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PubMed2003

Injury of mouse brain mitochondria induced by cigarette smoke extract and effect of vitamin C on it in vitro.

OBJECTIVE: To investigate the toxicity of cigarette smoke extract (CSE) and nicotine on mouse brain mitochondria as well as the protective effect of vitamin C in vitro. METHOD: Mouse brain mitochondria in vitro was incubated with CSE or nicotine in the absence or presence of vitamin C for 60 minutes, and the changes of mitochondrial function and structure were measured. RESULTS: CSE inhibited mitochondrial ATPase and cytochrome C oxidase activities in a dose-dependent manner. However, no significant changes in the peroxidation indices were observed when mitochondrial respiratory enzymes activity was inhibited, and protection of mitochondria from CSE-induced injury by vitamin C was not displayed in vitro. The effect of CSE on mouse brain mitochondria swelling response to calcium stimulation was dependent on calcium concentrations. CSE inhibited swelling of mitochondria at 6.5 mumol/L Ca2+, but promoted swelling response at 250 mumol/L Ca2+. Nicotine, the major component of cigarette smoke, showed no significant damage in mouse brain mitochondria in vitro. The CSE treatment induced mitochondrial inner membrane damage and vacuolization of the matrix, whereas the outer mitochondrial membrane appeared to be preserved. CONCLUSION: The toxic effect of CSE on brain mitochondria may be due to its direct action on enzymatic activity rather than through oxygen free radical injury. Nicotine is not the responsible component for the toxicity of CSE to brain mitochondria.

Adenosine Triphosphatases↗
PubMed1991

Chronic intracochlear electrical stimulation induces selective survival of spiral ganglion neurons in neonatally deafened cats.

Ten newborn kittens were deafened by systemic administration of neomycin sulfate. Profound hearing losses were documented by ABR and FFR (500 Hz) testing. At 9-17 weeks of age, the young deafened cats were unilaterally implanted with a multichannel scala tympani electrode. Six of the animals were chronically stimulated at 6 dB above electrically evoked ABR thresholds for 1 h/day for periods of 1 month or 3 months. Stimuli were charge-balanced biphasic pulses (200 microseconds/phase, 30 pps.) The remaining 4 cats underwent identical deafening and implantation schedules but were not stimulated. Results indicate that administration of neomycin in neonatal cats induced degeneration of hair cells and spiral ganglion cell loss that was bilaterally symmetrical between the two cochleas of each individual animal, although there was variation between animals in the severity of the ototoxic drug effect. In animals receiving passive (unstimulated) implants, morphometric analysis of spiral ganglion cell density showed no significant difference in ganglion cell survival between the implanted cochleas and the contralateral control ears. In contrast, animals that were chronically stimulated for 3 months showed significantly better neuronal survival in implanted and stimulated cochleas as compared to contralateral deafened control ears. The induced conservation of spiral ganglion neurons was observed consistently within the basal cochlear region near the stimulating electrodes. In more apical regions there was no significant difference between the stimulated and control cochleas. The mechanisms underlying this selective conservation of spiral ganglion neurons induced by chronic intracochlear electrical stimulation are uncertain. Since no comparable chronic stimulation studies have been conducted in adults, it is not known whether similar conservation effects could be induced in mature animals.

Animals↗
PubMed1991

Pharmacological control of muscular activity in the sea urchin larva--IV. Effects of monoamines and adenosine.

1. The muscular activity of the sea urchin pluteus is affected by catecholamines. alpha-Agonists in high concentrations bring about a strong, temporary, stimulation. 2. The stimulation by beta-agonists tends to be masked by different mechanisms. 3. Serotonin brings about a strong stimulation of long duration, even at 10(-7) M. It reactivates larvae where the activity has declined after exposure to catecholamines. A dopamine-effect at 10(-5)-5 x 10(-6) M is similar to that of serotonin. The effect of adenosine is similar to that of dc-c-AMP. 4. The action of the alpha- and beta-agonists and adenosine appears to involve an increased respectively excessive Ca2(+)-influx, directly or indirectly mediated by c-AMP. 5. It is suggested that a strong Ca2(+)-influx induces an outflux of K+ leading to hyperpolarization. Serotonin may decrease the K(+)-outflux.

Adenosine↗
PubMed1999

Nicotine-induced hyperlocomotion is not modified by the estrous cycle, ovariectomy and estradiol replacement at physiological level.

