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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antinociceptive action of three classes of gamma-aminobutyric acid (GABA) agonists was examined in mice using the hot-plate and tail-immersion tests. A significant increase in reaction time was noted in the hot-plate test after treatment with the direct-acting GABA receptor agonists, kojic amine or 4,5,6,7-tetrahydroisoxazolo[5,4-C] pyridin-3-ol, with gamma-vinyl GABA, an inhibitor of GABA degradation, or with nipecotic acid ethyl ester, an inhibitor of high-affinity GABA transport. Studies with naloxone indicated that the increase in pain threshold was not mediated through the brain opiate system, although it was possible to reverse the antinociceptive effect of these drugs with atropine. Receptor binding experiments indicated that except for the ethyl ester of nipecotic acid, the GABA agonists have little affinity for the cholinergic muscarinic receptor site. Atropine, at a dose that completely blocked the antinociceptive action of kojic amine, was unable to attenuate the sedative effects of this drug. These findings suggest that, regardless of their mechanism, the three types of GABA agonists tested are capable of inducing an antinociceptive response in mice and that this action is apparently secondary to a GABA-mediated increase in brain cholinergic function.
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PMID:Comparison of the antinociceptive effect of gamma-aminobutyric acid (GABA) agonists: evidence for a cholinergic involvement. 706 60

Spinal neostigmine produces analgesia in chronically prepared rats, but not in sheep. However, since pain itself activates bulbospinal inhibitory pathways, neostigmine may be more effective in the postoperative period. We examined in sheep the antinociceptive effect of intrathecal neostigmine in the acute postoperative period and determined the muscarinic receptor subtype activated by neostigmine. A cervical intrathecal catheter was inserted via a laminotomy in 14 sheep that then received, in random order 1 mg of spinal neostigmine or saline on postoperative Day 1 and the other injection on postoperative Day 2. Three additional sheep received, on separate days, intrathecal neostigmine alone or with the muscarinic receptor subtype-specific antagonists pirenzepine (M1) 2 mg or AFDX-116 (M2) 2 mg. Antinociception was tested using a mechanical stimulus after each injection. Baseline withdrawal threshold did not change postoperatively. Intrathecal neostigmine, but not saline caused antinociception on both of the first two postoperative days. In contrast, intrathecal neostigmine caused no antinociception in another similar study performed at least 5 days after surgery. Pirenzepine, but not AFDX-116, abolished antinociception from neostigmine, suggesting an action on M1 subtype muscarinic receptors. Intrathecal neostigmine is antinociceptive in sheep during the acute postoperative period, and these data suggest that spinal cholinergic tone, and hence intrathecal neostigmine's analgesic effect, may be enhanced during the acute postoperative period.
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PMID:Postoperative analgesia from intrathecal neostigmine in sheep. 776 41

Electric spinal cord stimulation (SCS) is widely used as a treatment modality for ischemic pain in peripheral arterial insufficiency. The background for the therapeutic effect may be a temporary inhibition of sympathetically maintained peripheral vasoconstriction. In this series of experiments, the involvement of different types of cholinergic and adrenergic receptor subclasses in the vasodilatory effect was explored in anesthetized rats. The microcirculation in hindlimb skin and hamstring muscle was studied by the laser Doppler technique. The ganglionic blocker hexamethonium as well as the nicotinic receptor antagonist chlorisondamine abolished the effect in both vascular beds, whereas the muscarinic receptor antagonists pirenzepine and atropine were ineffective. Among the adrenergic receptor active compounds, phentolamine, prazosine (an alpha 1-receptor antagonist), and clonidine in high doses suppressed the SCS-induced vasodilation. Yohimbine (an alpha 2-receptor antagonist) did not alter the effect. The beta-adrenergic compounds had a differential effect on muscle and skin perfusion. Atenolol, a beta 1-receptor antagonist, inhibited SCS-induced vasodilation only in the skin, whereas the beta 2-receptor antagonist butoxamine selectively depressed the muscle response. The vasodilatory effect of SCS in the animal model used here seems to a large extent to be mediated by an inhibitory effect on peripheral vasoconstriction maintained via efferent sympathetic activity involving nicotinic transmission in the ganglia and the postganglionic alpha 1-adrenoreceptors. The involvement of beta-receptors seems to be different in skin and muscle, beta 1 being more important for the changes in the skin and beta 2 being more important for those in muscle. The high-intensity antidromic response, earlier believed to explain how SCS exerted its vasodilatory effect, was resistant to cholinergic and adrenergic manipulations and seems to depend on entirely different mechanisms.
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PMID:Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. 780 15

