The phospholipase C-IP3 pathway is involved in muscarinic antinociception.
(41/481)
The cellular events involved in muscarinic analgesia were investigated in the mouse hot-plate test. Intracerebroventricular (i.c.v.) pretreatment with antisense oligonucleotides (aODNs) against the alpha subunit of G(q) and G(11) proteins prevented the analgesia induced by physostigmine and oxotremorine. Furthermore, administration of the phospholipase C (PLC) inhibitor U-73122, as well as the injection of an aODN complementary to the sequence of PLCbeta(1), antagonized the increase of the pain threshold induced by both cholinomimetic drugs. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or treatment with heparin, an IP(3) receptor antagonist, the antinociception induced by physostigmine and oxotremorine was dose-dependently antagonized. I.c.v. pretreatment with TMB-8, a blocker of Ca(2+) release from intracellular stores, prevented the increase of pain threshold induced by the investigated cholinomimetic drugs. Coadministration of Ca(2+) restored the muscarinic analgesia in LiCl, heparin, and TMB-8-preatreated mice. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitor calphostin C, resulted in a dose-dependent enhancement of physostigmine- and oxotremorine-induced antinociception. The administration of PKC activators, such as PMA and PDBu, dose dependently prevented the cholinomimetic drug-induced increase of pain threshold. Neither aODNs nor pharmacological treatments employed produced any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate a role for the PLC-IP(3) pathway in central muscarinic analgesia in mice. Furthermore, activation of PKC by cholinomimetic drugs may represent a pathway of negative modulation of muscarinic antinociception. (+info)
Septal modulation of excitatory transmission in hippocampus.
(42/481)
Application of the acetylcholinesterase inhibitor physostigmine to conventional hippocampal slices caused a significant reduction of field excitatory postsynaptic potentials (EPSPs) elicited by single pulse stimulation to the medial perforant path. Similar but smaller effects were obtained in the lateral perforant path and other excitatory pathways within hippocampus. The reductions were blocked by atropine, were not accompanied by evident changes in the EPSP waveform, and were eliminated by lesions to the cholinergic septo-hippocampal projections. Antidromic responses to mossy fiber stimulation, recorded in stratum granulosum, were not affected by the drug. However, paired-pulse facilitation was reliably increased, indicating that the depressed synaptic responses were secondary to reductions in transmitter release. The absence of cholinergic axo-axonic connections in the molecular layer suggests that physostigmine reduces presynaptic release by increasing retrograde signaling from the granule cells. In accord with this, an antagonist of the CB1 cannabinoid receptor eliminated the effects of physostigmine on synaptic responses, while an antagonist of the presynaptically located m2 muscarinic acetylcholine receptor did not. This is in contrast to previously reported effects involving application of cholinergic agonists, in which presynaptic inhibition likely results from direct activation of presynaptically located muscarinic receptors. In summary, it is proposed that the cholinergic inputs from the septum to the middle molecular layer modulate, via endocannabinoid release, the potency of the primary excitatory afferent of hippocampus. (+info)
Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine.
(43/481)
In the mammalian neocortex, the EEG reflects the state of behavioral arousal. The EEG undergoes a transformation, known as activation, during the transition from sleep to waking. Abundant evidence indicates the involvement of the neurotransmitter acetylcholine (ACh) in EEG activation; however, the cellular basis of this involvement remains unclear. We have used electrophysiological techniques with in vivo and in vitro preparations to demonstrate actions of endogenous ACh on neurons in auditory neocortex. In vivo stimulation of the nucleus basalis (NB), a primary source of neocortical ACh, (1) elicited EEG activation via cortical muscarinic receptors, (2) depolarized cortical neurons, and (3) produced a change in subthreshold membrane potential fluctuations from large-amplitude, slow (1-5 Hz) oscillations to low-amplitude, fast (20-40 Hz) oscillations. The NB-mediated change in pattern of membrane potential fluctuations resulted in a shift of spike discharge pattern from phasic to tonic. Stimulation of afferents in the in vitro neocortex elicited cholinergic actions on putative layer 5 pyramidal neurons. Acting via muscarinic receptors, endogenous ACh (1) reduced slow, rhythmic burst discharge and facilitated higher-frequency, single-spike discharge in burst-generating neurons, and (2) facilitated the appearance and magnitude of intrinsic membrane potential oscillations. These in vivo and in vitro observations suggest that neocortical activation results from muscarinic modulation of intrinsic neural oscillations and firing modes. Rhythmic-bursting pyramidal neurons in layer 5 may act as cortical pacemakers; if so, then modifying their discharge characteristics could alter local cortical networks. Larger, intercortical networks could also be modified, due to the widespread projections of NB neurons. Thus, NB cholinergic neurons may play a critical role in producing different states of neocortical function. (+info)
Effect of humoral modulators of morphine-induced increase in locomotor activity of mice.
