Search PubMed⌕ Search

Biomedical subjects

D Grundy

Publications and source records attributed to D Grundy.

At least 37 records · Page 2Linked to original sources
PubMed2002

Cosensitivity of vagal mucosal afferents to histamine and 5-HT in the rat jejunum.

A complex sensitivity of afferent nerves in the mesentery of the rat jejunum to systemic administration of histamine has recently been demonstrated. In the present study, we aimed to characterize subpopulations of mesenteric afferents that mediate this afferent nerve response. Multiunit afferent discharge was recorded from mesenteric nerves supplying the proximal jejunum in anesthetized rats. The majority of mesenteric bundles (84%) exhibited biphasic responses to histamine (8 micromol/kg), and these bundles also responded to 2-methyl-5-HT (2m5HT). In contrast, monophasic responses lacked a short-latency component, and these bundles failed to respond to 2m5HT. Single-unit analysis revealed a population of afferents that possessed cosensitivity for 2m5HT and histamine. This population of afferents was absent in chronically vagotomized animals, whereas mucosal anesthesia with luminal lidocaine reversibly converted the biphasic profile to a monophasic one. Ondansetron (500 microg/kg) blocked the response to 2m5HT with no effect on the profile of the histamine response, whereas pyrilamine (5 mg/kg) blocked the histamine response without affecting the response to 2m5HT. We conclude that histamine-sensitive afferents exist in the rat proximal jejunum that also respond to 5-HT via the 5-HT3 receptor. These fibers appear to be vagal afferents originating in the intestinal mucosa and may be involved in the organization of mast cell-mediated responses.

Anesthetics, Local↗
PubMed2002

Mesenteric afferent nerves are sensitive to vascular perfusion in a novel preparation of rat ileum in vitro.

Using novel in vitro preparations of vascularly perfused rat ileum, we investigated mesenteric afferent sensitivity to vascular perfusion. Gut (GPP) and vascular (VPP) perfusion pressures were recorded simultaneously with afferent discharge (AD). After preconstriction (L-phenylephrine), capsaicin (100 microM, gut lumen) caused a transient increase in AD and a sustained fall in VPP, supporting afferent modulation of vascular tone. In turn, AD was affected by vascular perfusion rate (VPR). Increasing VPR step-wise (0.6 to 1.0, 1.4 and 1.8 ml/min) caused concomitant falls in AD, returning at 0.6 ml/min. Terminating flow (5 min) increased AD. Afferent responses were independent of changes in GPP, vascular O2, or the gut "tube" ("gut-off"). In gut-off studies, where capsaicin (100 nM ia) still reduced VPP, flow-associated falls in AD were abolished by the enzyme neuraminidase (0.2 U/ml ia or extravascularly over 20 min). In contrast, increased AD after stopped flow was unaffected. We propose that mesenteric afferents "sense" changes in vascular perfusion. The precise stimuli (pressure and/or flow) and the physiological relevance to control of local circulation remain to be determined.

Animals↗
PubMed2001

Somatostatin sst(2) receptor-mediated inhibition of mesenteric afferent nerves of the jejunum in the anesthetized rat.

BACKGROUND & AIMS: Octreotide inhibits visceral sensations in clinical studies, but the site of action and the receptor type(s) involved are unknown. Our aim was to investigate the effects of octreotide, the selective sst(2) receptor agonist (BIM 23027), and the sst(2) antagonist (Cyanamid154806) on the activity of mesenteric afferent fibers innervating the rat jejunum. Their effects were investigated on baseline discharge, mechanosensitivity, and responses to algesic chemicals. METHODS: Extracellular multiunit recordings of jejunal afferent nerve firing were made in pentobarbitone-anesthetized (60 mg/kg intraperitoneally) male Wistar rats. RESULTS: Octreotide and BIM23027 (0.001-100 microg/kg intravenously) each evoked a long-lasting inhibition of baseline discharge, which was blocked by cyanamid 154806 (3 mg/kg) and absent in chronically vagotomized animals. Afferent responses to bradykinin were also inhibited by an sst(2) receptor-mediated mechanism but were unaffected by vagotomy. Ramp distentions of the jejunum evoked a biphasic activation of afferent nerve discharge, the low threshold component of which was attenuated in vagotomized animals. Sst(2) receptor agonists significantly inhibited the mechanosensitivity of spinal, but not vagal, afferents. CONCLUSIONS: These data suggest that activation of somatostatin sst(2) receptors inhibit populations of mesenteric afferents likely to be involved in nociceptive transmission.

