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)

Glutamate is the major fast excitatory transmitter in the central nervous system. While normal synaptic transmission is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, N-methyl-D-aspartate (NMDA) receptors are thought to selectively contribute to plasticity. Genetically enhancing NMDA receptor functions enhances animal behavior in normal physiological learning and enhances their sensitivity in the case of tissue injury. One major mechanism for NMDA receptors is synaptic long-term potentiation (LTP). Here we present evidence that NMDA receptors not only contribute to normal synaptic responses induced by stimulation of local layer V or white matters, but also contribute to generation of action potentials induced by a depolarizing step applied to the soma. Calcium-calmodulin sensitive adenylyl cyclase 1 and cAMP signal pathways likely mediate these effects. Considering the importance of cingulate neurons in nociception and pain, our results provide a new mechanism for NMDA receptor contributing to neuronal synaptic transmission, spiking properties in forebrains, and possible forebrain-related behavioral nociceptive responses and pain.
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PMID:Forebrain NMDA receptors contribute to neuronal spike responses in adult mice. 1717 85

Management of pain by opioid analgesics is confounded by central adverse effects that limit clinical dosages. Consequently, there is considerable interest to understand peripheral analgesic effects of opioids. The actions of opioids on peripheral sensory neurons have been difficult to study because of a general lack of effect of opioid agonists on nociceptor function in culture despite documented presence of opioid receptors. In this study, the micro-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO), did not alter guanosine 5'-O-(3-[(35)S]thio)-triphosphate (GTPgamma[(35)S]) binding, adenylyl cyclase activity, or neuropeptide release in primary cultures of rat trigeminal ganglion (TG). However, after brief exposure to bradykinin (BK), DAMGO stimulated GTPgamma[(35)S] binding and inhibited both prostaglandin E(2) (PGE(2))-stimulated adenylyl cyclase activity and BK/PGE(2)-stimulated neuropeptide release. The effect of BK was blocked by the B(2) antagonist HOE 140 [D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin], but not by the B(1) antagonist, Lys-[Leu8]des-Arg9-BK, and was mimicked by the protease-activated receptor-2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-NH(2), and by activation of protein kinase C (PKC) or by administration of arachidonic acid (AA). The enhanced responsiveness of micro-opioid receptor signaling by BK priming was blocked by both cyclooxygenase and PKC inhibitors; however, the effect of AA was blocked only by a cyclooxygenase inhibitor. The results indicate that micro-opioid receptor signaling in primary sensory TG neurons is enhanced by activation of phospholipase C-coupled receptors via a cyclooxygenase-dependent AA metabolite that is downstream of PKC.
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PMID:Rapid modulation of micro-opioid receptor signaling in primary sensory neurons. 1734 22

Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.
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PMID:Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5. 1741 Jun 41

Prostaglandin E2 (PGE2) is a well-known inflammatory mediator that enhances the excitability of DRG neurons. Homomeric P2X3 and heteromeric P2X2/3 receptors are abundantly expressed in dorsal root ganglia (DRG) neurons and participate in the transmission of nociceptive signals. The interaction between PGE2 and P2X3 receptors has not been well delineated. We studied the actions of PGE2 on ATP-activated currents in dissociated DRG neurons under voltage-clamp conditions. PGE2 had no effects on P2X2/3 receptor-mediated responses, but significantly potentiated fast-inactivating ATP currents mediated by homomeric P2X3 receptors. PGE2 exerted its action by activating EP3 receptors. To study the mechanism underlying the action of PGE2, we found that the adenylyl cyclase activator, forskolin and the membrane-permeable cAMP analogue, 8-Br-cAMP increased ATP currents, mimicking the effect of PGE2. In addition, forskolin occluded the enhancement produced by PGE2. The protein kinase A (PKA) inhibitors, H89 and PKA-I blocked the PGE2 effect. In contrast, the PKC inhibitor, bisindolymaleimide (Bis) did not change the potentiating action of PGE2. We further showed that PGE2 enhanced alpha,beta-meATP-induced allodynia and hyperalgesia and the enhancement was blocked by H89. These observations suggest that PGE2 binds to EP3 receptors, resulting in the activation of cAMP/PKA signaling pathway and leading to an enhancement of P2X3 homomeric receptor-mediated ATP responses in DRG neurons.
Mol Pain 2007 Aug 10
PMID:Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons. 1769 21

