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ABSTRACT: Environmental enrichment (EE) has a beneficial effect on rodent behaviour, neuronal plasticity and brain function. Although it may also improve stress coping, it is not known whether EE influences the brain response to an external (psychological) stressor such as water avoidance stress (WAS) or an internal (systemic) stressor such as gastrointestinal inflammation. This study hence explored whether EE modifies WAS-induced activation of the mouse corticolimbic system and whether this stress response is altered by gastritis or colitis. Male C67BL/6N mice were housed under standard or enriched environment for 9 weeks, after which they were subjected to a 1-week treatment with oral iodoacetamide to induce gastritis or oral dextran sulfate sodium to induce colitis. Following exposure to WAS the expression of c-Fos, a marker of neuronal activation, was measured by immunocytochemistry. EE aggravated experimentally induced colitis, but not gastritis, as shown by an increase in the disease activity score and the colonic myeloperoxidase content. In the brain, EE enhanced the WAS-induced activation of the dentate gyrus and unmasked an inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression within this part of the hippocampus. Conversely, EE inhibited the WAS-evoked activation of the central amygdala and prevented the inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression in this region. EE, in addition, blunted the WAS-induced activation of the infralimbic cortex and attenuated the inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression in this area. These data reveal that EE has a region-specific effect on stress-induced c-Fos expression in the corticolimbic system, which is likely to improve stress resilience. The response of the prefrontal cortex - amygdala - hippocampus circuitry to psychological stress is also modified by the systemic stress of gut inflammation, and this interaction between external and internal stressors is modulated by the housing environment.
PLoS ONE 01/2013; 8(1):e54811. · 4.09 Impact Factor
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Peter Holzer
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ABSTRACT: The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double-blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.
Current pharmaceutical design 06/2012; · 4.41 Impact Factor
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ABSTRACT: Ethologically based animal models are widely used; however, results from different laboratories vary significantly which may partly be due to the lack of standardization. Here, we examined the effects of circadian rhythm, lighting condition and mouse strain (BALB/c and C57BL/6, known to differ in measures of avoidance and risk assessment behavior) on two well established behavioral tests in mice: the Elevated Plus Maze (EPM) and the Open Field (OF). Parameters from both paradigms are commonly used as indices of anxiety-like behavior. BALB/c mice and C57BL/6 mice were independently tested in the morning and at night, in regular laboratory lighting and in the dark. We developed a novel method based on infrared lighting from below, coupled to respective video-tracking equipment, which facilitates standard testing of behavior interference-free in complete darkness. The two mouse strains differed in anxiety-related variables for the EPM in the dark, and for the OF in regular laboratory lighting. Moreover, BALB/c displayed greater anxiety-like behavior than C57BL/6 in the OF but less anxiety-like behavior than C57BL/6 in the EPM. Lighting condition has a major influence on both behavioral tests and this to a considerably larger extent than circadian rhythm. In addition, the lighting condition interacts strongly with the genetic background, producing discriminative differences in the anxiety-related variables depending on mouse strain and lighting condition. These results challenge the comparability of not sufficiently standardized tests of anxiety-like behavior and emphasize the need for controlling environmental variables in behavioral phenotyping.
Behavioural brain research 03/2011; 218(1):99-105. · 3.22 Impact Factor
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ABSTRACT: Peptide YY (PYY) and neuropeptide Y (NPY) are involved in regulating gut and brain function. Because gastrointestinal inflammation is known to enhance anxiety, we explored whether experimental colitis interacts with genetic deletion (knockout) of PYY and NPY to alter emotional-affective behaviour.
Male and female wild-type, NPY (NPY(-/-) ), PYY (PYY(-/-) ) and NPY(-/-) ; PYY(-/-) double knockout mice were studied in the absence and presence of mild colitis induced by ingestion of dextran sulphate sodium (2%) in drinking water. Anxiety-like behaviour was tested on the elevated plus maze and open field, and depression-like behaviour assessed by the forced swim test.
In the absence of colitis, anxiety-like behaviour was increased by deletion of NPY but not PYY in a test- and sex-dependent manner, while depression-like behaviour was enhanced in NPY(-/-) and PYY(-/-) mice of either sex. The severity of DSS-induced colitis, assessed by colonic myeloperoxidase content, was attenuated in NPY(-/-) but not PYY(-/-) mice. Colitis modified anxiety- and depression-related behaviour in a sex-, genotype- and test-related manner, and knockout experiments indicated that NPY and PYY were involved in some of these behavioural effects of colitis.
