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D Grundy

Publications and source records attributed to D Grundy.

At least 55 records · Page 3Linked to original sources
PubMed2000

The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat.

BACKGROUND: Noxious intestinal distention elicits a reflex depressor response in the sodium pentobarbitone anaesthetised rat, which can be used as an index of visceral nociception. 5-HT(3) receptor antagonists inhibit this reflex. Repeated colorectal distention (CRD) induces Fos like immunoreactivity (Fos-LI) in the rat spinal cord. AIMS: To examine the effect of the 5-HT(3) receptor antagonist alosetron on the depressor response to CRD, and on Fos expression in the lumbosacral spinal cord. METHODS: Male rats were anaesthetised with sodium pentobarbitone, and mean arterial blood pressure monitored during repeated colorectal balloon inflation before and after treatment with alosetron or saline. Rats anaesthetised with urethane and treated with alosetron or saline underwent a repeated CRD paradigm, after which the lumbosacral spinal cord was removed and processed for visualisation of Fos-LI. RESULTS: CRD elicited reproducible, volume dependent falls in arterial blood pressure, and repeated distention-effect curves were constructed. Alosetron (1-100 microg/kg intravenously) inhibited the depressor response to CRD in a dose related manner, with an ID(50) value of 3.0 microg/kg. Following repeated CRD, numbers of Fos-LI neurones were significantly increased to 1246 (total in 12 sections at 120 microm intervals from L6 to S1) compared with 49 in sham distended animals. Pretreatment with alosetron (100 microg/kg) significantly reduced numbers of Fos-LI neurones to 479.8. CONCLUSION: The 5-HT(3) receptor antagonist alosetron inhibits the depressor response to CRD in a potent and dose dependent manner. It also inhibits CRD induced Fos-LI in the spinal cord. These results suggest that 5-HT(3) receptors are involved in visceral nociceptive transmission, perhaps located on primary afferent or spinal neurones.

Animals↗
PubMed2000

Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans.

Duodenal lipid causes gastric relaxation, CCK secretion, and nausea. Vasopressin has been implicated in motion sickness-related nausea. We hypothesized that increasing doses of lipid enhance gastric relaxation and CCK-vasopressin secretion, resulting in a dose-related exacerbation of nausea. Nine healthy subjects received isotonic saline or lipid (1, 2, or 3 kcal/min, L1, L2, L3) duodenally. Changes in gastric volume, sensations, and plasma hormone levels were assessed during infusions and isobaric gastric distensions. Lipid infusions increased gastric volume, plasma CCK (but not vasopressin) levels, and gastric compliance during distensions, compared with saline. Plasma CCK levels were related to the dose of lipid administered [CCK levels at 30 min (pmol/l), saline: 1.1 +/- 0.2, L1: 1.8 +/- 0.2, L2: 3.0 +/- 0.2, L3: 4.3 +/- 0.6]. During distensions, nausea increased in intensity with increasing doses of lipid [score (where 0 is no sensation and 100 is strongest sensation), saline: 7 +/- 4, L1: 19 +/- 7, L2: 44 +/- 7, L3: 66 +/- 8]; however, no further rise in plasma CCK occurred. Because neither lipid nor distension alone induced significant nausea, we conclude that the interaction between these stimuli together with a modulation by CCK is responsible for the effects observed. Vasopressin is not involved in lipid- and distension-induced nausea.

Adult↗
PubMed1999

Sensitization of visceral afferents to bradykinin in rat jejunum in vitro.

1. We have investigated the effects of inflammatory mediators on visceral afferent discharge and afferent responses to bradykinin (BK) in rat jejunum using a novel in vitro technique. 2. Prostaglandin E2 (1 microM) augmented responses to BK without affecting basal firing, while histamine (100 microM) and adenosine (100 microM) activated basal discharge and enhanced BK responses. In contrast, 5-HT (100 microM) increased basal discharge without influencing responses to BK. 3. Afferent discharge induced by histamine was inhibited by both H1 (pyrilamine) and H3 (thioperamide) but not H2 (ranitidine) receptor antagonists at 10 microM. In contrast, sensitization to BK induced by histamine was inhibited by ranitidine (10 microM). 4. Afferent discharge induced by adenosine was blocked by the A1 receptor antagonist DPCPX (10 microM) but remained unaffected by A2A receptor blockade with ZM241385 (10 microM). In contrast, sensitization of BK responses by adenosine was unaffected by both antagonists. Basal discharge and BK-induced responses were unaffected by the A3 receptor agonist IB-MECA (1 microM). While involvement of A2B receptors is not excluded, adenosine may activate afferent discharge through A1 receptors, while sensitization to BK could involve a receptor other than A1, A2A or A3, possibly the A2B receptor. 5. Inhibition of cyclo-oxygenase with naproxen (10 microM) prevented sensitization after histamine but not adenosine. 6. Sensitization was mimicked by dibutyryl cAMP. This occurred without changes in basal firing and was unaffected by naproxen. 7. In conclusion, afferent discharge induced by BK is augmented by histamine, adenosine and PGE2, but not by 5-HT. Evidence suggests that sensitization involves separate mechanisms from afferent activation. Sensitization may be mediated by increases in cAMP following direct activation by mediators at the nerve terminal or through indirect pathways such as the release of prostaglandins.

