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)

We recently reported that micro-opioid receptor agonist morphine failed to induce its rewarding effects in rodents with sciatic nerve injury. In the present study, we investigated whether a state of neuropathic pain induced by sciatic nerve ligation could change the activities of the extracellular signal-regulated kinase (ERK) and p38 in the mouse lower midbrain area including the ventral tegmental area (VTA), and these changes could directly affect the development of the morphine-induced rewarding effect in mice. The sciatic nerve ligation caused a long-lasting and profound thermal hyperalgesia. A dose-dependent place preference induced by s.c. administration of morphine was observed in sham-operated mice, but not in sciatic nerve-ligated mice. We found here for the first time that nerve injury produces a sustained and significant reduction in protein levels of phosphorylated-ERK and -p38 in cytosolic preparations of the mouse lower midbrain. The inhibition of ERK activity by i.c.v. pre-treatment with either PD98059 or U0126 impaired the morphine-induced place preference. In contrast, i.c.v. treatment with a specific inhibitor of p38, SB203580, did not interfere with the morphine-induced rewarding effect. Immunohistochemical study showed a drastic reduction in phosphorylated-ERK immunoreactivity within tyrosine hydroxylase-positive cells of the VTA. These results suggest that a sustained reduction in the ERK-dependent signalling pathway in dopamine cells of the VTA may be implicated in the suppression of the morphine-induced rewarding effect under neuropathic pain.
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PMID:Role of extracellular signal-regulated kinase in the ventral tegmental area in the suppression of the morphine-induced rewarding effect in mice with sciatic nerve ligation. 1500 39

Group I metabotropic glutamate receptors (mGluRs) and their downstream signaling pathways, which involve the extracellular signal-regulated kinases (ERKs), have been implicated as mediators of plasticity in several pain models. In this study, we report that inflammation leads to a long-lasting enhancement of behavioral responses induced by activation of spinal group I mGluRs. Thus, the nocifensive response to intrathecal injection of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG) is significantly potentiated seven days following Complete Freund's Adjuvant (CFA)-induced inflammation of the hind paw. This potentiation is not associated with increased mGlu1 or mGlu5 receptor expression but is associated with increased levels of phosphorylated ERK in dorsal horn neurons. We also tested whether the increased behavioral response to DHPG following inflammation may be explained by enhanced coupling of the group I mGluRs to ERK activation. DHPG-induced ERK phosphorylation in the dorsal horn is not potentiated following inflammation. However, inhibiting ERK activation using a MEK inhibitor, U0126, following inflammation attenuates the intrathecal DHPG-induced behavioral responses to a greater extent than in control animals. The results from this study indicate that persistent ERK activation is required for the enhanced behavioral responses to spinal group I mGluR activation following inflammation and suggest that tonic modulation of ERK activity may underlie a component of central sensitization in dorsal horn neurons.
Pain 2004 Sep
PMID:Inflammation persistently enhances nocifensive behaviors mediated by spinal group I mGluRs through sustained ERK activation. 1532 16

Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
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PMID:Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. 1538 14

Damage to the nervous system can cause neuropathic pain, which is in general poorly treated and involves mechanisms that are incompletely known. Currently available animal models for neuropathic pain mainly involve partial injury of peripheral nerves. Multiple inflammatory mediators released from damaged tissue not only acutely excite primary sensory neurons in the peripheral nervous system, producing ectopic discharge, but also lead to a sustained increase in their excitability. Hyperexcitability also develops in the central nervous system (for instance, in dorsal horn neurons), and both peripheral and spinal elements contribute to neuropathic pain, so that spontaneous pain may occur or normally innocuous stimuli may produce pain. Inflammatory mediators and aberrant neuronal activity activate several signaling pathways [including protein kinases A and C, calcium/calmodulin-dependent protein kinase, and mitogen-activated protein kinases (MAPKs)] in primary sensory and dorsal horn neurons that mediate the induction and maintenance of neuropathic pain through both posttranslational and transcriptional mechanisms. In particular, peripheral nerve lesions result in activation of MAPKs (p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase) in microglia or astrocytes in the spinal cord, or both, leading to the production of inflammatory mediators that sensitize dorsal horn neurons. Activity of dorsal horn neurons, in turn, enhances activation of spinal glia. This neuron-glia interaction involves positive feedback mechanisms and is likely to enhance and prolong neuropathic pain even in the absence of ongoing peripheral external stimulation or injury. The goal of this review is to present evidence for signaling cascades in these cell types that not only will deepen our understanding of the genesis of neuropathic pain but also may help to identify new targets for pharmacological intervention.
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PMID:Cell signaling and the genesis of neuropathic pain. 1545 29