The GABA(B) receptor-mediated presynaptic inhibition of glycinergic transmission was studied from young rat substantia gelatinosa (SG) neurons using a conventional whole-cell patch clamp technique. Action potential-dependent glycinergic inhibitory postsynaptic currents (IPSCs) were recorded from SG neurons in the presence of 3 mM kynurenic acid and 10 microM SR95531. In these conditions, baclofen (30 microM), a selective GABA(B) receptor agonist, greatly reduced the amplitude of glycinergic IPSCs and increased the paired-pulse ratio. Such effects were completely blocked by 3 microM CGP55845, a selective GABA(B) receptor antagonist, indicating that the activation of presynaptic GABA(B) receptors decreases glycinergic synaptic transmission. Glycinergic IPSCs were largely dependent on Ca2+ influxes passing through presynaptic N- and P/Q-type Ca2+ channels, and these channels contributed equally to the baclofen-induced inhibition of glycinergic IPSCs. However, the baclofen-induced inhibition of glycinergic IPSCs was not affected by either 100 microM SQ22536, an adenylyl cyclase inhibitor, or 1 mM Ba2+, a G-protein coupled inwardly rectifying K+ channel blocker. During the train stimulation (10 pulses at 20 Hz), which caused a marked synaptic depression of glycinergic IPSCs, baclofen at a 30 microM concentration completely blocked glycinergic synaptic depression, but at a 3 microM concentration it largely preserved glycinergic synaptic depression. Such GABA(B) receptor-mediated dynamic changes in short-term synaptic plasticity of glycinergic transmission onto SG neurons might contribute to the central processing of sensory signals.
Pain 2008 Aug 31
PMID:GABA(B) receptor-mediated presynaptic inhibition of glycinergic transmission onto substantia gelatinosa neurons in the rat spinal cord. 1825 70

Recent studies suggest that sustained morphine-mediated paradoxical pain may play an important role in the development of analgesic tolerance. The intracellular signal transduction pathways involved in sustained opioid mediated augmentation of spinal pain neurotransmitter (such as calcitonin gene-related peptide (CGRP)) release are not fully clarified. Cyclic AMP (cAMP)-dependent protein kinase (PKA) plays an important role in the modulation of presynaptic neurotransmitter release. Moreover, we have shown earlier that sustained opioid agonist treatment leads to a Raf-1-dependent sensitization of adenylyl cyclase(s) (AC superactivation), augmenting forskolin-stimulated cAMP formation upon opioid withdrawal (cAMP overshoot). Therefore, in the present study we examined the role of Raf-1 in sustained morphine-mediated regulation of cAMP formation and basal CGRP release in vitro, in cultured neonatal rat dorsal root ganglion (DRG) neurons. We found that sustained morphine treatment significantly augments intracellular cAMP production as well as basal CGRP release from cultured neonatal rat DRG neurons. The selective PKA inhibitor, H-89, attenuates the sustained morphine-mediated augmentation of basal CGRP release, indicating that the cAMP/PKA pathway plays an important role in regulation of CGRP release from sensory neurons. Since our present data also demonstrated that selective Raf-1 inhibitor, GW 5074, attenuated both the cAMP overshoot and the augmentation of CGRP release mediated by sustained morphine in neonatal rat DRG neurons, we suggest that Raf-1-mediated sensitization of the intracellular cAMP formation may play an important role in sustained morphine-mediated augmentation of spinal pain neurotransmitter release.
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PMID:Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner. 1832 77

Identification of adaptations to chronic morphine that are causally associated with opioid tolerance formation has long been intensely pursued by the opioid research community. There is an impressive array of components of signaling pathways that are influenced by chronic opioid administration. This underscores the importance to tolerance mechanisms of the complex interplay of cellular adaptations that are downstream from the opioid receptor. A major impetus for this research remains the need to develop opioid agonists that are potent and efficacious activators of analgesic mechanisms without triggering opioid tolerance-producing adaptations. Implicit in most models of opioid tolerance is that their underlying mechanisms are invariant and independent of the system in which they have been observed. Reports that prior acute morphine treatment and pain could influence tolerance mechanisms were not understood on mechanistic levels and, consequently, were not incorporated into commonly used models of opioid tolerance. The recent demonstration that adenylyl cyclase/cAMP-related cellular adaptations to chronic morphine depend on cell state demonstrates that ongoing cell physiology is a critical determinant of tolerance mechanisms. The plasticity and pliability of cellular adaptations that mediate tolerance formation indicate that mechanisms underlying opioid analgesic tolerance could be a moving target. Although this might represent a daunting barrier to developing antitolerance pharmacotherapies, appreciation of this complexity could lead to the development of new pharmacotherapeutic approaches.
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PMID:The ambiguities of opioid tolerance mechanisms: barriers to pain therapeutics or new pain therapeutic possibilities. 1835 57

A major site of extrahypothalamic expression of corticotropin-releasing factor (CRF) and its G-protein-coupled CRF1 and CRF2 receptors is the amygdala, a key player in emotions and affective disorders. Pain-related plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) generates emotional-affective responses and anxiety-like behavior. CRF1 receptor antagonists have anxiolytic effects. Although both CRF1 and CRF2 receptors couple positively to adenylyl cyclase, they can have opposite effects, but the underlying mechanism is unknown. This study addressed CRF1 and CRF2 receptor functions and mechanisms in the amygdala in a model of arthritic pain. Using whole-cell patch-clamp recordings of CeLC neurons, we found that a selective CRF1 receptor antagonist (NBI27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)]) amino-pyridine inhibited synaptic facilitation in brain slices from arthritic rats through a postsynaptic mechanism. Inhibition of the NMDA receptor-mediated synaptic component was occluded by a protein kinase A (PKA) inhibitor, consistent with our previous demonstration of PKA-dependent increased NMDA receptor function in arthritis pain-related plasticity. NBI27914 also decreased neuronal excitability through inhibition of highly tetraethylammonium (TEA)-sensitive ion channels that contribute to action potential repolarization and firing rate. In contrast, a CRF2 receptor antagonist (astressin-2B [cyclo(31-34) [d-Phe11,His12,C alphaMeLeu13,39, Nle17, Glu31, Lys34] Ac-Sauvagine(8-40)]) facilitated synaptic transmission through presynaptic inhibition of GABAergic transmission (disinhibition). NBI27914 inhibited arthritis pain-related behaviors (audible and ultrasonic vocalizations and hindlimb withdrawal reflexes). Astressin-2B had no significant behavioral effect. The data suggest that endogenous CRF1 receptor activation in the amygdala contributes to pain-related synaptic facilitation, increased excitability, and pain behavior through a postsynaptic mechanism involving activation of PKA and highly TEA-sensitive K(+)-currents. Presynaptic CRF2 receptor-mediated inhibition does not reach behavioral significance.
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PMID:Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. 1840 Aug 85

The fragile X syndrome is caused by the lack of fragile X mental retardation protein (FMRP) attributable to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the CNS contribute to different brain functions, including learning/memory, mental disorders, drug addiction, and persistent pain. Most of the previous studies have been focused on downstream targets of FMRP in hippocampal neurons, and fewer studies have been reported for the second-messenger signaling pathways between group I mGluRs and FMRP. Furthermore, no molecular study has been performed in the anterior cingulate cortex (ACC), a key region involved in high brain cognitive and executive functions. In this study, we demonstrate that activation of group I mGluR upregulated FMRP in ACC neurons of adult mice through the Ca(2+)-dependent signaling pathways. Using genetic approaches, we found that Ca(2+)/calmodulin-stimulated adenylyl cyclase 1 (AC1) and calcium/calmodulin-dependent kinase IV (CaMKIV) contribute to the upregulation of FMRP induced by stimulating group I mGluRs. The upregulation of FMRP occurs at the transcriptional level. The cAMP-dependent protein kinase is activated by stimulating group I mGluRs through AC1 in ACC neurons. Both AC1 and CaMKIV contribute to the regulation of FMRP by group I mGluRs probably through cAMP response element-binding protein activation. Our study has provided the first evidence for a molecular link between group I mGluRs and FMRP in ACC neurons and may help us to understand the pathogenesis of fragile X syndrome.
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PMID:Roles of calcium-stimulated adenylyl cyclase and calmodulin-dependent protein kinase IV in the regulation of FMRP by group I metabotropic glutamate receptors. 1843 17

Neuropathic pain is caused by a primary lesion or dysfunction in the nervous system. Investigations have mainly focused on the spinal mechanisms of neuropathic pain, and less is known about cortical changes in neuropathic pain. Here, we report that peripheral nerve injury triggered long-term changes in excitatory synaptic transmission in layer II/III neurons within the anterior cingulate cortex (ACC). Both the presynaptic release probability of glutamate and postsynaptic glutamate AMPA receptor-mediated responses were enhanced after injury using the mouse peripheral nerve injury model. Western blot showed upregulated phosphorylation of GluR1 in the ACC after nerve injury. Finally, we found that both presynaptic and postsynaptic changes after nerve injury were absent in genetic mice lacking calcium-stimulated adenylyl cyclase 1 (AC1). Our studies therefore provide direct integrative evidence for both long-term presynaptic and postsynaptic changes in cortical synapses after nerve injury, and that AC1 is critical for such long-term changes. AC1 thus may serve as a potential therapeutic target for treating neuropathic pain.
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PMID:Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. 1863 48


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