Adenosine↗
PubMed1999

Excitatory effect of P2X receptor activation on mesenteric afferent nerves in the anaesthetised rat.

1. We examined the effects of P2X purinoceptor agonists and P2 purinoceptor antagonists on mesenteric afferent nerves supplying the jejunum in the pentobarbitone sodium-anaesthetised rat. 2. ATP (0. 01-10 mg kg-1, i.a.) and alpha,beta-methylene-ATP (1-30 microg kg-1, i.a.) each induced dose-dependent increases in afferent nerve discharge and intrajejunal pressure. The effect on afferent nerves comprised an early (< 2 s after administration) intense burst of activity followed by a later increase (> 2 s after administration), less pronounced in comparison, which coincided with elevated intrajejunal pressure. 3. Pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (20 mg kg-1, i.v.) and suramin (80 mg kg-1, i.v. ) each antagonised both the early and later increases in afferent nerve discharge elicited by alpha,beta-methylene-ATP (30 microg kg-1, i.a.). 4. Co-administration of omega-conotoxin MVIIA and omega-conotoxin SVIB (each at 25 microg kg-1, i.v.), or treatment with the selective 5-HT3 receptor antagonist alosetron (30 microg kg-1, i.v.), did not affect the rapid burst of afferent nerve activity elicited by alpha,beta-methylene-ATP (30 microg kg-1, i.a.). However, toxin treatment did attenuate the elevations in intrajejunal pressure and the corresponding later phases of evoked afferent discharge, while alosetron inhibited basal afferent nerve activity. 5. In summary, ATP and alpha,beta-methylene-ATP each evoke excitation of mesenteric afferent nerves in the anaesthetised rat. We propose that the early increase in mesenteric afferent nerve activity represents a direct effect on the nerve ending, mediated by P2X receptors, whereas the later increase reflects activation of mechanosensitive fibres secondary to elevated intrajejunal pressure.

Action Potentials↗
PubMed1999

Plasticity in the mesenteric afferent response to cisplatin following vagotomy in the rat.

The aim of this study was to investigate the actions of the cytotoxic drug cisplatin on populations of mesenteric afferents supplying the rat jejunum. Extracellular whole mesenteric nerve discharge was monitored and the activity of individual single afferent units determined using waveform discriminator software. Baseline whole nerve discharge was 21.5 +/- 3.8 impulses s(-1). Nerve discharge began to increase approximately 10 min after cisplatin administration, reached a plateau around 30 min, and remained elevated at 60 min (35.3 +/- 5.7 impulses s(-1), p < 0.01). Granisetron reversed the increase in nerve activity indicating that the response to cisplatin was mediated by the release of endogenous 5-HT acting on 5-HT3 receptors. Single afferent units, selected by waveform analysis on the basis of their response to exogenous 5-HT, showed a similar time course of activation following cisplatin. In contrast, the discharge frequency of afferent units that were insensitive to 5-HT was unaffected by cisplatin or granisetron. The sensitivity of mesenteric afferent bundles to exogenous 5-HT was absent in chronically vagotomized animals. However, cisplatin elicited an increase in nerve discharge in vagotomized animals that was not different from control (34.6 +/- 8.9 impulses s(-1)) but this increase was unaffected by treatment with granisetron. Thus, after vagotomy there is a switch from 5-HT3 mediated activation of vagal afferents to a 5-HT3-independent activation of non-vagal (possibly splanchnic) afferents. Since this later mechanism of activation is absent in control animals, it appears that there is plasticity in the gastrointestinal afferent sensitivity to cisplatin.

Animals↗
PubMed1999

The role of prostaglandins in the bradykinin-induced activation of serosal afferents of the rat jejunum in vitro.