Activation of extracellular signal-regulated kinase (ERK), a mitogen activated-protein kinase (MAPK), in dorsal horn neurons contributes to inflammatory pain by transcription-dependent and -independent means. We have now investigated if ERK is activated in the spinal cord after a spinal nerve ligation (SNL) and if this contributes to the neuropathic pain-like behavior generated in this model. An L5 SNL induces an immediate (<10 min) but transient (<6 h) induction of phosphoERK (pERK) restricted to neurons in the superficial dorsal horn. This is followed by a widespread induction of pERK in spinal microglia that peaks between 1 and 3 days post-surgery. On Day 10, pERK is expressed both in astrocytes and microglia, but by Day 21 predominantly in astrocytes in the dorsal horn. In the L5 DRG SNL transiently induces pERK in neurons at 10 min, and in satellite cells on Day 10 and 21. Intrathecal injection of the MEK (ERK kinase) inhibitor PD98059 on Day 2, 10 or 21 reduces SNL-induced mechanical allodynia. Our results suggest that ERK activation in the dorsal horn, as well as in the DRG, mediates pain through different mechanisms operating in different cells at different times. The sequential activation of ERK in dorsal horn microglia and then in astrocytes might reflect distinct roles for these two subtypes of glia in the temporal evolution of neuropathic pain.
Pain 2005 Mar
PMID:ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. 1573 40

We recently reported that hyperalgesia induced by the inflammatory mediator prostaglandin E(2) (PGE(2)) requires intact alpha1, alpha3 and beta1 integrin subunit function, whereas epinephrine-induced hyperalgesia depends on alpha5 and beta1. PGE(2)-induced hyperalgesia is mediated by protein kinase A (PKA), while epinephrine-induced hyperalgesia is mediated by a combination of PKA, protein kinase Cepsilon (PKCepsilon) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). We hypothesized that inflammatory mediator-induced hyperalgesia involves specific interactions between different subsets of integrin subunits and particular second messenger species. In the present study, function-blocking anti-integrin antibodies and antisense oligodeoxynucleotides were used to elucidate these interactions in rat. Hyperalgesia produced by an activator of adenylate cyclase (forskolin) depended on alpha1, alpha3 and beta1 integrins. However, hyperalgesia induced by activation of the cascade at a point farther downstream (by cAMP analog or PKA catalytic subunit) was independent of any integrins tested. In contrast, hyperalgesia induced by a specific PKCepsilon agonist depended only on alpha5 and beta1 integrins. Hyperalgesia induced by agonism of MAPK/ERK depended on all four integrin subunits tested (alpha1, alpha3, alpha5 and beta1). Finally, disruption of lipid rafts antagonized hyperalgesia induced by PGE(2) and by forskolin, but not that induced by epinephrine. Furthermore, alpha1 integrin, but not alpha5, was present in detergent-resistant membrane fractions (which retain lipid raft components). These observations suggest that integrins play a critical role in inflammatory pain by interacting with components of second messenger cascades that mediate inflammatory hyperalgesia, and that such interaction with the PGE(2)-activated pathway may be organized by lipid rafts.
Pain 2005 May
PMID:Primary afferent second messenger cascades interact with specific integrin subunits in producing inflammatory hyperalgesia. 1583 82

Brain-derived neurotrophic factor (BDNF) is a neurotrophin implicated in the phenomena of synaptic plasticity in the adult. It is found in terminals of nociceptive primary afferents. Following a pain-related stimulus, it is released in the spinal cord, where it activates its high-affinity receptor TrkB, leading to the phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK). A large body of evidence suggests that BDNF has a positive neuromodulatory effect on glutamate transmission in the spinal cord. However, none of these studies examined anatomically whether projection neurons known to be involved in transmission of nociceptive inputs express BDNF's receptor. Because the spinothalamic tract (STT) is a well-characterized pathway for its role in the transfer and integration of sensory and nociceptive informations, this study in rats aimed to 1) determine whether neurons of the STT pathway express the TrkB receptor, 2) establish the rostrocaudal and laminar distribution of STT-TrkB neurons in the whole spinal cord, and 3) test the potential functionality of TrkB expression in these cells by investigating the ability of BDNF to activate the MAP kinase ERK. Using tract tracing coupled to immunofluorescent labeling for TrkB, we observed that in all levels of the spinal cord most STT neurons were immunoreactive for TrkB. Furthermore, microinjections of BDNF into the spinal cord or release of endogenous BDNF by intraplantar injection of capsaicin activated ERK phosphorylation in TrkB-containing STT neurons. These data suggest an important role for BDNF in nociception as an activator of spinothalamic projection neurons.
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PMID:TrkB expression and phospho-ERK activation by brain-derived neurotrophic factor in rat spinothalamic tract neurons. 1597 64

