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Experientia Aug 1960
Topics: Muscarine; Parasympathomimetics
PubMed: 13783280
DOI: 10.1007/BF02157893 -
The Journal of Pharmacology and... Nov 2003Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce effective pain relief. Intrathecal injection of a small dose of neostigmine...
Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce effective pain relief. Intrathecal injection of a small dose of neostigmine produces a profound antiallodynic effect in rats with diabetic neuropathy. However, the mechanisms of increased antinociceptive effect of cholinergic agents on diabetic neuropathic pain are not clear. In the present study, we tested the hypothesis that spinal muscarinic receptors are up-regulated in diabetes. The withdrawal threshold of the hindpaw in response to noxious heat and pressure stimuli was determined in streptozotocin-induced diabetic and age-matched normal rats. Muscarine-stimulated guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding was used to assess the change of functional muscarinic receptors in the spinal cord in diabetes. The [3H]AF-DX 384 membrane binding was performed to determine the number and affinity of spinal cord M2 muscarinic receptors in normal and diabetic rats. We found that the antinociceptive effect of intrathecal 2 to 12 mug muscarine in diabetic animals was potentiated significantly compared with that in normal animals. The maximal muscarine-stimulated [35S]GTPgammaS binding was 112.5 +/- 8.3% in normal rats and 168.8 +/- 12.1% (P < 0.05) in diabetic rats. Although the KD value (2.9 nM) was similar in both groups, the Bmax of [3H]AF-DX 384 membrane binding was significantly higher in diabetic than in normal rats (255.2 +/- 5.9 versus 165.9 +/- 3.5 fmol/mg protein, P < 0.05). Collectively, these data strongly suggest that the muscarinic receptor is up-regulated in the dorsal spinal cord in diabetic rats. This finding probably accounts for the increased efficacy of the antinociceptive effect of intrathecal muscarinic agonists in diabetic neuropathic pain.
Topics: Analgesics; Animals; Binding Sites; Diabetic Neuropathies; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Spinal; Male; Muscarine; Muscarinic Agonists; Pain; Pain Measurement; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Spinal Cord; Sulfur Radioisotopes; Tritium; Up-Regulation
PubMed: 12966147
DOI: 10.1124/jpet.103.055905 -
FASEB Journal : Official Publication of... Jul 1988Advances in understanding the phosphoinositide cycle have helped unravel the chain of events initiated by muscarinic receptor stimulation. Hydrolysis of membrane... (Review)
Review
Advances in understanding the phosphoinositide cycle have helped unravel the chain of events initiated by muscarinic receptor stimulation. Hydrolysis of membrane phosphoinositides generates both diacylglycerol, an activator of protein kinase C, and inositol phosphates. In the nervous system, muscarinic receptors elicit a wide range of electrophysiological responses. Recent studies have made progress in identifying which of these neuronal muscarinic actions are mediated by activation of protein kinase C. Paradoxically, protein kinase C also exerts a strong inhibitory influence on muscarinic responses. This complex set of actions suggests that in addition to mediating certain muscarinic responses, protein kinase C also blocks signal transduction as part of a feedback mechanism.
Topics: Animals; Choline; Electrophysiology; Hippocampus; Humans; Muscarine; Neurons; Phorbol Esters; Phosphatidylinositols; Protein Kinase C; Receptors, Muscarinic
PubMed: 2838363
DOI: 10.1096/fasebj.2.10.2838363 -
Experientia Apr 1957
Topics: Muscarine; Parasympathomimetics; Stereoisomerism
PubMed: 13447894
DOI: 10.1007/BF02158131 -
Neuron Jul 1993M-current is widespread in the nervous system. It stabilizes cell excitability, and its suppression by muscarinic receptor activation underlies slow synaptic...
M-current is widespread in the nervous system. It stabilizes cell excitability, and its suppression by muscarinic receptor activation underlies slow synaptic transmission in sympathetic neurons. Suppression of M-current was one of the first examples of neuromodulation of a potassium current, but the mechanism is not understood. Single-channel recording was used to study this issue. An M-channel with two conductance states, which exhibited appropriate voltage-dependent kinetics with two modes of gating, has been resolved. Mode 1 comprises short open time, low open probability events, and mode 2 openings represent long open time, high open probability behavior. Muscarine decreased M-channel activity by selectively reducing mode 2 M-channel gating through a diffusible second messenger. It is suggested that control of modal gating may be a widespread mechanism for neuromodulation.
Topics: Animals; Electric Conductivity; Electrophysiology; Ion Channel Gating; Muscarine; Neurons; Potassium Channels; Rana catesbeiana; Sympathetic Nervous System
PubMed: 8338670
DOI: 10.1016/0896-6273(93)90272-s -
Biochemical and Biophysical Research... Apr 2020Previously, we found that muscarine downregulates the acetylcholine release at the frog neuromuscular junction acting via M3 muscarinic receptors. Here, the molecular...