Anesthesia↗
PubMed2001

Modulation of gastric distension-induced sensations by small intestinal receptors.

Duodenal lipid exacerbates gastrointestinal sensations during gastric distension. Using luminal application of the local anesthetic benzocaine, we investigated the role of intestinal receptors in the induction of these sensations. Nine healthy subjects were studied on five occasions, during which isotonic saline or 20% lipid (2 kcal/min), combined with (duodenal or jejunal) 0.75% benzocaine or vehicle at 2.5 ml/min, was infused intraduodenally before and during gastric distension. Intragastric pressures and volumes, gastrointestinal sensations, and plasma CCK levels were determined. Duodenal lipid combined with vehicle increased gastric volume (in ml: saline, -10 +/- 18; lipid/vehicle, 237 +/- 30) and plasma CCK [mean levels (pmol/l): saline, 2.0 +/- 0. 2; lipid/vehicle, 8.0 +/- 1.6] and, during distensions, induced nausea (scores: saline, 3 +/- 2: lipid/vehicle, 58 +/- 19) and decreased pressures at which fullness and discomfort occurred. Duodenal but not jejunal benzocaine attenuated the effect of lipid on gastric volume, plasma CCK, and nausea during distension (135 +/- 38 and 216 +/- 40 ml, 4.6 +/- 0.6 pmol/l and not assessed, and 37 +/- 12 and 64 +/- 21 for lipid + duodenal benzocaine and lipid + jejunal benzocaine, respectively) and on pressures for sensations. In conclusion, intestinal receptors modulate gastrointestinal sensations associated with duodenal lipid and gastric distension. There is also the potential for local neural mechanisms to regulate CCK release and thereby reduce afferent activation indirectly.

Adult↗
PubMed2001

Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents.

Visceral afferents are the information superhighway from the gut to the central nervous system. These sensory nerves express a wide range of membrane receptors that can modulate their sensitivity. In this themes article, we concentrate on those receptors that enhance the excitability of visceral afferent neurons. Some receptors are part of a modality-specific transduction pathway involved in sensory signaling. Others, which are activated by substances derived from multiple cellular sources during ischemia, injury, or inflammation, act in a synergistic fashion to cause acute or chronic sensitization of the afferent nerves to mechanical and chemical stimuli. Such hypersensitivity is the hallmark of conditions such as irritable bowel syndrome. Accordingly, these receptors represent a rational target for drug treatments aimed at attenuating both the inappropriate visceral sensation and the aberrant reflex activity that are the foundation for alterations in bowel function.

Afferent Pathways↗
PubMed2001

Modulation of gastric motor activity by a centrally acting stimulus, circular vection, in humans.

The aims of this study were to investigate gastric motor correlates of vection, a centrally acting stimulus, and relate these responses to the induction of motion sickness symptoms. Antral contractile activity and gastric volume retained after a liquid nutrient meal (600 ml) were assessed by magnetic resonance imaging in healthy subjects during two different protocols. Vection was induced by an optokinetic drum, and subjects repeatedly rated the intensity of vection and nausea on 0-10 analog scales. Vection delayed gastric emptying [99% (89-102%) [median (interquartile ranges)] of volume retained at 28 min; control situation: 79% (69-81%), P < 0.05]. Antral contractile activity followed a distinct time course of rapid decrease [-64% (-72 to -59%) change from baseline activity] immediately after onset of drum rotation followed by gradual recovery upon withdrawal of the stimulus. No relationship was found between the severity of nausea and inhibition of gastric emptying or antral contractile activity. The inhibition of antral contractile activity appears to be a good measure of the peripheral response to vection but is probably independent of subjective symptom induction.

Adult↗
PubMed2001

Vagal afferent responses to fatty acids of different chain length in the rat.

