The motor inhibitory system operating during active sleep is tonically suppressed by GABAergic mechanisms during other states.
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The present study was undertaken to explore the neuronal mechanisms responsible for muscle atonia that occurs after the microinjection of bicuculline into the nucleus pontis oralis (NPO). Specifically, we wished to test the hypothesis that motoneurons are postsynaptically inhibited after the microinjection of bicuculline into the NPO and determine whether the inhibitory mechanisms are the same as those that are utilized during naturally occurring active (rapid eye movement) sleep. Accordingly, intracellular records were obtained from lumbar motoneurons in cats anesthetized with alpha-chloralose before and during bicuculline-induced motor inhibition. The microinjection of bicuculline into the NPO resulted in a sustained reduction in the amplitude of the spinal cord Ia-monosynaptic reflex. In addition, lumbar motoneurons exhibited significant changes in their electrophysiological properties [i.e., a decrease in input resistance and membrane time constant, a reduction in the amplitude of the action potential's afterhyperpolarization (AHP) and an increase in rheobase]. Discrete, large-amplitude inhibitory postsynaptic potentials (IPSPs) were also observed in high-gain recordings from lumbar motoneurons. These potentials were comparable to those that are only present during the state of naturally occurring active sleep. Furthermore, stimulation of the medullary nucleus reticularis gigantocellularis evoked a large-amplitude IPSP in lumbar motoneurons after, but never prior to, the injection of bicuculline; this reflects the pattern of motor responses that occur in conjunction with the phenomenon of "reticular response-reversal." The preceding changes in the electrophysiological properties of motoneurons, as well as the development of active sleep-specific IPSPs, indicate that lumbar motoneurons are postsynaptically inhibited following the intrapontine administration of bicuculline in a manner that is comparable to that which occurs spontaneously during the atonia of active sleep. The present results support the conclusion that the brain stem-spinal cord inhibitory system, which is responsible for motor inhibition during active sleep, can be activated by the injection of bicuculline into the NPO. These data suggest that the active sleep-dependent motor inhibitory system is under constant GABAergic inhibitory control, which is centered in the NPO. Thus during wakefulness and quiet sleep, the glycinergically mediated postsynaptic inhibition of motoneurons is prevented from occurring due to GABAergic mechanisms. (+info)
Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans.
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The cholinesterase inhibitor neostigmine indirectly stimulates muscarinic M(1)/M(2)/M(3) receptors, thereby reducing colonic distension in acute colonic pseudo-obstruction. We investigated the dose-response profile for the colonic sensorimotor effects of neostigmine and bethanechol, a direct muscarinic M(2)/M(3) agonist in humans. A barostat-manometric assembly recorded phasic pressures, tone, and pressure-volume relationships (compliance) in the descending colon and rectum of 30 healthy subjects who received intravenous neostigmine (0.25, 0.75, or 1.5 mg; n = 15) or subcutaneous bethanechol (2.5, 5, or 10 mg; n = 15). Sensation to luminal distension was also assessed. Thereafter, the effects of neostigmine and bethanechol on colonic transit (geometric center) were compared with those of saline by scintigraphy in 21 subjects. Both drugs increased colonic phasic pressure activity, reduced rectal compliance, and enhanced urgency during rectal distension. Neostigmine also reduced colonic and rectal balloon volumes, reflecting increased tone by an average of 12% and 25% for the highest dose, respectively. Only neostigmine reduced colonic compliance, accelerated colonic transit [mean geometric center at 90 min 2.5 vs. 1.0 (placebo)], and increased pain perception during colonic distension. We conclude that neostigmine has more prominent colonic motor and sensory effects than bethanechol. Moreover, neostigmine induces coordinated colonic propulsion, perhaps by stimulating muscarinic M(1) receptors in the myenteric plexus. (+info)
Salivary enhancement: current status and future therapies.