(44/481)
The effect of humoral modulators on the morphine-induced increase in locomotor activity of mice was studied. The subcutaneous administration of 10 mg/kg of morphine-HC1 produced a marked increase in locomotor activity in mice. The morphine-induced hyperactivity was potentiated by scopolamine and attenuated by physostigmine. In contrast, both methscopolamine and neostigmine, which do not penetrate the blood-brain barrier, had no effect on the hyperactivity produced by morphine. Pretreatment of mice with alpha-methyltyrosine (20 mg/kg i.p., one hour), an inhibitor of tyrosine hydroxylase, significantly decreased the activity-increasing effects of morphine. On the other hand, pretreatment with p-chlorophenylalamine (3 X 320 mg/kg i.p., 24 hr), a serotonin depletor, caused no significant change in the hyperactivity. The study suggests that the activity-increasing effects of morphine are mediated by the release of catecholamines from adrenergic neurons in the brain. And the results are consistent with the hypothesis that morphine acts by retarding the release of acetylcholine at some central cholinergic synapses. It is also suggested from collected evidence that the activity-increasing effects of morphine in mice are mediated by mechanisms different from those which mediate the activity-increasing effects of morphine in rats. (+info)
Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats.
(45/481)
1. Bromocriptine (2, 4 and 8 mg kg-1, i.p.), physostigmine (0.05, 0.1 and 0.2 mg kg-1, i.p.) and pilocarpine (1, 3 and 5 mg kg-1, i.p.) induced dose-dependent yawning in rats. 2. These responses were reduced in a dose-dependent manner by pretreatment with morphine. 3. The inhibitory effect of morphine was reversed by naloxone. 4. Naloxone alone induced slight but significant yawning. 5. The present results suggest that morphine inhibits yawning in rats at an opiate receptor downstream from the sites at which cholinoceptor and dopamine D2 activation induce yawning. The anatomical location of these sites remains to be established. (+info)
An eserine-like action of chloral hydrate.
(46/481)
The intra-arterial injection of chloral hydrate potentiated the transmission of nerve impulses through the cat superior cervical ganglion, antagonized the ganglionblocking action of hexamethonium, and greatly enhanced the ganglion-stimulant action of acetylcholine. Effects on the ganglion-stimulant actions of carbachol, nicotine, tetramethylammonium and potassium chloride were slight or absent. Chloral hydrate itself usually had no direct stimulant action. The neuromuscular-blocking action of tubocurarine on the isolated rat diaphragm preparation was completely and rapidly reversed by chloral hydrate. This reversal was prevented by previoustreatment of the muscle with neostigmine. Chloral hydrate potentiated the actions of acetylcholine and nicotine on the isolated rabbit duodenum, and, in concentrations exceeding 1 mg/ml., produced a spasm which was abolished by hyoscine but not by mepyramine. It was concluded that these eserine-like effects were manifestations of an anticholinesterase action of chloral hydrate. Neither chloralose nor trichlorethanol showed evidence of this property. (+info)
Sympathetic vasodilatation in the rabbit ear.
(47/481)
Changes in the blood content of a 1 cm(2) portion of the intact rabbit's ear were studied with transillumination and a photocell. Stimulation of the post-ganglionic sympathetic nerves produced a decrease in blood content, attributable to vasoconstriction, followed by an increased blood content, attributable to vasodilatation. The vasodilatation was enhanced by eserine and decreased by atropine. Guanethidine abolished the vasoconstriction but not the vasodilatation. After the ganglion had been decentralized by degeneration of the pre-ganglionic sympathetic nerves the vessels had an increased sensitivity to acetylcholine and the vasodilatation in response to sympathetic stimulation was enhanced. It is concluded that sympathetic stimulation results in the liberation of acetylcholine which causes vasodilatation. (+info)
Effect of guanethidine, hemicholinium and mebutamate on the hypertensive response to eserine and catechol amines.
(48/481)
Guanethidine, hemicholinium and mebutamate were used to study the site and mechanism of the hypertensive response to eserine in the rat. Guanethidine was found to block very effectively the hypertensive effect of eserine and to produce at the same time a very strong potentiation of the response to catechol amines. Hemicholinium, after a certain latent period, also blocked the effect of eserine, at the same time leaving the response to adrenaline and noradrenaline intact. Mebutamate was also found to block the effect of eserine. The results of the present experiments suggest that eserine produces a central adrenergic activation in the rat. (+info)