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- Evidence for the involvement of peripheral β-adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats. [Journal Article, Research Support, Non-U.S. Gov't]
- Braz J Med Biol Res 2013 Sep; 46(9):735-8.
Dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) delay liquid gastric emptying (GE) in rats. We evaluated adrenergic participation in this phenomenon in a study in male Wistar rats (250-300 g) pretreated subcutaneously with guanethidine (GUA), 100 mg·kg-1·day-1, or vehicle (V) for 2 days before experimental treatments. Other groups of animals were pretreated intravenously (iv) 15 min before treatment with V, prazosin (PRA; 1 mg/kg), yohimbine (YOH; 3 mg/kg), or propranolol (PRO; 4 mg/kg), or with intracerebroventricular (icv) administration of 25 µg PRO or V. The groups were treated iv with saline or with 240 µmol/kg Dp, AA, or At. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. %GR (mean ± SE, n=8) indicated that GUA abolished the effect of Dp (GUA vs V=31.7 ± 1.6 vs 47.1 ± 2.3%) and of At (33.2 ± 2.3 vs 54.7 ± 3.6%) on GE and significantly reduced the effect of AA (48.1 ± 3.2 vs 67.2 ± 3.1%). PRA and YOH did not modify the effect of the drugs. %GR (mean ± SE, n=8) indicated that iv, but not icv, PRO abolished the effect of Dp (PRO vs V=29.1 ± 1.7 vs 46.9 ± 2.7%) and At (30.5 ± 1.7 vs 49 ± 3.2%) and significantly reduced the effect of AA (48.4 ± 2.6 vs 59.5 ± 3.1%). These data suggest activation of peripheral β-adrenoceptors in the delayed GE induced by phenylpyrazolone derivatives.
- Tetrodotoxin-dependent effects of menthol on mouse gastric motor function. [Journal Article, Research Support, Non-U.S. Gov't]
- Eur J Pharmacol 2013 Oct 15; 718(1-3):131-7.
Menthol, the main active constituent of peppermint oil, exerts gut spasmolytic effects, although its mechanism of action remains unclear. We investigated the effects of menthol on gastric emptying and spontaneous- or evoked- mechanical activity of whole murine stomach. Gastric emptying was calculated after i.p. administration of menthol (50mg/Kg). Responses induced by menthol on gastric intraluminal pressure and evoked-cholinergic contractions were analyzed in vitro. Menthol decreased the gastric emptying rate. In vitro, menthol (0.3-30 mM) produced a concentration-dependent relaxation of whole stomach, that was significantly reduced by tetrodotoxin or ω-conotoxin GVIA. The gastric relaxant responses were not affected by Nω-nitro-L-arginine methyl ester, inhibitor of nitric oxide-synthase, apamin or [Lys1,Pro2,5,Arg3,4,Tyr6] vasoactive intestinal peptide (VIP)(7-28), a VIP receptor antagonist, but they were significantly antagonized by atropine or guanethidine, a blocker of adrenergic neurotransmission. The joint application of atropine and guanethidine did not produce any additive effects on menthol effects. Phentolamine, an α-adrenoceptor antagonist, but not propranolol, a β-adrenoceptor antagonist, significantly reduced menthol responses and the contemporary administration of both adrenergic antagonists did not produce additive effects. Menthol (1-100 μM) produced a reduction of the electrically-evoked cholinergic contractions, which was prevented by guanethidine. Menthol did not affect the contractions induced by carbachol. In conclusion, menthol in mouse, is able to reduce the rate of gastric emptying and to relax the stomach in vitro. The latter effect appears due, almost in part, to neural mechanisms, with involvement of α-adrenoceptors leading to reduction of tonic ongoing release of acetylcholine.
- Properties of submucosal venules in the rat distal colon. [Journal Article, Research Support, Non-U.S. Gov't]
- Br J Pharmacol 2013 Nov; 170(5):968-77.