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Saliva provides the principal protective milieu for teeth by modulating oral microbial ecosystems and reversing the initial phases of caries development. Patients with inadequate salivary function are at increased risk for dental decay. Therefore, it is likely that therapies that increase overall fluid output of these individuals will reverse early carious lesions. The most common causes of salivary dysfunction are medication usage, Sjogren's syndrome, and damage of salivary parenchyma during therapeutic irradiation. For patients with remaining functional acinar tissue, treatment with the parasypathomimetic secretogogues pilocarpine and Cevimeline may provide relief. However, these medications do not benefit all patients. The possibilities of using gene therapy and tissue engineering to develop treatments for those with severe salivary dysfunction are discussed. (+info)
Regional differences in the response of feline esophageal smooth muscle to stretch and cholinergic stimulation.
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There are no objective differences in neural elements that explain regional differences in neural influences along the smooth muscle (SM) esophageal body (EB). Regional differences in muscle properties are present in the lower esophageal sphincter (LES). This study examines whether regional differences in SM properties exist along the EB and are reflected in length-tension relationships and responses to cholinergic excitation. Circular SM strips from feline EB at 1 cm (EB1) and 3 cm (EB3) above LES and from clasp and sling muscle bundles of LES were assessed in normal and calcium-free solutions with and without bethanechol stimulation. Neural inhibition was assessed by electrical field stimulation (EFS). EB3 developed significantly higher tension in response to stretch and to bethanechol than did EB1. The relaxation response to EFS in bethanechol-precontracted strips was less in EB3 than in EB1. In LES, clasp developed higher resting tension than sling but less active tension in response to bethanechol. EFS-induced relaxations of sling and clasp tissues precontracted by bethanechol were not different. In calcium-free solution, length-tension differences between EB3 and EB1 persisted, but those of LES clasp and sling were abolished. Therefore, regional myogenic differences exist in feline EB circular SM as well as in LES and may contribute to the nature of esophageal contraction. (+info)
Central cholinergic depletion induced by 192 IgG-saporin alleviates the sedative effects of propofol in rats.
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We examined the effect of central cholinergic depletion on the sedative potency of propofol in rats. Depletion was produced by intracerebroventricular administration of an immunotoxin specific to cholinergic neurones (192 IgG-Saporin; 2 microg). As a result of this lesion, acetylcholine concentration was reduced by about 40% in the frontoparietal cortex and in the hippocampus but was essentially normal in the striatum and cerebellum. Sedation in rats was assessed as the decrease in locomotor activity. Sedative potency of propofol (30 mg kg(-1) i.p.) was reduced by about 50% in rats who received the injection of 192 IgG-Saporin as compared to controls. These results show that a central cholinergic depletion alleviates the sedative effect of propofol, and indicates that basal forebrain cholinergic neurones might mediate part of the sedative/hypnotic effects of propofol. (+info)
Aldrin-induced locomotor activity: possible involvement of the central GABAergic-cholinergic-dopaminergic interaction.