These data demonstrate sex-dependent roles of NPY and PYY in regulation of anxiety- and depression-like behaviour in the absence and presence of colitis. Like NPY, the gut hormone PYY has the potential to attenuate depression-like behaviour but does not share the ability of NPY to reduce anxiety-like behaviour.
British Journal of Pharmacology 03/2011; 163(6):1302-14. · 4.41 Impact Factor
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ABSTRACT: Immune challenge by bacterial lipopolysaccharide (LPS) causes short-term behavioral changes indicative of depression. The present study sought to explore whether LPS is able to induce long-term changes in depression-related behavior and whether such an effect depends on mouse strain and social context. LPS (0.83 mg/kg) or vehicle was administered intraperitoneally to female CD1 and C57BL/6 mice that were housed singly or in groups of 4. Depression-like behavior was assessed with the forced swim test (FST) 1 and 28 days post-treatment. Group-housed CD1 mice exhibited depression-like behavior 1 day post-LPS, an effect that leveled off during the subsequent 28 days, while the behavior of singly housed CD1 mice was little affected. In contrast, singly housed C57BL/6 mice responded to LPS with an increase in depression-like behavior that was maintained for 4 weeks post-treatment and confirmed by the sucrose preference test. Group-housed C57BL/6 mice likewise displayed an increased depression-like behavior 4 weeks post-treatment. The behavioral changes induced by LPS in C57BL/6 mice were associated with a particularly pronounced rise of interleukin-6 in blood plasma within 1 day post-treatment and with changes in the dynamics of the corticosterone response to the FST. The current data demonstrate that immune challenge with LPS is able to induce prolonged depression-like behavior, an effect that depends on genetic background (strain). The discovery of an experimental model of long-term depression-like behavior after acute immune challenge is of relevance to the analysis of the epigenetic and pathophysiologic mechanisms of immune system-related affective disorders.
PLoS ONE 01/2011; 6(6):e20719. · 4.09 Impact Factor
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Peter Holzer
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ABSTRACT: Several of the 28 mammalian transient receptor potential (TRP) channel subunits are expressed throughout the alimentary canal where they play important roles in taste, chemo- and mechanosensation, thermoregulation, pain and hyperalgesia, mucosal function and homeostasis, control of motility by neurons, interstitial cells of Cajal and muscle cells, and vascular function. While the implications of some TRP channels, notably TRPA1, TRPC4, TRPM5, TRPM6, TRPM7, TRPV1, TRPV4, and TRPV6, have been investigated in much detail, the understanding of other TRP channels in their relevance to digestive function lags behind. The polymodal chemo- and mechanosensory function of TRPA1, TRPM5, TRPV1 and TRPV4 is particularly relevant to the alimentary canal whose digestive and absorptive function depends on the surveillance and integration of many chemical and physical stimuli. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 appear to be essential for the absorption of Ca(2+) and Mg(2+), respectively, while TRPM7 appears to contribute to the pacemaker activity of the interstitial cells of Cajal, and TRPC4 transduces smooth muscle contraction evoked by muscarinic acetylcholine receptor activation. The implication of some TRP channels in pathological processes has raised enormous interest in exploiting them as a therapeutic target. This is particularly true for TRPV1, TRPV4 and TRPA1, which may be targeted for the treatment of several conditions of chronic abdominal pain. Consequently, blockers of these TRP channels have been developed, and their clinical usefulness has yet to be established.
Current pharmaceutical biotechnology 11/2010; 12(1):24-34. · 3.40 Impact Factor
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Peter Holzer
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ABSTRACT: The therapeutic action of opioid analgesics is compromised by peripheral adverse effects, among which constipation is the most disabling as laxatives often fail to provide satisfactory relief. This review highlights recent advances in the specific control of opioid-induced constipation by opioid receptor antagonists with limited systemic bioavailability or a peripherally restricted site of action.
The specific management of opioid-induced bowel dysfunction is currently based on three drug entities: oral alvimopan for the shortening of postoperative ileus associated with opioid-induced pain control after bowel resection, subcutaneous methylnaltrexone for the reduction of opioid-induced constipation in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the treatment of noncancer and cancer pain. All three drug entities have been shown to attenuate opioid-induced motor stasis in the gut with a favorable adverse effect profile, while the analgesic effect of opioids remains unabated.
The availability of opioid receptor antagonists with restricted access to the central nervous system provides a novel opportunity to specifically control opioid-induced constipation and other peripheral adverse effects of opioid analgesics. Further studies are needed to evaluate the long-term efficacy, safety and cost-effectiveness of this approach.
