calcium (Ca V 3) channels in regulating bladder afferent responses to distension. Using single-cell reverse-transcription polymerase chain reaction and immunofluorescence, we revealed ubiquitous expression of Ca V 3.2, but not Ca V 3.1 or Ca V 3.3, in in idual bladder-innervating dorsal root ganglia neurons. Pharmacological inhibition of Ca V 3.2 with TTA-A2 and ABT-639, selective blockers of T-type calcium channels, dose-dependently attenuated ex-vivo bladder afferent responses to distension in the absence of changes to muscle compliance. Further evaluation revealed that Ca V 3.2 blockers significantly inhibited both low- and high-threshold afferents, decreasing peak responses to distension, and delayed activation thresholds, thereby attenuating bladder afferent responses to both physiological and noxious distension. Nocifensive visceromotor responses to noxious bladder distension in vivo were also significantly reduced by inhibition of Ca V 3 with TTA-A2. Together, these data provide evidence of a major role for Ca V 3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 26-06-2019
DOI: 10.1111/NMO.13669
Abstract: Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.
Publisher: American Physiological Society
Date: 12-2018
Abstract: Processes involved in regulation of energy balance and intermediary metabolism are aligned to the light-dark cycle. Shift-work and high-fat diet (HFD)-induced obesity disrupt circadian rhythmicity and are associated with increased risk of nonalcoholic fatty liver disease. This study aimed to determine the effect of simulating shift work on hepatic lipid accumulation in lean and HFD mice. C57BL/6 mice fed a standard laboratory diet (SLD) or HFD for 4 wk were further allocated to a normal light (NL) cycle (lights on: 0600–1800) or rotating light (RL) cycle [3 days NL and 4 days reversed (lights on: 1800–0600) repeated] for 8 wk. Tissue was collected every 3 h beginning at 0600. HFD mice gained more weight than SLD mice, and RL mice gained more weight than NL mice. SLD-NL and HFD-NL mice, but not RL mice, were more active, had higher respiratory quotients, and consumed/expended more energy during the dark phase compared with the light phase. Blood glucose and plasma cholesterol and triglyceride concentrations were elevated in HFD and SLD-RL compared with SLD-NL mice. Hepatic glycogen was elevated in HFD compared with SLD mice. Hepatic triglycerides were elevated in SLD-RL and HFD mice compared with SLD-NL. Circadian rhythmicity of hepatic acetyl-CoA carboxylase (ACACA) mRNA was phase shifted in SLD-RL and HFD-NL and lost in HFD-RL mice. Hepatic ACACA protein was reduced in SLD-RL and HFD mice compared with SLD-NL mice. Hepatic adipose triglyceride lipase was elevated in HFD-NL compared with SLD-NL but lower in RL mice compared with NL mice irrespective of diet. In conclusion, an RL cycle model of shift work promotes weight gain and hepatic lipid storage even in lean conditions. NEW & NOTEWORTHY In this publication we describe the effects of a rotating light cycle model of shift work in lean and high-fat diet-induced obese mice on body mass, diurnal patterns of energy intake and expenditure, and hepatic lipid storage. The data indicate that modeling shift work, via a rotating light cycle, promotes weight gain and hepatic lipid accumulation even in mice on a standard laboratory diet.
Publisher: Wiley
Date: 11-09-2019
DOI: 10.1111/NMO.13711
Abstract: Gastric vagal afferents (GVAs) respond to mechanical stimulation, initiating satiety. These afferents exhibit diurnal fluctuations in mechanosensitivity, facilitating food intake during the dark phase in rodents. In humans, desynchrony of diurnal rhythms (eg, shift work) is associated with a higher risk of obesity. To test the hypothesis that shift work disrupts satiety signaling, the effect of a rotating light cycles on diurnal rhythms in GVA mechanosensitivity in lean and high-fat diet (HDF)-induced obese mice was determined. Male C57BL/6 mice were fed standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks, mice were randomly allocated to a normal light (NL 12 hour light: 12 hour dark lights on at zeitgeber time [ZT] 0) or rotating light (RL 3-day NL cycle, 4-day reversed light cycle [lights on: ZT12] repeated) cycle for 8 weeks. At week 12, eight mice from each group were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 hour intervals starting at ZT0. SLD-RL and HFD-RL gained more weight compared to SLD-NL and HFD-NL mice, respectively. Gonadal fat pad mass was higher in SLD-RL compared to SLD-NL mice. In SLD-NL mice, tension and mucosal receptor mechanosensitivity exhibited diurnal rhythms with a peak at ZT9. These rhythms were lost in SLD-RL, HFD-NL, and HFD-RL mice and associated with d ened diurnal rhythms in food intake. GVA diurnal rhythms are susceptible to disturbances in the light cycle and/or the obese state. This may underpin the observed changes in feeding behavior.