1. This study was performed to elucidate the role of prostaglandins in the action of bradykinin on serosal afferent neurones supplying the rat jejunum. Extracellular recordings of multi-unit activity were made from serosal afferents in isolation, using a novel in vitro preparation. The discharge of single afferents within the multi-unit recording was monitored using waveform discrimination software. 2. All afferents tested were both mechano- and capsaicin sensitive. Application of bradykinin elicited increases in whole nerve discharge in a concentration-dependent manner. The agonist potency estimate (EC50) was 0.62 +/- 0.12 microM and is consistent with an interaction at the B2 receptor subtype. 3. The stimulatory effect of bradykinin on serosal afferents was antagonized by a specific antagonist of the B2 receptor, HOE140. In contrast, a selective B1 receptor antagonist, [des-Arg10]HOE140, had no effect. The IC50 estimate obtained for HOE140 was 1.6 nM and again consistent with an interaction at B2 receptors. 4. The response to a submaximal concentration of bradykinin (1 microM) was significantly reduced to 24.4 +/- 54.9 % of control following blockade of cyclo-oxygenase activity with naproxen (10 microM). The addition of 1 microM prostaglandin E2 (PGE2), in the presence of naproxen, had no direct effect on afferent activity, but fully restored the response to bradykinin in 15 single afferents. 5. In summary, bradykinin stimulates serosal afferents by a direct action on kinin B2 receptors that are present on serosal afferent terminals. The response to bradykinin is dependent on the presence of prostaglandins, particularly PGE2. We suggest that bradykinin has a self-sensitizing action, whereby it stimulates the release of PGE2, which in turn sensitizes the endings of serosal afferent neurones responsive to bradykinin.

Animals↗
PubMed1998

Serotonin and cholecystokinin activate different populations of rat mesenteric vagal afferents.

This electrophysiological study was performed to elucidate the interactions of serotonin (5-hydroxytryptamine, 5-HT) and cholecystokinin (CCK) on mesenteric afferents supplying the rat jejunum. 5-HT and CCK produced characteristic responses in multi-unit recordings of mesenteric afferents. Waveform analysis to extract single units from the whole nerve recording identified populations of single afferents that were sensitive to either 5-HT or CCK, but not both. Furthermore, devazepide (0.5 mg/kg) completely abolished the response to CCK without altering the response to 5-HT while granisetron (0.5 mg/kg) abolished the response to 5-HT with no effect on the response to CCK. These results suggest that there are discrete, noninteractive populations of jejunal afferents that possess either 5-HT3 or CCK-A receptors but not both.

Animals↗
PubMed1998

The role of endogenous cholecystokinin in the sensory transduction of luminal nutrient signals in the rat jejunum.

Some vagal afferent fibres are exquisitely sensitive to exogenous administration of cholecystokinin (CCK) but their sensitivity to endogenous CCK released by luminal stimuli has not been demonstrated directly, although implied from reflex and behavioural studies. We have therefore utilised electrophysiological techniques to record afferent discharge in mesenteric nerve bundles supplying the rat jejunum in response to luminal application of casein acid hydrolysate (CAH). CAH stimulated whole nerve afferent discharge in both in vivo and in vitro preparations (P < 0.01) while single unit analysis revealed that fibres sensitive to CAH also responded to exogenous CCK. The responses to both CCK and CAH were abolished by the CCKA antagonist devazepide. This study therefore supports the hypothesis that a functional relationship exists between CCK-containing enteroendocrine cells and the afferent fibres whose terminals lie within close proximity.

Afferent Pathways↗
PubMed1998

Sensitivity to 5-hydroxytryptamine in different afferent subpopulations within mesenteric nerves supplying the rat jejunum.

1. This study was performed to elucidate the type of afferents that mediate the multiple actions of 5-hydroxytryptamine (5-HT) on mesenteric nerve discharge. Electrophysiological recordings were made from mesenteric afferents innervating the mid-jejunum of the urethane-anaesthetized rat. The discharge of single nerves within the whole nerve recording was monitored using waveform discrimination software. 2. Afferents responded to 5-HT in one of two ways: a short latency, transient excitation mediated by 5-HT3 receptors, or a delayed onset, more prolonged effect that was 5-HT2A receptor mediated. Afferents showing the 5-HT3-mediated response did not respond to luminal distension but were sensitive to intraluminal hydrochloric acid (150 mM) in twenty-eight of twenty-nine experiments. In eight experiments, the 5-HT3-mediated response was reversibly abolished by a 2 min exposure to intraluminal application of local anaesthetic (2 % Xylocaine). 3. Mechanosensitive afferents which responded to distension (< 10 cmH2O) did not show a 5-HT3-mediated response (P = 0.92, n = 14), and maintained this mechanosensitivity after luminal anaesthesia. Mechanosensitive afferents did show a secondary response to 5-HT that was significantly attenuated by atropine (100-200 microg kg-1), whereas hexamethonium (8 mg kg-1) had no effect. 4. In animals whose vagal afferent contribution to their mesenteric nerves had been eliminated by chronic truncal vagotomy, the 5-HT3-mediated response was absent in thirty-six of thirty-six nerve bundles. In contrast, mechanosensitivity to distension and the secondary response to 5-HT could still be evoked. 5. These results suggest that 5-HT stimulates mesenteric afferents by a direct action on 5-HT3 receptors that are present on vagal mucosal afferent terminals. The mucosal afferent response to luminal acid, however, was unaffected by treatment with granisetron (0.5 mg kg-1) indicating that endogenous 5-HT from enterochromaffin cells is not essential for transduction of this luminal signal. In contrast, mechanosensitivity in non-vagal afferents was modulated by 5-HT following an intestinal motor response which was influenced by cholinergic tone.