Current opinion in anaesthesiology 10/2010; 23(5):616-22.
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ABSTRACT: Transient receptor potential ankyrin 1 (TRPA1) channels are expressed by primary afferent neurones and activated by irritant chemicals including allyl isothiocyanate (AITC). Here we investigated whether intracolonic AITC causes afferent input to the spinal cord and whether this response is modified by mild colitis, morphine or a TRPA1 channel blocker.
One hour after intracolonic administration of AITC to female mice, afferent signalling was visualized by expression of c-Fos in laminae I-II(o) of the spinal dorsal horn at sacral segment S1. Mild colitis was induced by dextran sulphate sodium (DSS) added to drinking water for 1 week.
Relative to vehicle, AITC (2%) increased expression of c-Fos in the spinal cord. Following induction of mild colitis by DSS (2%), spinal c-Fos responses to AITC, but not vehicle, were augmented by 41%. Colonic inflammation was present (increased myeloperoxidase content and disease activity score), whereas colonic histology, locomotion, feeding and drinking remained unchanged. Morphine (10 mg.kg(-1)) or the TRPA1 channel blocker HC-030031 (300 mg.kg(-1)) inhibited the spinal c-Fos response to AITC, in control and DSS-pretreated animals, whereas the response to intracolonic capsaicin (5%) was blocked by morphine but not HC-030031.
Activation of colonic TRPA1 channels is signalled to the spinal cord. Mild colitis enhanced this afferent input that, as it is sensitive to morphine, is most likely of a chemonociceptive nature. As several irritant chemicals can be present in chyme, TRPA1 channels may mediate several gastrointestinal pain conditions.
British Journal of Pharmacology 07/2010; 160(6):1430-42. · 4.41 Impact Factor
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P Holzer
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ABSTRACT: Acidosis in the gastrointestinal tract can be both a physiological and pathological condition. While gastric acid serves digestion and protection from pathogens, pathological acidosis is associated with defective acid containment, inflammation and ischaemia. The pH in the oesophagus, stomach and intestine is surveyed by an elaborate network of acid-sensing mechanisms to maintain homeostasis. Deviations from physiological values of extracellular pH (7.4) are monitored by multiple acid sensors expressed by epithelial cells and sensory neurones. Protons evoke multiple currents in primary afferent neurones, which are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential (TRP) vanilloid-1 (TRPV1) ion channels have been most thoroughly studied. ASICs survey moderate decreases in extracellular pH whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6. Other molecular acid sensors comprise TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), epithelial Na(+) channels, two-pore domain K(+) (K₂(P)) channels, ionotropic purinoceptors (P2X), inward rectifier K(+) channels, voltage-activated K(+) channels, L-type Ca²(+) channels and acid-sensitive G-protein-coupled receptors. Most of these acid sensors are expressed by primary sensory neurones, although to different degrees and in various combinations. As upregulation and overactivity of acid sensors appear to contribute to various forms of chronic inflammation and pain, acid-sensitive ion channels and receptors are also considered as targets for novel therapeutics.
Acta Physiologica 04/2010; 201(1):63-75. · 3.09 Impact Factor
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ABSTRACT: Neuropeptide Y participates in the acute behavioural responses to immune challenge, since Y2 receptor knockout (Y2⁻/⁻) mice are particularly sensitive to the short-term anxiogenic-like effect of bacterial lipopolysaccharide. The present exploratory study addressed the involvement of Y2 and Y4 receptors in the long-term behavioural responses to immune challenge. A single intraperitoneal injection of lipopolysaccharide (0.83 mg/kg) to control mice did not affect open field behaviour 3 h post-treatment but enhanced anxiety-like behaviour in Y2⁻/⁻ as well as Y4⁻/⁻ mice. Four weeks post-treatment this behavioural effect of lipopolysaccharide persisted in Y4⁻/⁻ mice but had gone in Y2⁻/⁻ mice. Depression-related behaviour in the forced swim test was enhanced 1 day post-lipopolysaccharide in control and Y2⁻/⁻ mice, but not in Y4⁻/⁻ mice. Four weeks post-treatment, the depressogenic-like effect of lipopolysaccharide had waned in control mice, persisted in Y2⁻/⁻ mice and was first observed in Y4⁻/⁻ mice. In summary, knockout of Y2 and/or Y4 receptors unmasks the ability of a single lipopolysaccharide injection to cause a delayed and prolonged increase in anxiety- and/or depression-like behaviour. These findings suggest that neuropeptide Y acting via Y2 and Y4 receptors prevents the development of long-term anxiety- and depression-like behaviour caused by acute immune challenge.