Publisher: Frontiers Media SA
Date: 31-07-2018
Publisher: American Physiological Society
Date: 05-2021
DOI: 10.1152/AJPRENAL.00065.2021
Abstract: This article describes, for the first time, to our knowledge, the direct inhibitory effect of cannabinoid 2 receptor agonists on guinea pig mucosal bladder afferents. The cannabinoid 2 receptor is involved in pain and inflammation, suggesting that this may be a viable target for treatment of bladder disorders such as cystitis.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2021
DOI: 10.1038/S41598-021-98831-X
Abstract: The voiding of urine has a clear circadian rhythm with increased voiding during active phases and decreased voiding during inactive phases. Bladder spinal afferents play a key role in the regulation of bladder storage and voiding, but it is unknown whether they exhibit themselves a potential circadian rhythm. Therefore, this study aimed to determine the mechano- and chemo- sensitivity of three major bladder afferent classes at two opposite day-night time points. Adult female guinea pigs underwent conscious voiding monitoring and bladder ex vivo single unit extracellular afferent recordings at 0300 h and 1500 h to determine day-night modulation of bladder afferent activity. All guinea pigs voided a higher amount of urine at 1500 h compared to 0300 h. This was due to an increased number of voids at 1500 h. The mechano-sensitivity of low- and high-threshold stretch-sensitive muscular-mucosal bladder afferents to mucosal stroking and stretch was significantly higher at 1500 h compared to 0300 h. Low-threshold stretch-insensitive mucosal afferent sensitivity to stroking was significantly higher at 1500 h compared to 0300 h. Further, the chemosensitivity of mucosal afferents to N-Oleoyl Dopamine (endogenous TRPV1 agonist) was also significantly increased at 1500 h compared to 0300 h. This data indicates that bladder afferents exhibit a significant time-of-day dependent variation in mechano-sensitivity which may influence urine voiding patterns. Further studies across a 24 h period are warranted to reveal potential circadian rhythm modulation of bladder afferent activity.
Publisher: Frontiers Media SA
Date: 05-07-2021
DOI: 10.3389/FPHAR.2021.708989
Abstract: The recent surge in research on cannabinoids may have been fueled by changes in legislation in several jurisdictions, and by approval for the use of cannabinoids for treatment of some chronic diseases. Endocannabinoids act largely, but not exclusively on cannabinoid receptors 1 and 2 (CBR1 and CBR2) which are expressed in the bladder mainly by the urothelium and the axons and endings of motor and sensory neurons. A growing body of evidence suggests that endocannabinoid system constitutively downregulates sensory bladder function during urine storage and micturition, under normal physiological conditions. Similarly, exogenous cannabinoid agonists have potent modulatory effects, as do inhibitors of endocannabinoid inactivation. Results suggest a high potential of cannabinoids to therapeutically ameliorate lower urinary tract symptoms in overactive bladder and painful bladder syndromes. At least part of this may be mediated via effects on sensory nerves, although actions on efferent nerves complicate interpretation. The sensory innervation of bladder is complex with at least eight classes identified. There is a large gap in our knowledge of the effects of endocannabinoids and synthetic agonists on different classes of bladder sensory neurons. Future studies are needed to reveal the action of selective cannabinoid receptor 2 agonists and/or peripherally restricted synthetic cannabinoid receptor 1 agonists on bladder sensory neurons in animal models of bladder diseases. There is significant potential for these novel therapeutics which are devoid of central nervous system psychotropic actions, and which may avoid many of the side effects of current treatments for overactive bladder and painful bladder syndromes.
Publisher: MDPI AG
Date: 19-08-2020
DOI: 10.3390/NU12092493
Abstract: The stomach is the primary source of the orexigenic and adiposity-promoting hormone, ghrelin. There is emerging evidence on the nutrient-mediated modulation of gastric ghrelin secretion. However, limited information is available on gastric nutrient-sensing mechanisms in high-fat diet (HFD)-induced obesity. This study investigated the impact of HFD-induced obesity on the expression of nutrient chemosensors in mouse stomach, particularly ghrelin cells. Male C57BL/6 mice were fed either a standard laboratory diet (SLD) or HFD for 12 weeks. The expression of ghrelin, enzymes involved in ghrelin production (PC1/3, GOAT) and nutrient chemosensors (CD36, FFAR2& , GPR93, CaSR, mGluR4 and T1R3) was determined by quantitative RT-PCR in the mouse corpus and antrum. Immunohistochemistry assessed the protein expression of CaSR and ghrelin in the corpus and antrum. Antral mRNA levels of CaSR and PC1/3 were increased in HFD compared to SLD mice, while mRNA levels of all other nutrient chemosensors examined remained unchanged. CaSR immunolabelling was observed in the gastric antrum only. Nearly 80% of antral ghrelin cells expressed CaSR, with a similar cell density and co-expression in SLD and HFD mice. In conclusion, HFD-induced obesity increased CaSR mRNA expression in mouse antrum. However, the high antral co-expression of CaSR and ghrelin was unaltered in HFD compared to SLD mice.