Previously, we found that muscarine downregulates the acetylcholine release at the frog neuromuscular junction acting via M3 muscarinic receptors. Here, the molecular mechanisms underlying the inhibitory effect of muscarine on the quantal secretion of acetylcholine were studied. Inhibition of phospholipase C (with U-73122) prevented the reduction of evoked neurotransmitter release induced by muscarine. Interruption of synthesis of phosphatidylinositol 3-phosphate by the inhibitor of phosphoinositide-3-kinase (wortmannin) did not affect the depressant action of muscarine but precluded the restoration of secretion after removal of muscarine from the bathing solution. The effect of muscarine was not significantly modified by the blockade of endocannabinoid receptors (with AM 281), but it was abolished by the inhibitor of nitric oxide synthase (L-NAME) as well as extracellular nitric oxide (NO) chelator (hemoglobin). Moreover, muscarine increased NO-sensitive dye fluorescence in junctional region, which was prevented by the M3 receptor antagonist 4-DAMP. The data obtained indicate that the attenuation of acetylcholine release mediated by muscarine is associated with a change in the activity of both lipid-metabolizing enzymes and NO synthases.
Topics: Acetylcholine; Animals; Cannabinoids; Motor Neurons; Muscarine; Muscarinic Agonists; Nitric Oxide; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phospholipids; Ranidae; Receptor, Muscarinic M3; Synapses; Type C Phospholipases
PubMed: 32029276
DOI: 10.1016/j.bbrc.2020.01.112 -
Journal of Pharmacological and... 2023The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has...
The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has dramatically improved over the last two decades, this is the first time that isolation and electrophysiological recordings have been carried out on tick neurons from the synganglion. Method: We developed a simple protocol for synganglion neuron isolation and used a whole-cell patch clamp to measure ionic currents induced by acetylcholine, nicotine and muscarine. Relatively large neurons (∼ 25 μm and ∼ 35 μm) were isolated and 1 mM acetylcholine was used to induce strong inward currents of -0.38 ± 0.1 nA and - 1.04 ± 0.1 nA, respectively, with the corresponding cell capacitances being at around 142 pF and 188 pF. In addition, successive application of 1 mM acetylcholine through ∼25 μm and ∼ 35 μm cells for increasing amounts of time resulted in a rapid reduction in current amplitudes. We also found that acetylcholine-evoked currents were associated with a reversible increase in intracellular calcium levels for each neuronal type. In contrast, 1 mM muscarine and nicotine induced a strong and non-reversible increase in intracellular calcium levels. This study serves as a proof of concept for the mechanical isolation of tick synganglion neurons followed by their electrophysiological recording. This approach will aid investigations into the pharmacological properties of tick neurons and provides the tools needed for the identification of drug-targeted sites and effective tick control measures.
Topics: Animals; Ixodes; Nicotine; Acetylcholine; Calcium; Muscarine; Neurons
PubMed: 37866797
DOI: 10.1016/j.vascn.2023.107473 -
Progress in Brain Research 2004M1 and M4 muscarinic receptors are the most prevalent receptors for acetylcholine in the brain, and m1-toxin1 and m4-toxin are the most specific ligands yet found for... (Review)
Review
M1 and M4 muscarinic receptors are the most prevalent receptors for acetylcholine in the brain, and m1-toxin1 and m4-toxin are the most specific ligands yet found for their extracellular faces. Both toxins are antagonists. These toxins and their derivatives with biotin, radioiodine and fluorophores are useful for studying M1- and M4-linked neurotransmission. We have used the rat striatum for many studies because this tissue express exceptionally high concentrations of both receptors, the striatum regulates movement, and movement is altered by antimuscarinic agents, M1-knockout and M4-knockout. These toxins and their derivatives may also be used for studies of M1 and M4 receptors in the hippocampus and cortex.
Topics: Animals; Brain; Cholinergic Fibers; Corpus Striatum; Motor Activity; Muscarine; Muscarinic Antagonists; Receptors, Muscarinic; Synaptic Transmission; Toxins, Biological
PubMed: 14650911
DOI: 10.1016/S0079-6123(03)45008-5 -
Current Medicinal Chemistry Dec 2003Acetylcholine, the first identified neurotransmitter acts on both types of cholinergic receptors. Both rigid and flexible derivatives of acetylcholine could either be... (Review)
Review
Acetylcholine, the first identified neurotransmitter acts on both types of cholinergic receptors. Both rigid and flexible derivatives of acetylcholine could either be selective muscarinic or selective nicotinic agonists while some compounds show activity at both receptor subclasses. Earlier structure-activity considerations are revisited. Ligand and receptor based calculations have been applied in the hope to identify characteristic geometrical and steric requirements for the activity on the receptor subtypes. Results are treated critically and applied cautiously for predicting selective structural requirements by the cholinergic receptor subclasses.
Topics: Acetylcholine; Animals; Binding Sites; Dioxolanes; Models, Molecular; Muscarine; Muscarinic Agonists; Nicotine; Nicotinic Agonists; Receptors, Muscarinic; Receptors, Nicotinic; Stereoisomerism; Structure-Activity Relationship; Sulfoxides
PubMed: 14529475
DOI: 10.2174/0929867033456521 -
Behavioural Brain Research Feb 2023Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events....
Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2 µg/µl/side, and rapamycin, an mTOR inhibitor (0.02 µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6 µg/µl/side) and muscarine (0.02 µg/µl/side), respectively, had no effect, while the higher doses (6 and 2 µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.
Topics: Animals; Male; Rats; Avoidance Learning; Fear; Hippocampus; Muscarine; Muscarinic Antagonists; Nicotine; Rats, Wistar; Receptors, Cholinergic; Sirolimus; TOR Serine-Threonine Kinases; Extinction, Psychological; Memory
PubMed: 36179804
DOI: 10.1016/j.bbr.2022.114129