Journal of Psychopharmacology 11/2009; 24(10):1551-60. · 3.04 Impact Factor
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ABSTRACT: As the use of the 5-HT(3) receptor antagonist alosetron (GlaxoSmithKline) and the 5-HT(4) receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated.
Phenobarbital-anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance.
Intravenous alosetron (0.03-0.3 mg.kg(-1)) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15-20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5-HT(3) receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3-1.0 mg.kg(-1)) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon.
Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment-associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open.
British Journal of Pharmacology 09/2009; 158(5):1210-26. · 4.41 Impact Factor
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Peter Holzer
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ABSTRACT: Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal mu-, kappa- and delta-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, beta-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.
Regulatory Peptides 05/2009; 155(1-3):11-7. · 2.11 Impact Factor
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ABSTRACT: Peptide YY (PYY) and neuropeptide Y (NPY) have been proposed to participate in the control of energy homeostasis. Since these activities show circadian variations, we explored the circadian pattern of locomotor, exploratory and ingestive behaviour in male and/or female mice with disrupted genes for PYY (PYY-/-), NPY (NPY-/-) as well as PYY plus NPY (PYY+NPY-/-). The effect of bacterial lipopolysaccharide (LPS, 0.1 mg/kg intraperitoneally) on these behaviours was also examined. The animals were housed singly in cages fitted with sensors for water and food intake and two infrared frames for recording ambulation and rearing under a 12 h light/dark cycle for 4 days. Locomotor and exploratory behaviour was decreased in female NPY-/- as well as male and female PYY+NPY-/- mice during the photo- and scotophase, and in male PYY-/- mice during the scotophase. Significant decreases in water and food intake were seen in female NPY-/- as well as male and female PYY+NPY-/- mice during the photophase. The effect of LPS to attenuate ingestive behaviour during the light and/or dark phase was most pronounced in PYY-/- and NPY-/- mice. These findings attest to a circadian cycle- and gender-related role of NPY and PYY in the control of behaviours that balance energy intake and energy expenditure. Both peptides stimulate feeding and drinking to balance the energy demand that they generate by enforcing the circadian pattern of locomotion and exploration. In addition, they counteract the anorectic and antidipsogenic effects of immune challenge.
Behavioural brain research 05/2009; 203(1):97-107. · 3.22 Impact Factor
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ABSTRACT: Lafutidine is a histamine H2 receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge.
Adult rats were treated with vehicle, lafutidine (10 - 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry.
Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H2 receptor antagonist cimetidine had similar but weaker effects.
These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H2 receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.
BMC Gastroenterology 02/2009; 9:40. · 2.42 Impact Factor
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Peter Holzer
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ABSTRACT: Acidosis is a noxious condition associated with inflammation, ischaemia or defective acid containment. As a consequence, acid sensing has evolved as an important property of afferent neurons with unmyelinated and thinly myelinated nerve fibres. Protons evoke multiple currents in primary afferent neurons, which are carried by several acid-sensitive ion channels. Among these, acid-sensing ion channels (ASICs) and transient receptor potential (TRP) vanilloid-1 (TRPV1) ion channels have been most thoroughly studied. ASICs survey moderate decreases in extracellular pH, whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6. Two-pore-domain K(+) (K(2P)) channels are differentially regulated by small deviations of extra- or intracellular pH from physiological levels. Other acid-sensitive channels include TRPV4, TRPC4, TRPC5, TRPP2 (PKD2L1), ionotropic purinoceptors (P2X), inward rectifier K(+) channels, voltage-activated K(+) channels, L-type Ca(2+) channels, hyperpolarization-activated cyclic nucleotide gated channels, gap junction channels, and Cl(-) channels. In addition, acid-sensitive G protein coupled receptors have also been identified. Most of these molecular acid sensors are expressed by primary sensory neurons, although to different degrees and in various combinations. Emerging evidence indicates that many of the acid-sensitive ion channels and receptors play a role in acid sensing, acid-induced pain and acid-evoked feedback regulation of homeostatic reactions. The existence and apparent redundancy of multiple pH surveillance systems attests to the concept that acid-base regulation is a vital issue for cell and tissue homeostasis. Since upregulation and overactivity of acid sensors appear to contribute to various forms of chronic pain, acid-sensitive ion channels and receptors are considered as targets for novel analgesic drugs. This approach will only be successful if the pathological implications of acid sensors can be differentiated pharmacologically from their physiological function.
