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)

The effect on the nociceptive tail-flick (TF) reflex of cardiopulmonary chemoreceptor and arterial baroreceptor activation, producing Bezold-Jarisch like- and baro-reflex responses, respectively, was analysed in lightly halothane-anaesthetized rats. Intra-cardiac administration of phenylbiguanide (5-100 microg/kg, into the right atrium) or veratrine (30-150 microg/kg, into the left ventricle), which both elicited the characteristic Bezold-Jarisch-like cardiovascular reflex responses (hypotension and bradycardia), produced a dose-dependent increase in TF latency. A similar inhibitory influence on the TF reflex was noted upon baroreflex activation by acute administration of phenylephrine (15-50 microg/kg i.v.) or aortic depressor nerve stimulation (100-400 microA). As expected from the involvement of local excitatory amino acid receptors in both vagally mediated cardiovascular reflex responses and inhibition of the TF reflex, microinjections of kynurenic acid (3 nmol/0.1 microl), an N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonist, into the nucleus tractus solitarius, prevented the cardiovascular responses as well as the concomitant increase in TF latency produced by cardiopulmonary chemoreceptor and baroreceptor stimulations. The present data show that induction of the cardiopulmonary chemoreceptor and baroreceptor reflexes produces an antinociceptive effect which can be assessed using the TF test, and that glutamate ionotropic receptors within the nucleus tractus solitarius mediate this effect.
Pain 2002 Sep
PMID:Antinociceptive effect of cardiopulmonary chemoreceptor and baroreceptor reflex activation in the rat. 1223 85

We investigated the expression of two candidate transducers of noxious stimuli in peripheral tissues, the vanilloid receptor subtype 1 (VR1) and the P2X(3), a subunit of the ionotropic P2X receptor for ATP, in spared L4 DRG neurons following L5 spinal nerve ligation, a neuropathic pain model. VR1 mRNA expression increased in the small- and medium-sized DRG neurons from the first to 28th day after injury, and this up-regulation corresponded well with the development and maintenance of thermal hyperalgesia of the hind paw. The increase in VR1-immunoreactive (ir) neurons was confirmed at the third day after surgery. In contrast, there was no change in expression of P2X(3) mRNA over 4 weeks after ligation, or in the percentage of P2X(3)-ir neurons observed 3 days after surgery. Our data suggests that increased VR1 in the spared L4 DRG may contribute to the exaggerated heat response observed in this neuropathic pain model. Taken together with the previous reports that P2X(3) expression increases in the spared DRG neurons in other neuropathic pain models, there appears to be differences in the phenotypic changes and pathomechanisms of the various neuropathic pain models.
Pain 2002 Sep
PMID:VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation. 1223 89

The present study examined the effect of a spinally administered excitatory amino acid antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1, 2.5, 5 microg) on responses of spinal dorsal horn neurons to graded intensities (20, 40, 60, 80 mmHg) of colorectal distention (CRD). Extracellular single unit recordings were made from 28 dorsal horn neurons in the L6-S2 spinal cord. Neurons excited by CRD were subclassified as short latency abrupt (SLA) neurons and short latency sustained (SLS) neurons. The response to graded intensities of CRD was dose-dependently attenuated in 9/17 SLA neurons (53%). The response to CRD was also dose-dependently attenuated in 8/11 SLS neurons (73%). The response to CRD in the remaining eight SLA neurons and three SLS neurons was not attenuated by CNQX. Comparing only neurons that were significantly attenuated by the CNQX, it was found that the magnitude of attenuation of the response to noxious CRD (80 mmHg) produced by 5 microg CNQX was significantly greater in SLA (63 +/-6%) vs. SLS (40 +/- 6%) neurons. While CNQX produced a significant attenuation of the response to innocuous CRD (20 mmHg), there was no difference between the SLA and SLS neurons. The effects of CNQX on the response to somatic stimulation (touch, pinch) of the cutaneous receptive field of these 28 neurons were qualitatively examined in all neurons and quantitatively examined in nine neurons (five SLA and four SLS neurons). CNQX generally decreased the response to pinch or touch, even if CNQX did not attenuate the response to CRD. These results suggest that subpopulations of SLA and SLS neurons are differentially modulated by non-NMDA ionotropic excitatory amino acid receptors and that these neuronal subtypes contribute differently to visceral sensory processing. Furthermore, the lack of correlation between the effects of CNQX on visceral and somatic sensory processing in the same neuron underscores potential differences in processing of visceral and somatic pain.
Pain 2002 Sep
PMID:Differential effects of spinal CNQX on two populations of dorsal horn neurons responding to colorectal distension in the rat. 1223 99