Venules within the gut wall may have intrinsic mechanisms for maintaining the circulation even upon the intestinal wall distension. We aimed to explore spontaneous and nerve-mediated contractile activity of colonic venules.Changes in the diameter of submucosal venules of the rat distal colon were measured using video microscopy. The innervation of the microvasculature was investigated using fluorescence immunohistochemistry.Submucosal venules exhibited spontaneous constrictions that were abolished by blockers of L-type Ca(2+) channels (1 μM nicardipine), Ca(2+)-ATPase (10 μM cyclopiazonic acid), IP3 receptor (100 μM 2-APB), Ca(2+)-activated Cl(-) channels (100 μM DIDS) or store-operated Ca(2+) entry channels (10 μM SKF96365). Transmural nerve stimulation (TNS at 10 Hz) induced a phasic venular constriction that was blocked by phentolamine (1 μM, α-adrenoceptor antagonist) or sympathetic nerve depletion using guanethidine (10 μM). Stimulation of primary afferent nerves with TNS (at 20 Hz) or capsaicin (100 nM) evoked a sustained venular dilatation that was attenuated by calcitonin gene-related peptide (CGRP) 8-37 (2 μM), a CGRP receptor antagonist. Immunohistochemistry revealed sympathetic and primary afferent nerves running along submucosal venules.Submucosal venules of the rat distal colon exhibit spontaneous constrictions that appear to primarily rely on Ca(2+) release from sarcoplasmic reticulum and subsequent opening of Ca(2+)-activated Cl(-) channels that trigger Ca(2+) influx through L-type Ca(2+) channels. Venular contractility is modulated by sympathetic as well as CGRP-containing primary afferent nerves, suggesting that submucosal venules may play an active role in regulating the microcirculation of the digestive tract.
- Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization. [Journal Article, Research Support, Non-U.S. Gov't]
- Nat Commun 2013.:2316.
During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver-brain-adipose axis activation. Moreover, the blockade of glycogenolysis [corrected] through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver-brain-adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions.
- Diffused and Sustained Inhibitory Effects of Intestinal Electrical Stimulation on Intestinal Motility Mediated via Sympathetic Pathway. [JOURNAL ARTICLE]
- Neuromodulation 2013 Aug 7.
The aims were to investigate the energy-dose response effect of intestinal electrical stimulation (IES) on small bowel motility, to compare the effect of forward and backward IES, and to explore the possibility of using intermittent IES and mechanism of IES on intestinal motility.Five dogs implanted with a duodenal cannula and one pair of intestinal serosal electrodes were studied in five sessions: 1) energy-dose response study; 2) forward IES; 3) backward IES; 4) intermittent IES vs. continuous IES; 5) administration of guanethidine. The contractile activity and tonic pressure of the small intestine were recorded. The duration of sustained effect after turning off IES was manually calculated.1) IES with long pulse energy dose dependently inhibited contractile activity and tonic pressure of the small intestine (p < 0.001). 2) The duration of sustained inhibitory effect of IES on the small intestine depended on the energy of IES delivered (p < 0.001). 3) The potency of the inhibitory effect was the same between forward and backward IES. 4) The efficacy of intermittent IES was the same as continuous IES in inhibiting motility of the small intestine. 5) Guanethidine blocked the inhibitory effect of IES on intestinal motility.IES with long pulses inhibits small intestinal motility; the effect is energy-dose dependent, diffused, and sustained. Intermittent IES has the same efficacy as the continuous IES in inhibiting small intestinal motility. Forward and backward IES have similar inhibitory effects on small bowel motility. This IES-induced inhibitory effect is mediated via the sympathetic pathway.
- Acute and chronic effects of desvenlafaxine on gastrointestinal transit and motility in dogs. [Journal Article]
- Neurogastroenterol Motil 2013 Oct; 25(10):824-e637.
Antidepressants are commonly used for treating functional gastrointestinal (GI) diseases. However, little is known whether antidepressants improve or impair GI motility. This study aimed at exploring possible effects of a serotonin-norepinephrine reuptake inhibitor, desvenlafaxine succinate (DVS), on GI motility in dogs.Eight dogs chronically implanted with a duodenal cannula and a colon cannula were used in the study. Experiments were performed to assess the effects of a single dose of DVS (50 or 100 mg) and DVS given 50 mg once a day for 2 weeks on gastric emptying of solid, small intestinal transit, and colon transit and contractions.(1) DVS significantly delayed gastric emptying of solid at a single dose of 50 or 100 mg. The inhibitory effect on gastric emptying was completely blocked by guanethidine (an adrenergic blocking agent). (2) DVS at a single dose of 50 or 100 mg accelerated colon transit, but showed no effects on small bowel transit. (3) DVS at a single dose of 50 mg enhanced colon contractions and guanethidine blocked the effect. (4) Surprisingly, DVS given at 50 mg once daily for 2 weeks did not alter gastric emptying, small bowel transit or colon transit.Acute DVS delays gastric emptying of solid and enhances the contractions of the colon, which may be mediated via the sympathetic mechanism. Acute DVS promotes the transit of the colon but not the small intestine. However, chronic administration of DVS does not seem to alter GI motility.
- Physiological regulation of pro-inflammatory cytokines expression in rat cardiovascular tissues by sympathetic nervous system and angiotensin II. [Journal Article, Research Support, Non-U.S. Gov't]
- Gen Physiol Biophys 2013 Dec; 32(4):569-75.