The present study was designed to examine some of the pharmacological properties of venom from the stonefish (Synanceja trachynis), with particular reference to the presence in the venom of pain-producing/enhancing substances. Stonefish venom (1-6 micrograms/ml) produced concentration-dependent contractile responses in guinea-pig isolated ileum. No tachyphylaxis, or reduction in responses with time, was observed to venom (3 micrograms/ml) in ileum. The response to venom (3 micrograms/ml) was not significantly affected by the histamine antagonist mepyramine (0.5 microM), or a preceding anaphylactic response. Mecamylamine, 5HT-desensitization or EXP3174 failed to have any significant effect on responses to venom (3 micrograms/ml). Responses to venom (3 micrograms/ml) were significantly inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the leukotriene D4 receptor antagonist FLP55712 (1 microM), the thromboxane A2 receptor antagonist GR32191B (1 microM), the muscarinic receptor antagonist atropine (10 nM) and the neurokinin-1 receptor antagonist CP96345 (0.1 microM). Venom (6 micrograms/ml) produced contractile responses in the rat isolated vas deferens which were abolished by the alpha 1-adrenoceptor antagonist prazosin (0.3 microM) and significantly potentiated by the neuronal uptake inhibitor DMI (1 microM). However, noradrenergic transmitter depletion with reserpine (5 mg/kg, i.p.) did not significantly inhibit responses to venom (6 micrograms/ml). Histamine fluorometric and phospholipase A2 assays failed to detect significant quantities of either substance in the venom. These results suggest that stonefish venom may cause the release of acetylcholine, substance P, and cyclooxygenase products, or contain components which act at these receptors. The venom also appears to contain a component which is a substrate for neuronal uptake and has a direct action at alpha 1-adrenoceptors.
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PMID:Pharmacological studies of stonefish (Synanceja trachynis) venom. 784 90

Recent studies have suggested that a spinal cholinergic system is important in spinal nociceptive modulation. In the present study, the role of a nitric oxide (NO)-generating system in spinal cholinergic modulation of nociception was examined in awake rats. Intrathecal (i.t.) administration of the cholinergic muscarinic receptor antagonist atropine produced a dose-dependent (1.4-14.4 nmol) decrease in the mechanical threshold for tail withdrawal, which was reversed rapidly (2-3 min) by subsequent i.t. administration of the NO precursor, L-arginine (10 pmol to 10 nmol). Intrathecal administration of L-arginine alone (10 pmol to 10 nmol) produced a dose-dependent increase in the mechanical nociceptive withdrawal threshold of the tail. The reflexive withdrawal of the tail produced by noxious heat was not significantly affected by i.t. administration of either atropine or L-arginine. Inhibition of the NO-cGMP pathway by i.t. administration of either Nw-nitro-L-arginine methyl ester (L-NAME, 10 nmol) or methylene blue (10 nmol) significantly enhanced the magnitude and prolonged the time course of the decrease in the mechanical threshold for tail withdrawal produced by i.t. pretreatment with atropine (1.4 nmol). Neither L-NAME nor methylene blue affected mechanical withdrawal thresholds in rats pretreated with saline. These data suggest that the production of endogenous NO is required for tonic inhibition of spinal nociceptive mechanical transmission. Moreover, the present data support the speculation that there exists in the lumbar spinal cord a tonic, cholinergic modulation of NO synthase.
Pain 1993 Jul
PMID:Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission. 839 74

Butylthio[2.2.2], ((+)-(S)-3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-azabicyclo[2.2.2] octane; LY297802/NNC11-1053) is a muscarinic receptor ligand which is equiefficacious to morphine in producing antinociception. In vitro, butylthio[2.2.2] had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for several other neurotransmiter receptors and uptake sites. In isolated tissues, butylthio[2.2.2] was an agonist with high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.33 nM), but it was an antagonist at M2 receptors in guinea pig atria (pA2 = 6.9) and at M3 receptors in guinea pig urinary bladder (pA2 = 7.4) and a weak partial agonist in guinea pig ileum, which contains a heterogeneous population of muscarinic receptors. In vivo, butylthio[2.2.2] was without effect on acetylcholine, dopamine and serotonin levels in rat brain. Moreover, butylthio[2.2.2] did not decrease charcoal meal transit in mice, nor did it significantly alter heart rate in rats. Further, butylthio[2.2.2] did not produce parasympathomimetic effects such as salivation or tremor in mice, but it antagonized salivation and tremor produced by the nonselective muscarinic agonist oxotremorine. The present data demonstrate that butylthio[2.2.2] is a novel muscarinic receptor mixed agonist/antagonist and its pharmacological profile suggests that it may have clinical utility in the management of pain as an alternative to opioids.
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PMID:Pharmacology of butylthio[2.2.2] (LY297802/NNC11-1053): a novel analgesic with mixed muscarinic receptor agonist and antagonist activity. 915 98