Drimanial, a new sesquiterpene isolated from the barks of the plant Drimys winteri (Winteraceae), given systemically, intraplantarly, or by spinal or supraspinal routes, produced pronounced antinociception against both phases of formalin-induced licking. The systemic injection of drimanial also inhibited, in a graded manner, the pain-related behaviours induced by intraplantar or intrathecal (i.t.) administration of glutamate. Moreover, drimanial also caused marked inhibition of the nociception induced by i.t. administration of a metabotropic glutamate agonist (1S,3R)-ACPD, without affecting nociceptive responses induced by ionotropic agonists (NMDA, kainate, AMPA) or by substance P. The antinociception caused by drimanial was not influenced by naloxone, nor did it interfere with the motor coordination of animals in the rota-rod test. Furthermore, drimanial caused graded inhibition of [(3)H]glutamate binding in cerebral cortical membranes from mice, with an IC(50) value of 4.39 micro M. Together, these results provide strong evidence indicating that the sesquiterpene drimanial produces antinociception in mice at peripheral, spinal and supraspinal sites. An interaction with metabotropic glutamate receptors seems to contribute to the mechanisms underlying its antinociceptive action.
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PMID:Evidence for the involvement of glutamatergic receptors in the antinociception caused in mice by the sesquiterpene drimanial. 1224 63

Adenosine is a ubiquitous homeostatic substance released from most cells, including neurones and glia. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors (GPCR; A(1), A(2A), A(2B), A(3)) that can inhibit (A(1)) or enhance (A(2)) neuronal communication. Interactions between adenosine receptors and other G-protein-coupled receptors, ionotropic receptors and receptors for neurotrophins also occur, and this might contribute to a fine-tuning of neuronal function. Manipulations of adenosine receptors influence sleep and arousal, cognition and memory, neuronal damage and degeneration, as well as neuronal maturation. These actions might have therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, as well as for other neurological situations such as epilepsy, idiopathic pain or even drug addition. Peripheral side effects associated with adenosine receptor agonists limit their usefulness in therapeutics; in contrast, adenosine receptor antagonists appear to have less side effects as it is the case of the well-known non-selective antagonists theophylline (present in tea) or caffeine (abundant in coffee and tea), and their emerging beneficial actions in Parkinson's disease and Alzheimer's disease are encouraging. A(1) receptor antagonism may also be useful to enhance cognition and facilitate arousal, as well as in the periphery when deficits of neurotransmitter release occur (e.g. myasthenic syndromes). Enhancement of extracellular adenosine levels through drugs that influence its metabolism might prove useful approaches in situations such as neuropathic pain, where enhanced activation of inhibitory adenosine A(1) receptors is beneficial. One might then consider adenosine as a fine-tuning modulator of neuronal activity, which via subtle effects causes harmonic actions on neuronal activity. Whenever this homeostasis is disrupted, pathology may be installed and selective receptor antagonism or agonism required.
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PMID:Adenosine receptors in the nervous system: pathophysiological implications. 1257 92

Activation of spinal cord dorsal horn ionotropic glutamate receptors leads to pain-related behaviors. However, the role of spinal metabotropic glutamate receptors (mGlu), particularly the mGlu5 receptor subtype, in nociception has not been well characterized. A recently described subtype selective and potent mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP) was used to evaluate the role of the mGlu5 receptor in cold sensitivity. Intrathecal (i.t.) injection of group I (mGlu1 and mGlu5 receptors) mGlu receptor-selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) increased the hind paw frequency and duration of lifting of rats placed on a cold (4 degrees C) surface, a behavior similarly observed in rats with a chronic constriction injury (CCI) of the sciatic nerve. In contrast, rats i.t. injected with DHPG did not display increased lifting when placed on a room temperature surface. I.t. injection of MPEP before i.t. injection of DHPG blocked DHPG-evoked cold hypersensitivity, suggesting that activation of spinal mGlu5 receptors induces this behavioral response. In contrast, i.t. injection of MPEP after i.t. injection of DHPG had no effect. In addition, i.t. injection of MPEP did not affect cold hypersensitivity in rats with a CCI. These data suggest that acute activation of spinal cord mGlu5 receptors results in increased sensitivity to cold, but ongoing cold hypersensitivity does not involve activation of the mGlu5 receptor.
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PMID:Acute activation of the spinal cord metabotropic glutamate subtype-5 receptor leads to cold hypersensitivity in the rat. 1264 79