Pro-inflammatory cytokines regulation by sympathetic nervous system (SNS) and angiotensin II (ANG II) was widely described in cardiovascular system, but the role of such neuro-humoral interaction needs further investigation in this context. We tested SNS-ANG II interaction on IL-6 and TNF-α mRNA expression in left ventricle and aorta from normotensive rats by sympathectomy with guanethidine and blockade of the ANG II AT1 receptors (AT1R) antagonist with losartan. mRNA synthesis of IL-6 and TNF-α were performed by Q-RT-PCR. In the left ventricle, IL-6 mRNA increased by 63% (p < 0.01) after sympathectomy, still unchanged after losartan treatment and decreased by 38% (p < 0.05) after combined treatment. TNF-α mRNA decreased by 44% (p < 0.01), only after combined treatment. In the aorta, IL-6 mRNA increased equally by 65% (p < 0.05) after sympathectomy or losartan treatment. TNF-α mRNA decreased by 28, 41, and 42% (p < 0.05) after sympathectomy, losartan and combined treatments, respectively. Our data suggest that ANG II stimulates directly (via AT1R) and indirectly (via SNS) IL-6 mRNA synthesis in left ventricle and aorta and TNF-α mRNA in left ventricle. ANG II seems unable to influence directly TNF-α mRNA synthesis in the aorta but can stimulate this cytokine via SNS. The results are relevant to prevent or reduce proinflammatory cytokines overexpression seen in cardiovascular diseases.
- Sympathetic fiber sprouting in inflamed joints and adjacent skin contributes to pain-related behavior in arthritis. [Journal Article, Research Support, Non-U.S. Gov't]
- J Neurosci 2013 Jun 12; 33(24):10066-74.
Although chronic pain is the most common symptom of arthritis, relatively little is known about the mechanisms driving it. Recently, a sprouting of autonomic sympathetic fibers into the upper dermis of the skin, an area that is normally devoid of them, was found in the skin following chronic inflammation of the rat hindpaw. While this sprouting only occurred when signs of joint and bone damage were present, it remained to be clarified whether it was a consequence of the chronic inflammation of the skin or of the arthritis and whether it also occurred in the joint. In the present study, we used a model of arthritis in which complete Freund's adjuvant (CFA) was injected into the rat ankle joint. At 4 weeks following CFA treatment, there was an increase in sympathetic and peptidergic fiber density in the ankle joint synovium. We also observed a sympathetic, but not peptidergic, fiber sprouting in the skin over the joint, which may be a consequence of the increased levels of mature nerve growth factor levels in skin, as revealed by Western blot analysis. The pharmacological suppression of sympathetic fiber function with systemic guanethidine significantly decreased the pain-related behavior associated with arthritis. Guanethidine completely suppressed the heat hyperalgesia and attenuated mechanical and cold hypersensitivity. These results suggest that transmitters released from the sprouted sympathetic fibers in the synovial membrane and upper dermis contribute to the pain-related behavior associated with arthritis. Blocking the sympathetic fiber sprouting may provide a novel therapeutic approach to alleviate pain in arthritis.
- Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome. [Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, U.S. Gov't, Non-P.H.S.]
- Pain 2013 Aug; 154(8):1224-36.
In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. Our approach involved catecholamine depletion using 6-hydroxydopamine or, alternatively, guanethidine, to explore sympathetic contributions. Both agents substantially reduced nociceptive sensitization and selectively reduced the production of IL-6 in skin. Antagonism of IL-6 signaling using TB-2-081 also reduced sensitization in this model. Experiments using a rat keratinocyte cell line demonstrated relatively high levels of β2-adrenergic receptor (β2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1β, tumor necrosis factor (TNF)-α, or nerve growth factor. Stimulation of the cells also promoted phosphorylation of the mitogen-activated protein kinases P38, extracellular signal-regulated kinase, and c-Jun amino-terminal kinase. Based on these in vitro results, we returned to animal testing and observed that the selective β2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective β2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1β, TNF-α, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates β2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization.
- Interventions for treating pain and disability in adults with complex regional pain syndrome. [Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't, Review]
- Cochrane Database Syst Rev 2013.:CD009416.
There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used.To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS).We identified Cochrane reviews and non-Cochrane reviews through a systematic search of the following databases: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Ovid MEDLINE, Ovid EMBASE, CINAHL, LILACS and PEDro. We included non-Cochrane systematic reviews where they contained evidence not covered by identified Cochrane reviews. The methodological quality of reviews was assessed using the AMSTAR tool.We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes of quality of life, emotional well being and participants' ratings of satisfaction or improvement. Only evidence arising from randomised controlled trials was considered. We used the GRADE system to assess the quality of evidence.We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable.There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events.There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control.For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn.There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult.