Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined the modulation by acetylcholine of electrocorticographical (ECoG) ictal events and spontaneous pain-like behaviors following cortical application of the GABA(A) antagonist picrotoxin in the awake rat. Distilled water as vehicle, the cholinomimetic substance eserine, and the general muscarinic antagonist atropine were microinjected 10 min before the second microinjection of 2 microg picrotoxin into the hind paw region of the somatomotor cortex (SmI). Under these conditions, we observed that eserine (physostigmine, 1 microg, 10 microg, and 20 microg) did not consistently modify the number of the picrotoxin-induced ECoG spikes and bursts, but instead produced a massive enhancement of the number of hind paw licks compared with vehicle at 10 microg and, to a lesser extent, the number of the stereotyped "turn-in" and "neglected" paws following picrotoxin. In contrast, atropine (1 microg, 10 microg, and 20 microg) increased the number of the picrotoxin-induced spikes and bursts at 10 microg and, at all doses, decreased the number of the picrotoxin-induced pain-like symptoms. Statistically significant changes for the number of paw lifts, licks, and "turn-in" paws were observed only with 10 microg. These results tend to show that epilepsy and pain are not strictly related to each other and also emphasize the cortex as a target for interactions between GABA and acetylcholine relative to "central" pain.
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PMID:Cholinergic modulation of the picrotoxin-induced electrocorticographical events and behavioral "pain-like" symptoms at somatomotor cortical level in the rat. 943 3

To understand the biological basis of anxiety, the following psychological aspects are discussed: The difference between "trait" and "state" anxiety, types of anxiety as related to knowledge about causes and consequences, anxiety as a chronological process involving coping strategies and different levels of responses. The lack of specificity is physiological indicators of anxiety is demonstrated by experiments based on electrodermal and cardiovascular responses. Among hormones, special emphasis is placed on the constellation between catecholamines and cortisol as being relevant for anxiety research. It is emphasized that configurations of hormone parameters may be more relevant predictors for anxiety than single response values, and the study of postoperative catecholamine and cortisol responses is used for demonstrating differences between patients in a high and low preoperative state of anxiety. Differences are observed only on the emotional and pain response levels, but not in physiological parameters. The neurophysiological model representing central nervous system substrates for anxiety is the behavioural inhibitory system described in the theory by Gray [17], and the most relevant transmitters noradrenaline, serotonin, and the GABA-system are discussed with regard to their relevance for anxiety in animal studies, in studies using provocation tests with pharmacological substances, and in clinical studies with anti-anxiety drugs. Experimental anxiety research in psychology is frequently characterised by significant interactions between many mediators of responses, in particular the type of stressor, the level of trait anxiety and other personality variables, and the type of substances used. It is concluded that stressors as well as drugs frequently do not specifically induce anxiety but may nonspecifically affect general arousal and may only be operating in certain groups and certain levels of stress intensity.
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PMID:[Explanatory models of anxiety from the viewpoint of biopsychology and pharmacopsychology]. 944 74

Microinjection of baclofen, a gamma-aminobutyric acidB (GABA[B]) receptor agonist, in the nucleus raphe magnus (NRM) or nucleus reticularis gigantocellularis pars alpha (NGCpalpha) of the rat produces antinociception at doses of 0.1-1.0 ng and hyperalgesia at doses of 30-150 ng in the tail-flick test. The antinociception is proposed to result from disinhibition of spinally-projecting neurons in this region that contain serotonin. The hyperalgesia is proposed to result either from inhibition of these neurons or from disinhibition of a serotonergic pain facilitatory pathway that also originates in this area of the ventromedial medulla. To determine the involvement of bulbospinal serotonergic pathways in the biphasic effects of baclofen, rats were pretreated intrathecally with either 30 microg of methysergide or saline. Ten minutes later, either saline, 0.5 ng or 150 ng of baclofen was microinjected in the NRM and NGCpalpha, and alterations in nociceptive threshold were assessed by the tail-flick and hot-plate tests. Intrathecal pretreatment with methysergide prevented the increase in tail-flick latency produced by 0.5 ng of baclofen, but did not prevent the decrease in tail-flick latency produced by 150 ng of baclofen. Neither dose of baclofen altered hot-plate latency and this lack of effect was unchanged by methysergide. These data support the idea that the antinociceptive effect of low doses of baclofen in the tail-flick test is mediated by disinhibition of a bulbospinal serotonergic projection and release of serotonin in the spinal cord. These data also suggest that the hyperalgesia produced by high doses of baclofen does not result from disinhibition of a serotonergic pain facilitatory pathway, but rather from direct inhibition of tonically-active pain inhibitory neurons in the NRM and NGCpalpha.
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PMID:Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat. 957 93

Denervation of the hindpaw in rodents triggers autotomy, a behaviour of licking, scratching and self-mutilation of the denervated paw. This behaviour has been used as a model of paraesthesia, dysaesthesia and neuropathic pain. HA and LA rats are lines that have been genetically selected for high or low levels of autotomy, respectively. Compared to intact LA rats, HA rats are more sensitive to convulsions induced by pentylenetetrazol (PTZ), a blocker of the chloride channel associated with the GABA(A) receptor. Here we tested whether an acute administration of a sedative but not anaesthetic dose of pentobarbital (PB) would differentiate between these rat lines, in a number of sensory and motor tests performed in intact rats. This drug was tested since in contrast to PTZ, PB enhances central nervous system (CNS) inhibition by increasing chloride flux through the same channel. We found that PB was significantly more ataxic, antinociceptive, and reduced touch sensitivity in LA rats, compared to HA rats. These results suggest that HA and LA rats genetically differ in the levels of central inhibitions mediated by the GABA system presumably at the chloride channel. This difference may be associated with the dichotomous expression of neuropathic pain in these rat lines.
Pain 1998 Apr
PMID:Differential sensory-motor effects of pentobarbital in intact rats genetically selected for high vs. low neuropathic pain-related behaviour. 958 65