The present study was designed to investigate whether nicotine's effect on locomotion might be modulated by the ovarian hormone at physiological level. Rats at normal cycling of estrus and diestrus were selected for the comparison of nicotine-induced hyperlocomotion based on the document that the release of striatal dopamine was greatest at the estrous phase. Ovariectomized rats primed with or without estrogen at physiological level were also selected for comparison. Increase in spontaneous locomotion by nicotine was statistically significant at the doses of 0.15 and 0.3 mg/kg (p < 0.001). The stimulating effect of nicotine led the locomotor response to almost the same magnitude in all hormonal groups studied. Nicotine-induced hyperlocomotion appeared to be mediated by central nicotinic receptor because it was blocked by mecamylamine (0.5 and 1.0 mg/kg, i.p.). Also it was blocked by haloperidol (0.04 and 0.08 mg/kg, i.p.) indicating the involvement of dopaminergic neurotransmission. These effects were similar in all groups regardless of the estrous cycle or ovariectomy. The observed data provided behavioral evidence to suggest that the effect of nicotine on locomotion-related dopaminergic neurons might not be modified by the physiological action of estrogen.

Animals↗
PubMed2003

Recovery of high blood pressure after chronic lesions of the commissural NTS in SHR.

Acute electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) reduce blood pressure (BP) in SHR but not in normotensive Wistar-Kyoto and Wistar rats and abolish the pressor response to intravenous injection of potassium cyanide. We investigated the chronic effect of commNTS lesions on mean arterial pressure (MAP), and on baroreceptor and chemoreceptor reflex responses in SHR. The contribution of the sympathetic nervous system and the hormones vasopressin and angiotensin II to maintenance of BP in lesioned SHR was also investigated. MAP fell to normotensive levels the day after lesioning the commNTS but returned to the hypertensive level 9 days later. The reflex tachycardia evoked by sodium nitroprusside remained attenuated for 10 days after commNTS lesions but became enhanced 30 days after commNTS lesions. The pressor component of the chemoreflex elicited by potassium cyanide remained blocked for 30 days after lesions. Vasopressin antagonist or ACE blocker did not change MAP in sham or commNTS-lesioned SHR. Ganglionic blockade with hexamethonium elicited similar reductions in MAP in sham and commNTS-lesioned SHR. Results demonstrated that commNTS lesions in SHR produce a transient fall in BP and a long-lasting inhibition of the pressor response of the chemoreflex. Therefore, the blockade of the pressor response to peripheral chemoreflex activation is not sufficient to chronically reduce MAP in SHR. In the chronic absence of the commNTS, other subnuclei of the NTS or other brain stem nuclei may reorganize to replace the function of commNTS neurons, restoring sympathetic activity and high BP in SHR.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

Neurons dissociated from rat myenteric plexus retain differentiated properties when grown in cell culture. III. Synaptic interactions and modulatory effects of neurotransmitter candidates.

We have used intracellular recordings to study synaptic interactions between myenteric neurons grown in dissociated cell culture. Intracellular stimulation of individual myenteric neurons caused several types of synaptic effects in nearby neurons: fast excitatory synaptic potentials mediated by nicotinic acetylcholine receptors; slow, non-cholinergic synaptic potentials; dual transmission having both fast cholinergic and slow non-cholinergic components and inhibition of spontaneously occurring fast nicotinic synaptic potentials. Fast nicotinic synaptic potentials were elicited by about 40% of neurons tested and often occurred spontaneously. The fast synaptic potentials were similar to those that have been studied in other autonomic neurons with respect to their estimated reversal potential and their sensitivity to cholinergic antagonists. The amplitudes of the fast synaptic potentials declined if evoked at frequencies greater than 0.5 Hz. Potentiation of the fast synaptic potentials was observed following high-frequency stimulation of presynaptic neurons. Several transmitter candidates modulated fast cholinergic transmission. Substance P and vasoactive intestinal peptide promoted nicotinic transmission by causing increased amplitudes of evoked and spontaneous fast synaptic potentials and an increased frequency of spontaneous synaptic potentials. gamma-Aminobutyrate and [Met]enkephalin both caused decreased amplitudes and frequency of nicotinic synaptic potentials. Serotonin depressed synaptic potentials in some neurons while enhancing them or having no effect in others. Slow, non-cholinergic, synaptic potentials were elicited by about 10% of neurons tested. These synaptic effects lasted 15-300s, caused depolarizations of 3-15 mv and were accompanied by increased neuronal input resistance. The transmitter(s) causing these slow synaptic potentials has not yet been identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Evidence of nonadrenergic, noncholinergic contraction in rat urinary bladder by 1,1-dimethylphenylpiperazinium stimulation in vivo.

Nonadrenergic, noncholinergic (NANC) contraction has been demonstrated in animal urinary bladder. However, the exact nature of the NANC innervation is still unclear. 1,1-Dimethylphenylpiperazinium (DMPP), which generates action potentials in the cell body of the postganglionic neuron and causes neurotransmitter release (both acetylcholine and noradrenaline), was given intravenously (0.1-0.7 mg/kg) to 3-month-old female Wistar rats under anesthesia (n = 20). Intravesical pressure, heart rate and blood pressure of the rats were monitored on Gould polygraph. Monophasic dose-dependent contractile response was observed upon administration of DMPP in 12 of 20 rats. After total adrenergic and cholinergic blockade with atropine, guanethidine, phentolamine and propranolol, the contractile response was reduced, not completely, in the animals. At the dose of 0.7 mg/kg, the contraction was reduced to about 48% of the original response. The study provides in vivo evidence for NANC contraction in the rat urinary bladder, moreover, the neurotransmitter is released from the postganglionic neurons.

Action Potentials↗
PubMed1995

Neurogenic vasodilation in canine uterine and iliac arteries.

OBJECTIVE: To investigate neurogenic control of uterine and iliac arterial tone with reference to nerve-derived nitric oxide. DESIGN: Mechanisms underlying the response to perivascular nerve stimulation were studied under alpha-adrenoceptor blockade. METHODS: Mechanical responses to nerve stimulation by nicotine were isometrically recorded in isolated canine uterine and iliac arterial strips. Nitric oxide synthase was stained immunohistochemically. RESULTS: The arterial strips responded to nicotine mainly with a contraction, which was reversed to a relaxation by prazosin. The responses were abolished by hexamethonium. The relaxation was not influenced by timolol and atropine but was suppressed by NG-nitro-L-arginine, a nitric oxide synthase inhibitor; the inhibition was reversed by L-arginine. Internal iliac arterial strips also responded to nicotine with a relaxation under prazosin treatment, the magnitude of which was appreciably less than that in the uterine artery. Histochemical study demonstrated that perivascular nerve fibres exhibit nitric oxide synthase immunoreactivity. CONCLUSION: Canine uterine arteries are innervated by adrenergic, vasoconstrictor and nitroxidergic vasodilator nerves, and the neurogenic vasodilation is evidently more marked than that in other canine arteries, including the iliac artery.

Animals↗
PubMed1994

Muscarinic and nicotinic modulation of cortical acetylcholine release monitored by in vivo microdialysis in freely moving adult rats.

The aim of the present study was to investigate, using in vivo dialysis, the existence of muscarinic and nicotinic receptors controlling acetylcholine release in the cortex of freely behaving rats. Various muscarinic receptor antagonists, including the nonselective blocker atropine, and a variety of M2 drugs (AF-DX116, AF-DX384, AQ-RA 741) potently stimulated, in a concentration-dependent manner, the in vivo release of acetylcholine in the rat cortex. The effects of all these antagonists were long lasting. The nature of these putative muscarinic autoreceptors is likely of the pharmacologically defined M2 subtype on the basis of the high potency of the antagonists of the AF-DX series and the variability and shorter duration of action of the effects of the prototypic M1 blocker, pirenzepine. 4-DAMP, a purported M3 blocker, also potently stimulated in vivo cortical acetylcholine release, but this likely relates to its now established, rather limited selectivity for any given muscarinic receptor subtypes. Peripheral and central injections of nicotine also induced the in vivo release of acetylcholine in the rat cortex, albeit with a lower potency and shorter duration of action than muscarinic antagonists. Interestingly, the combination of a muscarinic antagonist, such as atropine, AF-DX 116, or AF-DX384, in the presence of nicotine, induced tremendous releases of cortical acetylcholine up to 8- to 10-fold over basal values. This is clearly more than a simply additive effect, and it reveals the great capacity of cortical cholinergic nerve terminals to synthesize and release acetylcholine. Optimal pharmacological manipulations of these putative muscarinic and nicotinic autoreceptors could thus be useful in disorders in which the activity of cholinergic inputs is decreased, such as in Alzheimer's disease.

Acetylcholine↗
PubMed1976

Life-span investigations for carcinogenicity of some immune-stimulating, immunodepressive and neurotropic substances in Sprague-Dawley-rats.

In a long-term trial in a total of 858 Sprague-Dawley-rats of both sexes the possible carcinogenicity of 12 substances was investigated. Complete Freunds' adjuvant which is among the immune-stimulating substances was found to decrease significantly the lifetime of the animals; whereas an increase in tumor incidences was not observed. Bacille Calmette-Guérin (BCG), human albumin, and vitamin-A-acid were neither carcinogenic, nor had they an influence on the survival times. Rabbit-antirat lymphocytic serum which is a well-known immunodepressive agent caused a significant decrease in survival times, it was not found to be carcinogenic. The known carcinogenic properties of cyclophosphamide were verified. The applied dose of this compound significantly reduced the mean survival times of the animals. Hydrocortisone and amethopterin were found to have no carcinogenic effects. Atropine, pilocarpine, nicotine, and phenyl-ethyl-barbituric acid (phenobarbital) which are known to have neurotropic effects were tested. Nicotine and phenobarbital were found to diminish the mean survival times. None of these neurotropic substances was found to be carcinogenic.

Animals↗
PubMed2004

Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2.

Early studies revealed that cigarette smoke promotes gastric cancer growth through the induction of cyclooxygenase-2 (COX-2). Nicotine, one of the active ingredients in cigarette smoke, has detrimental effects in the stomach. To date, there is no direct evidence to validate the effect of nicotine on gastric tumor growth and its carcinogenic mechanism(s). We therefore investigated whether nicotine could promote tumor growth and neovascularization in vivo, and the biological mechanism(s) in connection with the signaling cascade involving COX-2 and extracellular signal-regulated protein kinase (ERK). Athymic nude mice, with gastric cancer cells (AGS) orthotopically implanted into the gastric wall, treated with nicotine (50 or 200 microg/ml) in their drinking water for 3 months developed larger tumor areas than mice in the control group. Nicotine further increased proliferating cellular nuclear antigen (PCNA) staining and microvessel density by 70 and 30%, respectively, with concomitant activation of ERK phosphorylation, COX-2 and vascular endothelial growth factor (VEGF) expression in the tumors. Intraperitoneal administration of a selective COX-2 inhibitor (SC-236, 2 mg/kg) prevented the nicotine-induced tumor growth and neovascularization dose-dependently. Consistent with our animal model, an in vitro study also demonstrated that incubation with nicotine (50-200 microg/ml) for 5 h stimulated cell proliferation dose-dependently and increased COX-2 expression, prostaglandin E(2) (PGE(2)) and VEGF release, as well as activation of ERK phosphorylation. Pre-treatment with specific mitogen-activated protein kinase kinase (MEK) inhibitors (U0126 or PD98059) attenuated COX-2 expression and subsequent PGE(2) release by nicotine. Furthermore, the stimulatory action of nicotine on cancer cell growth and angiogenic factor VEGF production was suppressed by inhibitors of MEK (U0126) and COX-2 (SC-236). These findings reveal a direct promoting action of nicotine on the growth of gastric tumor and neovascularization through sequential activation of the ERK/COX-2/VEGF signaling pathway, which can be targeted for chemoprevention of gastric cancer, particularly in cigarette smokers.

Adenocarcinoma↗
PubMed2000

The development and expression of locomotor sensitization to nicotine in the presence of ibogaine.

Ibogaine is a naturally occurring psychoactive alkaloid with claimed efficacy in the treatment of certain drug addictions, including nicotine. It has been reported to be a non-competitive blocker of nicotinic receptors, with a potent inhibitory action on nicotinic acetylcholine receptor-mediated catecholamine release. We have investigated the effect of different doses of ibogaine on the development and expression of sensitization to the locomotor stimulant effect of nicotine in rats, a facilitatory process in which a history of exposure to nicotine results in enhanced locomotor activity when the same dose of nicotine is administered repeatedly. The effects were determined of co-administering ibogaine (0.0, 5.0 or 10 mg/kg i.p.) with nicotine (0.0 or 0.4 mg/kg s.c.) daily for 21 days. Dose-response curves for nicotine (0.04-0.8 mg/kg s.c.) were then determined in groups of 10 rats. There was clear sensitization of the locomotor activity produced by nicotine in photocell activity cages but co-administration of ibogaine with nicotine had no effect on the degree of sensitization. Ibogaine (5-20 mg/kg) itself did not influence locomotor activity and was also without effect on the expression of the sensitized response to 0.4 mg/kg of nicotine (n = 10). Thus, there was no evidence that ibogaine may retard or suppress sensitization to nicotine.

Animals↗
PubMed1988

Pharmacologic consequences of the vascular permeability of chromaffin cell transplants in CNS pain modulatory regions.

The transplantation of peripheral neural tissue into the CNS has been shown to alter blood-brain barrier (BBB) permeability to intravascularly injected proteins such as horseradish peroxidase. The pharmacological consequences of such BBB alterations following the transplantation of adrenal medullary tissue, isolated bovine chromaffin cell suspensions, or PC12 cell suspensions into the pain modulatory regions of the periaqueductal gray (PAG) or subarachnoid space of the lumbar spinal cord were studied using agents that normally do or do not readily pass the BBB. The injection of nicotine in animals with adrenal medullary or chromaffin cell transplants produces potent analgesia, most likely due to the stimulated release of opioid peptides and catecholamines from the transplanted cells. This analgesia could be blocked by nicotinic antagonist mecamylamine, which normally passes the BBB, but not by nicotinic antagonist hexamethonium, which normally does not readily pass the BBB. Furthermore, quaternary nicotinic agonists tetramethylammonium and 1,1-dimethyl-phenyl-piperazinium had no effect on pain sensitivity in animals with adrenal medullary implants. The Met-enkephalin peptide analog, D-Ala-Met-enkephalinamide, which normally does not alter pain sensitivity when injected systemically due to limited penetration to the CNS, produced analgesia in animals with adrenal medullary, bovine chromaffin cell, and PC12 cell implants in the PAG, but not in control gelfoam-implanted animals. This analgesia, as well as analgesia induced by nicotine, was completely blocked by naloxone pretreatment, but not by naloxone methobromide, a quaternary derivative of naloxone that does not normally pass the BBB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1971

Nicotinic stimulant action of some tolyl and xylyl analogues of 1,1-dimethyl-4-phenylpiperazinium (DMPP).

1. The nicotinic stimulant properties of DMPP have been compared with those of its ortho-, meta- and para-tolyl analogues, and its 2,6- and 3,5-xylyl analogues, on the blood pressure of the cat and on the semispinalis cervicis muscle of the chick.2. A single ortho-methyl group does not significantly change the nicotinic activity, but two such groups greatly reduce or abolish activity. Meta- or para-methyl substitution reduces activity, but does not abolish it.3. The effect on nicotinic activity of methyl substitution in the phenyl ring of DMPP closely parallels the effect of ring-methyl substitution in phenyl choline ether.4. Ortho-methyl substitution has been shown spectroscopically to alter markedly the spatial orientation of the phenyl ring of DMPP relative to the piperazine ring. The effect of these conformational changes on nicotinic activity is discussed in relation to a recent hypothesis concerning the conformation of acetylcholine required for interaction with nicotinic receptors.5. The compounds tested had no muscarinic activity on the isolated guinea-pig ileum.

Animals↗
PubMed2006

Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors.

In a series of studies carried out in different experimental models, we investigated the type(s) of lung afferents and mechanism(s) underlying the cigarette smoke-induced airway irritation and cough. In healthy non-smokers, the intensity of airway irritation and cough evoked by cigarette smoke was markedly reduced after premedication with hexamethonium. A similar pattern of responses was also triggered by inhalation of nicotine aerosol. These studies in human subjects suggested nicotine as the primary causative agent in cigarette smoke that evokes airway irritation. Indeed, single-fiber recording experiments performed in anesthetized dogs showed that both C-fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one puff of cigarette smoke, and the intensity of this stimulatory effect was related to the nicotine content in the cigarette and abolished by hexamethonium. To further study the direct effect of nicotine on these sensory nerves, we measured the change in intracellular calcium concentration ([Ca(2+)](i)) of pulmonary sensory neurons isolated from the nodose and jugular ganglia of adult rats. Our results showed that nicotine evoked an abrupt and transient increase in [Ca(2+)](i) in approximately 34% of the 522 neurons tested, and 1,1-dimethyl-4-phenylpiperazinium, a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a similar pattern of response as that of nicotine in these neurons. In conclusion, results of these studies show that nicotine exerts a direct stimulatory effect on vagal pulmonary sensory neurons. This stimulatory effect of nicotine is primarily responsible for the airway irritation and cough evoked by inhaled cigarette smoke, and is mediated through an activation of the NnAChRs.

Adult↗
PubMed1985

In vivo regulation of [3H]acetylcholine recognition sites in brain by nicotinic cholinergic drugs.

The in vivo regulation of [3H]acetylcholine [( 3H]ACh) recognition sites on nicotinic receptors in rat brain was examined by administering drugs that increase stimulation of nicotinic cholinergic receptors, either directly or indirectly. After 10 days of treatment with the cholinesterase inhibitor diisopropyl fluorophosphate, [3H]ACh binding in the cortex, thalamus, striatum, and hypothalamus was decreased. Scatchard analyses indicated that the decrease in binding in the cortex was due to a reduction in the apparent density of [3H]ACh recognition sites. In contrast, after repeated administration of nicotine (5-21 days), the number of [3H]ACh recognition sites was increased in the cortex, thalamus, striatum, and hypothalamus. Similar effects were observed in the cortex and thalamus following repeated administration of the nicotinic agonist cytisin. The nicotinic antagonists mecamylamine and dihydro-beta-erythroidine did not alter [3H]ACh binding following 10-14 days of administration. Further, concurrent treatment with these antagonists and nicotine did not prevent the nicotine-induced increase in these binding sites. The data indicate that [3H]ACh recognition sites on nicotinic receptors are subject to up- and down-regulation, and that repeated administration of nicotine results in a signal for up-regulation, probably through protracted desensitization at the recognition site.

Acetylcholine↗
PubMed1981

Two components from eye tissue that differentially stimulate the growth and development of ciliary ganglion neurons in cell culture.

Survival and development of chick ciliary ganglion neurons in vivo appear to depend on information from the embryonic eye structure that contains the postsynaptic targets of the neurons. We have tested embryonic eye extracts on ciliary ganglion neurons in dissociated cell culture for stimulation of growth and development. Control conditions were chosen that permitted the long term maintenance of the neurons in the absence of tissue extracts of conditioned medium. The conditions included coating the culture substratum with fibroblast material and increasing the K+ concentration in the culture medium to 25 mM. Neurons survived for at least 3 weeks in control conditions. Two major components were resolved in eye extracts that stimulated growth and development of the neurons above the basal levels obtained with control conditions. One component, with an apparent molecular weight of about 2 X 10(4) by gel filtration analysis, stimulated neuronal growth without increasing the levels of choline acetyltransferase activity per neuron. The second component, with an apparent molecular weight of about 5 X 10(4), increased development of choline acetyltransferase levels per neuron but had no effect on neuronal growth. Both components were effective in normal K+ as well as 25 mM K+. These components may represent mechanisms by which the postsynaptic target tissue acts in vivo to direct the growth and development of ciliary ganglion neurons.

Animals↗
PubMed2006

The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model.

BACKGROUND & AIMS: The recently proposed Inflammatory Reflex describes an interaction between the vagus nerve and peripheral macrophages, resulting in attenuation of proinflammatory cytokine release in response to systemic exposure to bacterial endotoxin. The purpose of this study was to determine whether a similar vagus/macrophage axis modulates the inflammatory responses in the colon in mice. METHODS: We assessed the Disease Activity Index (DAI), macroscopic and histologic damage, serum amyloid-P level, and myeloperoxidase activity in colitis induced by administration of dextran sodium sulfate (DSS) in healthy and vagotomized C57BL/6 and in mice deficient in macrophage-colony stimulating factor (M-CSF)-induced and in hapten-induced colitis. A pyloroplasty was performed in vagotomized mice. RESULTS: DAI, macroscopic and histologic scores, myeloperoxidase activity, levels of serum amyloid-P, and colonic tissue levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha were increased significantly in vagotomized mice 5 days post-DSS and 3 days after hapten-induced colitis compared with sham-operated mice that received DSS or the hapten. Pretreatment with nicotine significantly decreased each of these markers in vagotomized mice with DSS colitis, and all markers except DAI and IL-6 in sham-operated DSS-treated mice. Conversely, hexamethonium treatment significantly increased each of these markers in the sham-operated DSS-treated mice. Vagotomy had no effect on the colitis in M-CSF-deficient mice. CONCLUSIONS: The vagus nerve plays a counterinflammatory role in acute colitis via a macrophage-dependent mechanism, involving hexamethonium-sensitive nicotinic receptors. The identification of a counterinflammatory neural pathway would open new therapeutic avenues for treating acute exacerbations of inflammatory bowel disease.

Animals↗