We have studied the modulatory effect of dehydroepiandrosterone (DHEA), the most abundant neurosteroid produced by glial cells and neurones, on membrane currents induced by the activation of ionotropic ATP (P2X) receptors in neonatal rat dorsal root ganglion neurones. ATP (1 microM) induced three types of currents/responses termed F (fast and transient), S (slowly desensitizing) and M (mixed, sum of F- and S-type responses). DHEA (10 nM to 100 microM) concentration-dependently increased the amplitude of plateau-like currents of S- and M-type responses evoked by submaximal (1 microM) but not saturating (100 microM or 1 mM) concentrations of ATP. Alphabeta-methylene ATP (alphabetame-ATP, 5 microM) also evoked F-, S- and M-type responses, the plateau phases of which were potentiated by lowering external pH (6.3) and by ivermectin (IVM, 3 microM), indicating the presence heteromeric P2X2-containing receptors and possibly of functional native P2X4/6 receptors. There was a strict correlation between the potentiating effects of low pH and DHEA on alphabetame-ATP responses but not between that of IVM and DHEA, suggesting that DHEA selectively modulated P2X2-containing receptors. DHEA also potentiated putative homomeric P2X2 receptor responses recorded in the continuous presence of 1 microM 2'-(or 3')-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP). Our results constitute the first demonstration of a fast potentiation of P2X receptors by a neurosteroid and suggest that DHEA could be an endogenous modulator of P2X2-containing receptors thereby contributing to the facilitation of the detection and/or the transmission of nociceptive messages, particularly under conditions of inflammatory pain where the P2X receptor signalling pathway appears to be upregulated.
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PMID:Dehydroepiandrosterone potentiates native ionotropic ATP receptors containing the P2X2 subunit in rat sensory neurones. 1284 12

Pain after nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.
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PMID:P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. 1291 63

There is strong evidence for the presence of nucleotide (P2) receptors in sensory neurons, which might play a role in the transmission of pain signals. In contrast, virtually nothing is known about P2 receptors in satellite glial cells (SGCs), which are the main glial cells in sensory ganglia. We investigated the possibility that P2 receptors exist in SGCs in murine trigeminal ganglia, using Ca(2+) imaging, patch-clamp recordings, and immunohistochemistry. We found that ATP caused an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in SGCs. As adenosine had no effect on [Ca(2+)](i), and the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid largely blocked the response to ATP we conclude that P1 receptors did not contribute to the responses. We obtained the following evidence that the responses to ATP were mediated by metabotropic P2Y receptors: (i) persistence of the responses in Ca(2+)-free solution, (ii) inhibition of the response by cyclopiazonic acid, (iii) [Ca(2+)](i) increases in response to the P2Y agonists uridine triphosphate, adenosine thiodiphosphate, and 2-methylthio ADP, and (iv) failure of the P2X agonist alpha,beta-methylene ATP to elicit a response. Agonists of P2Y(1) receptors and uridine triphosphate, an agonist at P2Y(2) and P2Y(4) receptors, induced [Ca(2+)](i) increases suggesting that at least these P2Y receptor subtypes are present on SGCs. Using an antibody against the P2Y(4) receptor, we found immunopositive SGCs. Patch-clamp recordings of SGCs did not reveal any inward current due to ATP. Therefore, there was no evidence for the activation of ionotropic P2X receptors under the present conditions. The results indicate the presence of functional nucleotide (P2Y) receptors in SGCs.
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PMID:P2 receptors in satellite glial cells in trigeminal ganglia of mice. 1292 3

Neuropathic pain and epileptic seizures bear several similarities, among them is the response to anticonvulsant drugs. It has therefore been hypothesized that epileptiform activity of nociceptive spinal dorsal horn neurons may contribute to paroxysmal forms of neuropathic pain. We used patch-clamp and field potential recordings from young rat spinal cord slices to test if nociceptive dorsal horn structures are indeed able to sustain epileptiform activity. Application of the convulsant 4-aminopyridine (100 microM) evoked epileptiform activity that was most pronounced in superficial dorsal horn and involved nociceptive lamina I neurons with a projection to the brain. The epileptiform activity was dependent on fast excitatory and inhibitory synaptic transmission through ionotropic glutamate receptors and GABA(A) receptors. During epileptiform activity, previously silent polysynaptic pathways from primary afferent C-fibers to superficial dorsal horn neurons were opened. Stimulation of primary afferents at Adelta- and C-fiber intensity interfered with the epileptiform rhythm, suggesting that both affect the same dorsal horn structures. Similar to neuropathic pain, spinal dorsal horn epileptiform activity was much less reduced by classical analgesics than by anticonvulsant agents.
Pain 2003 Sep
PMID:Epileptiform activity in rat spinal dorsal horn in vitro has common features with neuropathic pain. 1449 51


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