The synaptic relationships between primary afferent central endings containing substance P (SP) and calcitonin gene-related peptide (CGRP) and GABAergic interneurons in the guinea pig substantia gelatinosa of the lumbar spinal dorsal horn were studied. The pre-embedding PAP method was used for detection of GABA and the post-embedding double immunogold labeling method for SP and CGRP detection. Immunogold particles specific for SP and CGRP were mainly localized separately or together in large synaptic vesicles devoid of dense cores. SP and CGRP immunoreactivity was separate or co-localized in small roundish, slender, sinuous or large scalloped (fan-like) terminals with closely packed round agranular synaptic vesicles of various sizes and few large dense core vesicles and mitochondria, which are thought to be capsaicin-sensitive primary afferent terminals. These SP- and CGRP-immunoreactive boutons make presynaptic or symmetric contacts with GABAergic dendrites and soma. These findings suggest that the central endings of nociceptive primary afferents transmit pain stimuli to intrinsic inhibitory interneurons, thereby modulating nociceptive information via a postsynaptic circuit.
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PMID:Relationship of substance P- and CGRP-immunoreactive central endings of the primary afferent neurons to GABAergic interneurons in the guinea pig substantia gelatinosa. 958 14

Activation of GABA(B) receptors produces analgesia in acute and chronic pain models. Data indicate that a possible mechanism for this effect is a GABA(B) receptor-induced blockade of neurokinin-1 (NK-1) receptor gene expression in the spinal cord. While much more potent GABA(B) receptor agonists (CGP 44532) have been developed, there is no information on their antinociceptive properties or their ability to influence NK-1 receptors. To address these issues, rats were treated with baclofen or CGP 44532 and tested for sedation, ataxia, and pain-related behaviors in a chronic pain model (formalin hindpaw injection). In a separate group of experiments the analgesic response to a single dose of CGP 44532 was tested prior, and subsequent to, its chronic administration. The results indicate that CGP 44532 is a substantially more potent analgesic than baclofen. In addition, after chronic administration baclofen was no longer capable of inducing analgesia or of inhibiting the increased expression of NK-1R mRNA and CGP 44532 was still fully effective in both regards. The results suggest that GABA(B) agonists could be clinically useful analgesics.
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PMID:Regulation of neurokinin-1 receptor expression by GABA(B) receptor agonists. 958 30

The fact that centrally acting analgesics have abuse potential commensurate with their analgesic activity raises the question of whether these effects are related. The abuse potential of drugs depends on their ability to produce reinforcing effects, which are mediated by a neural system that includes the ventral tegmental dopamine cells and their connections with the ventral striatum. Morphine and amphetamine are both powerful analgesics and have high abuse potential. Their analgesic and reinforcing effects are mediated by similar receptors, similar sites of action, and overlapping neural substrates. These coincidences suggest that reinforcers may produce analgesia by transforming the aversive affective state evoked by pain into a more positive affective state. The implications of this hypothesis and its relation to other known mechanisms of analgesia are discussed. The hypothesis predicts that drugs with reinforcing effects should produce analgesia. A survey of drugs acting through 21 classes of receptors reveals that in 13 classes there is evidence for both analgesic and reinforcing effects that are approximately equipotent. The GABA(A) agonists were found to be the only drugs with confirmed abuse potential that lack analgesic activity. The interpretation of this and several other anomalous cases is discussed.
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PMID:Analgesia and abuse potential: an accidental association or a common substrate? 958 60

Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 micromol/kg, and 2.6 and 1.2 micromol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 micromol/site, and 0.4 and 0.9 micromol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 micromol/kg, 2.2 micromol/paw, 0.4 micromol/site and 0.14 micromol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 micromol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, L-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the L-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin. interaction of ATP-sensitive K+ channels, GABA(B) receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.
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PMID:Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests. Study of the mechanism of action. 959 21

This study used streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed mechanical hyperalgesia as soon as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the GABA(B) agonist, (+/-)baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)baclofen was necessary to reverse 4 week-diabetic rat hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-peptide antagonist for the substance P, neurokinin, (NK1) receptor, RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the N-methyl-D-aspartate (NMDA) receptor for glutamate, (+)MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced mechanical hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing pain. It is suggested that NMDA receptor antagonists may constitute an alternative therapy for diabetic neuropathic pain.
Pain 1998 May
PMID:A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. 969 68

Experimental studies indicate that the effects of spinal cord stimulation (SCS) on 'hypersymptoms' in neuropathic pain conditions may at least partly be mediated via GABAergic and adenosine-dependent mechanisms. Concomitant intrathecal administration of receptor-active drugs modulating the function of the GABA and adenosine systems may both depress and enhance the effects of SCS. The first few patients with simultaneous intrathecal administration of the GABAB agonist baclofen and/or adenosine together with SCS, when the stimulation alone proved insufficient, are reported.
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PMID:Modulation of spinal pain mechanisms by spinal cord stimulation and the potential role of adjuvant pharmacotherapy. 971 6


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