The role of cholecystokinin (CCK) in the effect of dietary lipid on proximal gastrointestinal function and satiety is controversial. Recent work suggests that fatty acid chain length may be a determining factor. We investigated the mechanism by which long- and short-chain fatty acids activate jejunal afferent nerves in rats. Whole mesenteric afferent nerve discharge was recorded in anaesthetized male Wistar rats during luminal perfusion of saline, sodium oleate, and sodium butyrate (both 10 mM). Both fatty acids evoked characteristic afferent nerve responses, distinct from the mechanical response to saline, that were abolished in rats following chronic subdiaphragmatic vagotomy. The effect of oleate was abolished by the CCK-A receptor antagonist Devazepide (0.5 mg/kg), whereas the effect of butyrate persisted despite pretreatment with either Devazepide or a combination of the calcium channel inhibitors nifedipine (1 mg/kg) and the omega-conotoxins GVIA and SVIB (each 25 microg/kg). In summary, long- and short-chain fatty acids activate intestinal vagal afferents by different mechanisms; oleate acts via a CCK-mediated mechanism and butyrate appears to have a direct effect on afferent terminals.

Animals↗
PubMed2000

Descending influences from the infralimbic cortex on vago-vagal reflex control of gastric motor activity in the rat.

In experiments on urethane anaesthetised rats the influence of electrical stimulation of ventral areas of the medial prefrontal cortex (mPFC) on spontaneous and vagally-mediated gastric motility were studied. Stimulation of the mPFC resulted in gastric relaxation manifested as a fall in intragastric pressure from a baseline value of 5.0 +/- 0.5 cm H2O. These were most prominent following a short latency when the infralimbic cortex (IL) was stimulated (27.4 +/- 2.5% fall in gastric pressure). Electrical stimulation of the central end of one cervical vagus nerve caused a comparable decrease in gastric pressure (27.1 +/- 2.9%). The cortical mediated relaxation was reduced by atropine and abolished by vagotomy. The cortically induced gastric relaxation followed a shorter latency (5.9 +/- 1.0 s), time to nadir (20.1 +/- 2.7 s) and the half recovery time (21.5 +/- 4.0 s) than vagally mediated-relaxations (9.9 +/- 2.3, 56.0 +/- 5.3 and 83.4 +/- 9.5 s, respectively). Vagally mediated relaxations were inhibited by simultaneous stimulation of the infralimbic cortex. In this case the decrease of gastric pressure, the time to nadir and the half recovery time were significantly decreased in comparison with the gastric relaxatory responses to vagal stimulation alone (P < 0.05). We conclude that one way in which the mPFC influences gastric motility is via corticofugal projections from the infralimbic cortex to the brain-stem which modulate transmission of vago-vagal reflexes.

Animals↗
PubMed2000

Mediators of neuronal activation in the rat brainstem following intestinal anaphylaxis.

Brainstem neurones become activated following intestinal antigen challenge but the signalling mechanisms have not been resolved. Our aim was to determine the extent of brainstem activation after intestinal anaphylaxis induced by chicken egg albumin (EA). An increase in Fos-positive neurones in the nucleus tractus solitarius (nTS) was observed following EA (P<0.05). Fos-expression was decreased following pretreatment with pyrilamine and ondansetron i.p. and to a similar extent when both antagonists were administered together (all P<0.05 vs. control). Indomethacin had no effect on Fos-expression after antigen challenge. 5-HT and histamine but not prostanoids, released following intestinal anaphylaxis, induce nTS activation via histamine H(1)- and 5-HT(3) receptors. Information on the intestinal inflammatory status is relayed centrally and may play a role in reflexes and behavioural responses to activation of the immune system.

Anaphylaxis↗
PubMed2000

Modulation of gastrointestinal afferent sensitivity by a novel substituted benzamide (ecabapide).