Action Potentials↗
PubMed1998

Direct and indirect actions of 5-hydroxytryptamine on the discharge of mesenteric afferent fibres innervating the rat jejunum.

1. This study was performed to elucidate the actions of 5-hydroxytryptamine (5-HT) on mesenteric afferent discharge and to determine the receptor-mechanisms responsible for these effects. The activity of mesenteric afferents innervating the mid-jejunum of urethane-anaesthetized rats was recorded with extracellular microelectrodes. The discharge of single nerves within the whole nerve recording was monitored using waveform discriminator software. 2. The intravenous injection of 5-HT produced a complex pattern of afferent activation with two distinct components which could be distinguished both in terms of the response characteristics and the receptors involved. Initially, in 64% of nerve bundles, there was a brief (2.0 +/- 0.1 s) but intense activation of afferent discharge with peak afferent firing increasing with incremental doses of 5-HT. The discharge frequency in seventeen single units from these bundles during the initial response to 10 micrograms 5-HT was 13.0 +/- 1.8 impulses s-1 from a baseline discharge of 1.0 +/- 0.1 impulses s-1. 3. This initial response was mimicked by the 5-HT3 receptor agonist, 2-methyl-5-HT, whereas 5-methoxytryptamine (5-MEOT, 10-100 micrograms) had no comparable effect. Similarly, the initial 4. 5-HT response was completely abolished by the 5-HT3 receptor antagonist, granisetron (0.5 mg kg-1). 5-HT also evoked, in approximately 35% of nerve bundles, a delayed response that single unit analysis showed to be mediated by an entirely different population of afferents from those activated during the initial response. This secondary response to 5-HT was characterized by a more prolonged (> 30 s) but less intense period of afferent activity which was coincident with an increase in intrajejunal pressure, and was mimicked by 5-MEOT (10-100 micrograms). The secondary response to 5-HT and the response to 5-MEOT were significantly attenuated by the 5-HT2A receptor antagonist, ketanserin (0.5 mg kg-1), which had no effect on the initial response. The initial response to 5-HT was unaffected by the L-type calcium channel inhibitor nifedipine (1 mg kg-1) or the N-type calcium channel inhibitor omega-conotoxin GVIA (25 micrograms kg-1). However, the secondary response to 5-HT was significantly reduced after treatment with nifedipine. 5. These results demonstrate that 5-HT activates different populations of afferent fibres innervating the rat jejunum. One population of afferents is activated directly via stimulation of 5-HT3 receptors, while another population responds to 5-HT with a time course consistent with secondary activation of mechanosensitive afferents following 5-HT2A-mediated contractile activity.

Action Potentials↗
PubMed1998

Characterization of adenosine receptors evoking excitation of mesenteric afferents in the rat.