Publisher: American Physiological Society
Date: 02-2021
Abstract: This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Frontiers Media SA
Date: 30-08-2023
DOI: 10.3389/FPHYS.2023.1239278
Abstract: A rhythmic expression of clock genes occurs within the cells of multiple organs and tissues throughout the body, termed “peripheral clocks.” Peripheral clocks are subject to entrainment by a multitude of factors, many of which are directly or indirectly controlled by the light-entrainable clock located in the suprachiasmatic nucleus of the hypothalamus. Peripheral clocks occur in the gastrointestinal tract, notably the epithelia whose functions include regulation of absorption, permeability, and secretion of hormones and in the myenteric plexus, which is the intrinsic neural network principally responsible for the coordination of muscular activity in the gut. This review focuses on the physiological circadian variation of major colonic functions and their entraining mechanisms, including colonic motility, absorption, hormone secretion, permeability, and pain signalling. Pathophysiological states such as irritable bowel syndrome and ulcerative colitis and their interactions with circadian rhythmicity are also described. Finally, the classic circadian hormone melatonin is discussed, which is expressed in the gut in greater quantities than the pineal gland, and whose exogenous use has been of therapeutic interest in treating colonic pathophysiological states, including those exacerbated by chronic circadian disruption.
Publisher: Wiley
Date: 27-11-2019
DOI: 10.1113/JP278696
Publisher: Springer Science and Business Media LLC
Date: 21-10-2022
DOI: 10.1038/S41598-022-22705-Z
Abstract: Melatonin is a circadian rhythm regulator capable of controlling a variety of physiological processes in the body. It predominantly acts via the melatonin 1 (MT1) and MT2 receptors expressed in the CNS neurons and peripheral organs and tissues. Melatonin can modulate urinary bladder function, however, to date it is not known if melatonin can regulate activity of sensory neurons innervating the bladder. Bladder afferents play an important role in urine storage and voiding. Therefore, this study aims to determine if melatonin can regulate mechanosensitivity of 2 major classes of sensory neurons in the guinea pig bladder: stretch-insensitive mucosal and low threshold stretch-sensitive muscular-mucosal afferents. The effects of melatonin on the mechanosensitivity of mucosal and muscular-mucosal afferents were measured ex vivo using single unit extracellular recording. Melatonin did not affect the responses of mucosal afferents to stroking of their receptive fields but did concentration-dependently, significantly inhibit 69% of muscular-mucosal afferents responses to stroking and bladder stretch. This inhibitory effect was not affected by the MT1 receptor antagonist, S26131 but was blocked by the selective MT2 receptor antagonists, K-185 and 4-P-PDOT. Forskolin significantly potentiated the responses of muscular-mucosal afferents to stroking and stretch, which were prevented by melatonin. These findings demonstrate a direct inhibitory effect of melatonin on the mechanosensitivity of low threshold stretch-sensitive muscular-mucosal bladder afferents acting via MT2 receptors, which is independent from its action on detrusor muscle. This may have important clinical implications for the treatment of many common bladder disorders including nocturia.
Publisher: Wiley
Date: 05-2020
DOI: 10.1113/JP279449
Publisher: Wiley
Date: 13-01-2023
DOI: 10.1111/BPH.16017
Abstract: Interstitial cystitis (=painful bladder syndrome) is a chronic bladder syndrome characterised by pelvic and bladder pain, urinary frequency and urgency, and nocturia. Transient receptor potential (TRP) channels are an attractive target in reducing the pain associated with interstitial cystitis. The current study aims to determine the efficacy of combination of TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8) channel inhibition in reducing the pain associated with experimental cystitis in guinea pigs. A novel animal model of non‐ulcerative interstitial cystitis has been developed using protamine sulfate/zymosan in female guinea pigs. Continuous voiding cystometry was performed in conscious guinea pigs. Ex vivo “close‐to‐target” single unit extracellular recordings were made from fine branches of pelvic nerves entering the guinea pig bladder. Visceromotor responses in vivo were used to determine the effects of TRP channel antagonists on cystitis‐induced bladder hypersensitivity. Protamine sulfate/zymosan treatment evoked mild inflammation in the bladder and increased micturition frequency in conscious animals. In cystitis, high threshold muscular afferents were sensitised via up‐regulation of TRPV1 channels, high threshold muscular–mucosal afferents were sensitised via TRPM8 channels, and mucosal afferents by both. Visceromotor responses evoked by noxious bladder distension were significantly enhanced in cystitis and were returned to control levels upon administration of combination of low doses of TRPV1 and TRPM8 antagonists. The data demonstrate the therapeutic promises of combination of TRPV1 and TRPM8 antagonists for the treatment of bladder hypersensitivity in cystitis.
No related grants have been discovered for Stewart Ramsay.