The effects of ecabapide, a novel substituted benzamide compound (3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylb enzamide) that has gastrointestinal prokinetic action, were examined on the discharge of extrinsic afferent nerves supplying the stomach and jejunum in anaesthetized rats. Ecabapide (60 and 180 microg kg(-1), i.v.) had no effect on the baseline discharge of vagal gastric distension-sensitive afferents or the stimulus-response profile to gastric distension. Ecabapide also had no effect on either spontaneous jejunal mesenteric afferent nerve discharge or responses to intestinal distension. Ecabapide (180 microg kg(-1)) significantly inhibited the maximum discharge of jejunal afferents induced by cholecystokinin (CCK8; 50 pmol, i.v.), whereas it failed to inhibit the excitatory action of 2-methyl-5-hydroxytryptamine (2Me-5-HT; 10 microg, i.v.), a selective 5-HT3 receptor agonist. A model of acute focal intestinal ischaemia was used to evaluate the actions of ecabapide on the discharge of activated jejunal afferents. Ischaemia produced a substantial increase in afferent discharge which was reproducible when the duration of ischaemia was limited to less than 10 min and repeated every 15 min. Ecabapide at doses of 60 and 180 microg kg(-1) significantly reduced ischaemia-induced increases in afferent discharge. In addition to its therapeutic efficacy as a gastrointestinal prokinetic agent, these findings show also that ecabapide may also have an inhibitory action on the discharge of intestinal afferents activated by ischaemia.

Afferent Pathways↗
PubMed2000

Cilansetron acts at its site of absorption to antagonize the sensitivity of mesenteric afferent fibres to 5-hydroxytryptamine in the rat jejunum.

The present study compares the efficacy of cilansetron, a 5-hydroxytryptamine (5-HT3)-receptor antagonist, delivered via intravenous and intraluminal routes, on the sensitivity of mesenteric afferent fibres supplying the proximal jejunum. Waveform analysis was performed to extract 5-HT sensitive single units from electrophysiological recordings of whole afferent nerve discharge. Dose effects of intravenous cilansetron (0.2-20 microg/kg) on the afferent response to 5-HT (10 microg) were examined to determine the threshold dose of cilansetron (2 microg/kg). This dose applied intraluminally to the region of jejunum innervated by the afferents, resulted in a greater degree of antagonism of the 5-HT response than intravenous administration (47.8+/-7.9 vs. 76.9+/-4.7%, P = 0.008). We concluded that cilansetron is active at its site of absorption to antagonize 5-HT3 receptors on vagal mucosal afferent terminals.

Absorption↗
PubMed2000

The effect of fentanyl, DNQX and MK-801 on dorsal horn neurones responsive to colorectal distension in the anaesthetized rat.

Certain dorsal horn neurones respond in a graded manner to noxious colorectal distension (CRD). Morphine inhibits these responses in the spinalized rat, but the role of excitatory amino acids in baseline visceral nociceptive transmission is less clear. This study examines the effect of the mu-opiate receptor agonist fentanyl, and the non-NMDA and NMDA antagonists DNQX and MK-801, respectively, on such responses to CRD in the sodium pentobarbitone-anaesthetized rat. Male rats were prepared for extracellular recording from the lumbosacral spinal cord. 90 neurones responsive to CRD, located throughout the dorsal horn, were classified according to their response duration and latency to 60 mmHg distension, as SL-A (short latency-abrupt; 59%), SL-S (short latency-sustained; 23%), L-L (long-latency; 10%) and Inhib (inhibited; 8%). Convergent cutaneous receptive fields were mapped for 79/90 neurones and classified as LT (low threshold), WDR (wide dynamic range) or HT (high threshold). CRD (20-100 mm Hg) elicited graded responses in most neurones. In 6/6 SL-S neurones, fentanyl (1-8 microg kg-1) dose-dependently inhibited the response to 60 mm Hg CRD, in a naloxone-sensitive manner, with an ID50 value (+/-95% confidence limits) of 2.48 (1.7-3. 7) microg kg-1. In 6/6 SL-A neurones, fentanyl had no significant effect on the response to CRD. DNQX (0.03-3 mg kg-1) produced a dose-dependent inhibition of the response to CRD in 5/5 SL-A neurones, with an ID50 value of 0.32 (0.01-41.1) mg kg-1. MK-801 (0. 03-0.3 mg kg-1) had no significant effect on responses to CRD in 6/6 SL-A neurones. The differential inhibitory effects of fentanyl on two neuronal subtypes may indicate functional differences. In SL-A neurones AMPA/kainate, but not NMDA receptors are involved in mediating baseline nociceptive neurotransmission.

Analgesics, Opioid↗
PubMed2000

Opioid-receptor-mediated excitation of rat mesenteric afferent fibres supplying the rat jejunum.