We examined the effects of adenosine receptor agonists and antagonists on the discharge of mesenteric afferent nerves supplying the jejunum in pentobarbitone sodium-anaesthetized rats. Adenosine (0.03-10 mg kg(-1), i.v.), NECA (0.3-300 microg kg(-1), i.v.) and the A1 receptor agonist, GR79236 (0.3-1000 microg kg(-1), i.v.), each induced dose-dependent increases in afferent nerve activity and intrajejunal pressure, hypotension and bradycardia. The A1 receptor antagonist, DPCPX (3 mg kg(-1), i.v.), antagonized all the effects of GR79236 but only the haemodynamic effects of adenosine and NECA. The A2A receptor antagonist, ZM241385 (3 mg kg(-1), i.v.), antagonized the hypotensive effect of NECA but none of the effects of GR79236. The A2A receptor agonist, CGS21680 (0.3-300 microg kg(-1), i.v.), and the A3 receptor agonist, IB-MECA (0.3-300 microg kg(-1), i.v.), each induced only a dose-dependent hypotension. Subsequent administration of adenosine (3 mg kg(-1), i.v.) induced increases in afferent nerve activity and intrajejunal pressure and bradycardia. ZM241385 (3 mg kg(-1), i.v.) antagonized the hypotensive effect of CGS21680 but not the effects of adenosine. Bethanechol (300 microg kg(-1), i.v.) evoked increases in afferent nerve activity and intrajejunal pressure, hypotension and bradycardia. However, adenosine (3 mg kg(-1), i.v.) evoked greater increases in afferent nerve activity than bethanechol despite inducing smaller increases in intrajejunal pressure. In summary, A1 and A2B and/or A2B-like receptors evoke adenosine-induced increases in mesenteric afferent nerve activity and intrajejunal pressure in the anaesthetized rat. Furthermore, elevations in intrajejunal pressure do not wholly account for adenosine-evoked excitation of mesenteric afferent nerves.

Adenosine↗
PubMed1998

Spinal cord injury management in Salisbury: the history of the Duke of Cornwall Spinal Treatment Centre.

One point remains paramount in our minds and that is, in order to achieve the goals we have set, we need vigorously to ensure that Spinal Units continue to be seen as the only facilities competent to provide for the diverse needs of spinal cord injured patients. We at the Duke of Cornwall Spinal Treatment Centre are fortunate in having a first class, expanding facility and have the tireless cooperation of both our staff and those of the other departments in Salisbury. We recognize also that we can play a leading role in the treatment of patients, not only from the Southwest, but, where and when appropriate, from further afield.

Electric Stimulation↗
PubMed1998

Presence of putative neurotransmitters in the myenteric plexus of the gastrointestinal tract and in the musculature of the urinary bladder of the ferret.

The innervation of the musculature in the ferret stomach, ileum, colon and urinary bladder was investigated using immunohistochemistry in noncolchicin-treated tissues. In the gastrointestinal tract two main subpopulations of myenteric neurones were found: cholinergic neurones expressing choline acetyltransferase (ChAT), which made up 68, 67 and 67% of the neurones in the stomach, ileum and colon, respectively, and nitrergic neurones containing nitric oxide synthase and NADPH-diaphorase (stomach: 23%, ileum: 21%, colon: 26%). In the stomach, cholinergic neurones expressed substance P (SP, 2% of all neurones), dopamine-beta-hydroxylase (DBH, 19%) but not tyrosine hydroxylase (TH) or vasoactive intestinal polypeptide (VIP), while nitrergic neurones contained VIP and neuropeptide Y (NPY). TH- but not DBH-immunoreactivity was observed in 4% of gastric neurones. Intense immunoreactivity in the musculature suggests that part of ChAT/SP- and NOS/NPY/VIP-positive neurones function as motorneurones. In the ileum, a high number (32%) of DBH-positive neurones was demonstrated. About half of the SP-positive neurones in the ileum also contained calcitonin gene-related peptide (CGRP). In the urinary bladder, only few intramural ganglia were observed. The smooth muscle was densely innervated by ChAT, NPY and DBH immunoreactive fibres. The data showed that the innervation of the ferret viscera exhibited similarities but also differences as compared with other mammalian species. Some of the chemical coding of myenteric neurones is remarkably similar to that observed in other mammals.

Animals↗
PubMed1998

Histamine sensitivity of mesenteric afferent nerves in the rat jejunum.

The concept of functional interaction between mast cells and intestinal afferents is gaining support. We have therefore characterized the action of histamine on jejunal afferent discharge in the anesthetized rat. Whole nerve mesenteric afferent discharge was recorded in conjunction with intestinal pressure in response to a range of histamine agonists and antagonists. Histamine at 2, 4, and 8 micromol/kg (iv) evoked a dose-dependent biphasic increase in afferent discharge together with a biphasic rise in intestinal pressure. However, these two events were mediated independently, since nifedipine (1 mg/kg) substantially reduced the intestinal pressure increase but not the afferent discharge. These responses were completely inhibited by pyrilamine (5 mg/kg) but unaffected by ranitidine (5 mg/kg) or thioperamide (2 mg/kg). Neither the selective H2 receptor agonist dimaprit nor the selective H3 receptor agonist R-alpha-methylhistamine caused any modulation of afferent discharge. We conclude that histamine stimulates an H1 receptor-mediated increase in mesenteric afferent discharge that is independent of intestinal motor events. This suggests that histamine potentially acts as a mediator in mast cell-to-afferent nerve communication in the small intestine.

Afferent Pathways↗