In this work we have studied the influences of nicotinic agents on the antinociception of morphine in formalin test. Nicotine (0.001-0.1 mg/kg) induced antinociception in mice in a dose-dependent manner in the early phase of formalin test, and also potentiated the morphine effect. The nicotinic receptor antagonist, mecamylamine (0.5 mg/kg), but not hexamethonium decreased the antinociception induced by nicotine (0.1 mg/kg) in both phases. The muscarinic receptor antagonist atropine (5 and 10 mg/kg) also decreased the response of nicotine. Mecamylamine, hexamethonium or atropine did not alter morphine antinociceptive response, while naloxone decreased responses induced by nicotine or morphine. The antagonists by themselves did not elicit any response in formalin test, however, high does of mecamylamine tend to increase pain response. It is concluded that central cholinergic and opioid receptor mechanisms may be involved in nicotine-induced antinociception.
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PMID:Involvement of cholinergic and opioid receptor mechanisms in nicotine-induced antinociception. 939 85

Recent studies suggested that the L-arginine/nitric oxide (NO)/cyclic GMP pathway is involved in the modulation of pain perception. The present experiments were undertaken to find out the role of this pathway in the antinociception induced by oxotremorine administration. Male mice of the CD-1 strain were injected with different doses of the muscarinic agonist oxotremorine (0.005, 0.01, 0.02, 0.03 mg/kg i.p.) 5 min after the administration of saline solution or the inhibitors of NO synthase NG-nitro-L-arginine methyl ester (L-NAME: 10 and 20 mg/kg, i.p.) or NG-nitro-L-arginine (N-ARG: 10 and 20 mg/kg i.p.). Oxotremorine induced a dose- and time-dependent analgesic effect in mice, which was significantly increased by L-NAME and N-ARG administration. Either doses of the NO inhibitors given alone had no effect on the nociceptive threshold. The present results show a role of NO in the antinociception mediated by the muscarinic receptor stimulation and suggest that it exerts an inhibitory action on cholinergic analgesia.
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PMID:Nitric oxide synthase inhibitors enhance the antinociceptive effects of oxotremorine in mice. 943 49

Venlafaxine blocks the specific monoamine transporters and is devoid of significant action on muscarinic cholinergic receptors. To our knowledge, no cases of glaucoma have been reported so far. Because pain perception involves both serotonergic and noradrenergic mechanisms, venlafaxine also may be useful in neuropathic pain therapy. We report on two patients with narrow angle glaucoma affected by chronic pain. When venlafaxine treatment was begun, their ocular pressure was steadily around 17-18 mmHg. Venlafaxine was chosen (daily dose 75 mg) because this drug is claimed not to bind on muscarinic cholinergic receptors. However, 4 days later the ocular pressure of the first patient increased to 22 mmHg, which led to suspension of the drug. The ocular pressure of the second patient was 18.5 mmHg after a week, 21 mmHg after 2 weeks, and 23 mmHg after 16 days. One week after suspension, ocular pressure of the patients was 17 and 18 mmHg, respectively. Possible explanations of this ocular effect are offered: pharmacokinetic interference on the drugs used in glaucoma treatment, in vivo action on the muscarinic receptor, indirect effect via dopaminergic receptors, or direct effect on the ocular sympathetic postganglionic neurones. In any case, from a clinical viewpoint, caution should be used when giving venlafaxine to patients with narrow-angle glaucoma, and ocular pressure must be monitored.
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PMID:Increased ocular pressure in two patients with narrow angle glaucoma treated with venlafaxine. 957 1

Systemic administration of cholinesterase inhibitors which cross the blood brain barrier have long been known to produce analgesia and enhance analgesia from opiates. A major site of analgesic action of cholinergic agents is the spinal cord. Muscarinic receptors are concentrated in the superficial layers of the dorsal horn of the spinal cord, an area of noxious sensory processing, and these reflect innervation primarily from cholinergic neurons with cell bodies deep in the neck of the dorsal horn. Spinal injection of cholinergic agonists results in analgesia which primarily reflects muscarinic receptor activation. Analgesia occurs in animal models of acute noxious stimulation and of chronic hypersensitivity pain. Although no cholinergic agonists have been tested for safety in humans, the cholinesterase inhibitor, neostigmine, has undergone such testing, and produces analgesia to experimental, acute postoperative, and chronic pain. Thus, muscarinic cholinergic agonists and cholinesterase inhibitors hold promise as non-opiate agents for the treatment of moderate to severe acute and chronic pain.
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PMID:Muscarinic-mediated analgesia. 1006 22


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