Handbook of experimental pharmacology 02/2009;
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ABSTRACT: BACKGROUND: Inflammation is commonly associated with hyperalgesia. Ideally, this change should abate once inflammation is resolved, but this is not necessarily the case because phenotypic changes in the tissue can persist, as appears to be the case in post-infectious irritable bowel syndrome. Basically, all primary afferent neurons supplying the gut can be sensitized in response to pro-inflammatory mediators, and the mechanisms whereby hypersensitivity is initiated and maintained are, thus, of prime therapeutic interest. EXPERIMENTAL AND CLINICAL FINDINGS: There is a multitude of molecular nocisensors that can be responsible for the hypersensitivity of afferent neurons. These entities include: (i) receptors and sensors at the peripheral terminals of afferent neurons that are relevant to stimulus transduction, (ii) ion channels that govern the excitability and conduction properties of afferent neurons, and (iii) transmitters and transmitter receptors that mediate communication between primary afferents and second-order neurons in the spinal cord and brainstem. Persistent increases in the sensory gain may result from changes in the expression of transmitters, receptors or ion channels; changes in the subunit composition and biophysical properties of receptors and ion channels; or changes in the structure, connectivity and survival of afferent neurons. Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons and whose number and function are altered in abdominal hypersensitivity. CONCLUSION: Emerging targets of therapeutic relevance include distinct members of the transient receptor potential (TRP) channel family (TRPV1, TRPV4, TRPA1), acid-sensing ion channels, protease-activated receptors, corticotropin-releasing factor receptors and sensory neuron-specific sodium channels.
Digestive Diseases 01/2009; 27 Suppl 1:24-30. · 2.37 Impact Factor
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ABSTRACT: Abstract
Background
Lafutidine is a histamine H<sub>2 </sub>receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge.
Methods
Adult rats were treated with vehicle, lafutidine (10 – 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry.
Results
Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H<sub>2 </sub>receptor antagonist cimetidine had similar but weaker effects.
Conclusion
These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H<sub>2 </sub>receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.
BMC Gastroenterology. 01/2009;
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ABSTRACT: Opioid analgesics are the cornerstone of pain management for moderate-to-severe cancer pain and, increasingly, chronic noncancer pain. Despite proven analgesic efficacy, the use of opioids is commonly associated with frequently dose-limiting constipation that seriously impacts on patients' quality of life. Agents currently used to manage opioid-induced constipation (OIC), such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective. A significant need therefore exists for more effective treatment options. A novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids involves the coadministration of a mu-opioid receptor antagonist with negligible systemic availability, such as oral naloxone. Combination therapy with prolonged-release (PR) oxycodone plus PR naloxone has been shown to provide effective analgesia while preventing or reducing constipation. The current article highlights this novel strategy in its potential to significantly improve the quality of life of patients suffering from chronic pain, affording patients the benefit of full analgesia, without the burden of OIC.
Pharmacology 11/2008; 83(1):10-7. · 1.79 Impact Factor
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Peter Holzer
Gut 08/2008; 57(7):882-4. · 10.11 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY) is involved in the regulation of emotional behavior, and there is indirect evidence for a role of NPY in the cerebral responses to peripheral immune challenge. Since the NPY receptors involved in these reactions are not known, we investigated the effect of Escherichia coli lipopolysaccharide (LPS) on emotional, locomotor and social behavior, body temperature and circulating corticosterone in female Y2 (Y2-/-) and Y4 (Y4-/-) receptor knockout mice. LPS (0.1mg/kg injected IP 2.5h before testing) increased rectal temperature in control and Y4-/- mice to a larger degree than in Y2-/- animals. Both Y2-/- and Y4-/- mice exhibited reduced anxiety-related and depression-like behavior in the open field, elevated plus-maze and tail suspension test, respectively. While depression-like behavior was not changed by LPS, anxiety-related behavior was enhanced by LPS in Y2-/-, but not control and Y4-/- animals. Y2-/- mice were also particularly susceptible to the effect of LPS to attenuate locomotor behavior and social interaction with another mouse. The corticosterone response to LPS was blunted in Y2-/- mice which presented elevated levels of circulating corticosterone following vehicle treatment. These data show that Y2-/- mice are particularly sensitive to the effects of LPS-evoked immune stress to attenuate locomotion and social interaction and to increase anxiety-like behavior, while the LPS-induced rise of temperature and circulating corticosterone is suppressed by Y2 receptor knockout. Our observations attest to an important role of endogenous NPY acting via Y2 receptors in the cerebral response to peripheral immune challenge.
Neuropharmacology 08/2008; 55(1):117-26. · 4.81 Impact Factor