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Aldrin (5 mg/kg/day, p.o.) under nontolerant condition, administered either for a single day or for 12 consecutive days, enhanced locomotor activity (LA) of rats. The increase in LA was greater in rats treated with aldrin for 12 consecutive days than that observed with a single dose. The aim of the present study is to evaluate the involvement of possible interactions of central GABAergic, cholinergic and dopaminergic systems using their agonist(s) and antagonist(s) in the regulation of LA in aldrin nontolerant rats. Administration of either L-DOPA along with carbidopa or bicuculline potentiated aldrin-induced increase in LA under nontolerant condition as well as LA of the control rats. Treatment with muscimol, haloperidol, atropine or physostigmine all decreased the LA of both aldrin nontolerant and control rats. Further, the application of (a) haloperidol along with bicuculline, atropine or physostigmine and (b) physostigmine along with bicuculline or L-DOPA + carbidopa significantly reduced LA but L-DOPA + carbidopa along with atropine or bicuculline increased LA of the control rats. These agonist(s)/antagonist(s)-induced decrease or increase in LA of the control rats were attenuated or potentiated, respectively, when those agonist(s)/antagonist(s) under abovementioned condition were administered to aldrin nontolerant rats. The attenuating or potentiating effects of aldrin on agonist(s)/antagonist(s) (either individually or in different combinations)-induced change in LA were greater in rats treated with aldrin for 12 consecutive days than that observed with a single-dose aldrin treatment. These results suggest that aldrin, under nontolerant condition, reduces central GABAergic activity and increases LA by activating dopaminergic system via inhibition of cholinergic activity. The treatment with aldrin for 12 consecutive days produces greater effect than that caused by a single-day treatment. (+info)
In testing the hypothesis that interleukin-4 receptor alpha-subunit (IL-4R alpha)-coupled signaling mediates altered airway smooth muscle (ASM) responsiveness in the atopic sensitized state, isolated rabbit tracheal ASM segments were passively sensitized with immunoglobulin E (IgE) immune complexes, both in the absence and presence of an IL-4R alpha blocking antibody (anti-IL-4R alpha Ab). Relative to control ASM, IgE-sensitized tissues exhibited enhanced isometric constrictor responses to administered ACh and attenuated relaxation responses to isoproterenol. These proasthmatic-like effects were prevented in IgE-sensitized ASM that were pretreated with anti-IL-4R alpha Ab. In complementary experiments, IgE-sensitized cultured human ASM cells exhibited upregulated expression of IL-13 mRNA and protein, whereas IL-4 expression was undetected. Moreover, extended studies demonstrated that 1) exogenous IL-13 administration to naive ASM elicited augmented contractility to ACh and impaired relaxation to isoproterenol, 2) these effects of IL-13 were prevented by pretreating the tissues with an IL-5 receptor blocking antibody, and 3) IL-13 administration induced upregulated mRNA expression and release of IL-5 protein from cultured ASM cells. Collectively, these findings provide new evidence demonstrating that the altered responsiveness of IgE-sensitized ASM is largely attributed to activation of an intrinsic Th2-type autocrine mechanism involving IL-13/IL-4R alpha-coupled release and action of IL-5 in the sensitized ASM itself. (+info)
Secretory modulation of basolateral membrane inwardly rectified K(+) channel in guinea pig distal colonic crypts.
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Cell-attached recordings revealed K(+) channel activity in basolateral membranes of guinea pig distal colonic crypts. Inwardly rectified currents were apparent with a pipette solution containing 140 mM K(+). Single-channel conductance (gamma) was 9 pS at the resting membrane potential. Another inward rectifier with gamma of 19 pS was observed occasionally. At a holding potential of -80 mV, gamma was 21 and 41 pS, respectively. Identity as K(+) channels was confirmed after patch excision by changing the bath ion composition. From reversal potentials, relative permeability of Na(+) over K(+) (P(Na)/P(K)) was 0.02 +/- 0.02, with P(Rb)/P(K) = 1.1 and P(Cl)/P(K) < 0.03. Spontaneous open probability (P(o)) of the 9-pS inward rectifier ((gp)K(ir)) was voltage independent in cell-attached patches. Both a low (P(o) = 0.09 +/- 0.01) and a moderate (P(o) = 0.41 +/- 0.01) activity mode were observed. Excision moved (gp)K(ir) to the medium activity mode; P(o) of (gp)K(ir) was independent of bath Ca(2+) activity and bath acidification. Addition of Cl(-) and K(+) secretagogues altered P(o) of (gp)K(ir). Forskolin or carbachol (10 microM) activated the small-conductance (gp)K(ir) in quiescent patches and increased P(o) in low-activity patches. K(+) secretagogues, either epinephrine (5 microM) or prostaglandin E(2) (100 nM), decreased P(o) of (gp)K(ir) in active patches. This (gp)K(ir) may be involved in electrogenic secretion of Cl(minus sign) and K(+) across the colonic epithelium, which requires a large basolateral membrane K(+) conductance during maximal Cl(-) secretion and, presumably, a lower K(+) conductance during primary electrogenic K(+) secretion. (+info)