The aim of the present study was to examine the sensitivity to opioid-receptor agonists of mesenteric afferents supplying the small intestine and to characterize the subpopulations of any responsive fibres. Mesenteric afferent discharge was recorded electrophysiologically in response to cumulative doses (1-400 microgram kg-1) of the mu-receptor agonist [D-ala,2 N- me-Phe4, Gly5-ol]-enkephalin (DAMGO), the delta-receptor agonist [D-ala,2 D-leu5]-enkephalin (DADLE) and the kappa-receptor agonist U-50488. DAMGO and DADLE, but not U-50488, markedly stimulated whole nerve mesenteric afferent discharge (P < 0.05) that was unrelated to intestinal motor events. Subpopulations of afferent fibres responding to DAMGO were examined using waveform analysis to identify single units from within the whole mesenteric nerve bundles. One population was CCK-sensitive (15/15 fibres) and the other was a subpopulation of mechanosensitive afferents that responded to distension (17/28). 5-HT-sensitive afferents did not respond to DAMGO (0/11). We conclude that specific subpopulations of mesenteric afferents respond to mu- and possibly delta- but not kappa-receptor agonists. This sensitivity to opioids may contribute to the antinociceptive property of vagal afferents.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2000

5-HT(3) and histamine H(1) receptors mediate afferent nerve sensitivity to intestinal anaphylaxis in rats.

BACKGROUND & AIMS: The mechanisms underlying brain stem activation during antigen challenge have not been resolved. Our aim was to characterize afferent nerve responses to intestinal anaphylaxis and determine the mediators involved in afferent activation. METHODS: Mesenteric afferent discharge was recorded electrophysiologically after intestinal anaphylaxis in anesthetized rats previously sensitized to chicken egg albumin (EA). RESULTS: Mesenteric afferent nerve discharge increased approximately 1 minute after luminal antigen but not bovine serum albumin (P < 0.001, EA vs. bovine serum albumin). Subsequent administration of antigen had no effect, but systemic EA evoked a marked increase in afferent discharge (P < 0. 05). Afferent responses were unrelated to intestinal motor activity, and the response to luminal antigen was attenuated by luminal anesthetic (1% lidocaine). The 5-HT(3)-receptor antagonist alosetron (30 microg. kg(-1)) and the histamine H(1)-receptor antagonist pyrilamine (5 mg. kg(-1)) markedly attenuated the response to luminal antigen; pretreatment with doxantrazole attenuated responses to both luminal and systemic antigen. CONCLUSIONS: 5-HT(3) and histamine, released from mast cells after intestinal anaphylaxis, stimulate mesenteric afferents via 5-HT(3) and histamine H(1) receptors. Information on intestinal immune status is rapidly relayed to the central nervous system and may play a role in neural reflexes and behavioral responses following activation of the immune system.

Anaphylaxis↗
PubMed2000

Prostaglandin EP receptor subtypes have distinctive effects on jejunal afferent sensitivity in the rat.

BACKGROUND & AIMS: Tissue levels of prostaglandin (PG) E(2) are increased in inflammatory bowel disease. The aim of this study was to characterize the potential for PGE(2) to modulate the sensitivity of intestinal afferents. METHODS: Electrophysiologic recordings were obtained from mesenteric afferent supplying the proximal jejunum of anesthetized rats. RESULTS: PGE(2) evoked a dose-dependent increase in afferent nerve discharge that was biphasic at higher doses. An early response phase, peak discharge frequency of 165.4 +/- 14.3 imp. s(-1), and duration of 20.2 +/- 1.2 seconds were followed by a plateau of elevated afferent nerve discharge lasting several minutes. The increase in afferent nerve discharge was accompanied by an increase in intestinal pressure of 4.4 +/- 0.5 cm H(2)O. Nifedipine (1 mg. kg(-1)) attenuated the pressure response and the plateau phase of afferent discharge, whereas the early component remained unchanged. In contrast, the early phase, but not the plateau phase, was reduced by luminal anesthetic. Experiments with EP receptor-selective agonists and the EP(1)-receptor antagonist AH-6809 (500 microg. kg(-1)) implicate EP1 receptors in the early response, and EP(2) receptors appeared to play a major role in the plateau phase. CONCLUSIONS: PGE(2) has complex actions on intestinal afferent discharge acting by direct and indirect mechanisms and mediated by different receptor subtypes.

Animals↗