In both the spared nerve injury (SNI) and spinal nerve ligation (SNL) rat peripheral neuropathic pain models the presynaptic inhibitory effect of the mu opioid receptor (MOR) agonist (DAMGO) on primary afferent-evoked excitatory postsynaptic currents (EPSCs) and miniature EPSCs in superficial dorsal horn neurons is substantially reduced, but only in those spinal cord segments innervated by injured primary afferents. The two nerve injury models also reduce the postsynaptic potassium channel opening action of DAMGO on lamina II spinal cord neurons, but again only in segments receiving injured afferent input. The inhibitory action of DAMGO on ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons is also reduced in affected segments following nerve injury. MOR expression decreases substantially in injured dorsal root ganglion neurons (DRG), while intact neighboring DRGs are unaffected. Decreased activation of MOR on injured primary afferent central terminals and the second order neurons they innervate may minimize any reduction by opioids of the spontaneous pain mediated by ectopic input from axotomized small diameter afferents. Retention of MOR expression and activity in nearby non-injured afferents will enable, however, an opioid-mediated reduction of stimulus-evoked and spontaneous pain carried by intact nociceptor afferents and we find that intrathecal DAMGO (1000 ng) reduces mechanical hypersensitivity in rats with SNL. Axotomy-induced changes in MOR may contribute to opioid- insensitive components of neuropathic pain while the absence of these changes in intact afferents may contribute to the opioid sensitive components.
Pain 2005 Sep
PMID:Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord. 1609 68

Nerve injury results in neuropathic pain, a debilitating pain condition. Whereas cannabinoids are consistently shown to attenuate neuropathic pain, the efficacy of opioids is highly controversial. Molecular mechanisms underlying analgesic effects of opioids and cannabinoids are not fully understood. We have shown that the signaling molecule ERK (extracellular signal-regulated kinase) is activated by C-fiber stimulation in dorsal horn neurons and contributes to pain sensitization. In this study, we examined whether opioids and cannabinoids can affect C-fiber-induced ERK phosphorylation (pERK) in dorsal horn neurons in spinal cord slices from normal and spinal nerve-ligated rats. In normal control spinal slices, capsaicin induced a drastic pERK expression in superficial dorsal horn neurons, which was suppressed by morphine (10 microM), the selective mu-opioid receptor agonist DAMGO [[d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (1 microM)], and the selective CB1 receptor ACEA agonist [arachidonyl-2'-chloroethylamide (5 microM)]. One week after spinal nerve ligation when neuropathic pain is fully developed, capsaicin induced less pERK expression in the injured L(5)-spinal segment. This pERK induction was not suppressed by morphine (10 microM) and DAMGO (1 microM) but was enhanced by high concentration of DAMGO (5 microM). In contrast, ACEA (10 microM) was still very effective in inhibiting capsaicin-induced pERK expression. In the adjacent L(4) spinal segment, both DAMGO and ACEA significantly suppressed pERK induction by capsaicin. These results indicate that, after nerve injury, opioids lose their capability to suppress C-fiber-induced spinal neuron activation in the injured L(5) but not in the intact L(4) spinal segment, whereas cannabinoids still maintain their efficacy.
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PMID:Different effects of opioid and cannabinoid receptor agonists on C-fiber-induced extracellular signal-regulated kinase activation in dorsal horn neurons in normal and spinal nerve-ligated rats. 1622 38

When expressed via an inducible promoter in human embryonic kidney 293 cells, the rat Mas-related gene D (rMrgD) receptor responded to beta-alanine but not L-alanine by elevating intracellular [Ca(2+)], stimulating phosphorylation of the mitogenactivated protein kinases known as extracellular signal-regulated kinase (ERK) 1 and ERK2 and translocating from the plasma membrane to punctate intracellular vesicles. By contrast, the related rat Mas-related gene E (rMrgE) receptor did not respond to beta-alanine. Coexpression of rMrgD with rMrgE, which occurs in peripheral nociceptive neurons, allowed coimmunoprecipitation of the two receptors and resulted in the detection of cell surface rMrgD-rMrgE heterodimers via timeresolved fluorescence resonance energy transfer. These interactions increased the potency of beta-alanine to phosphorylate ERK1 and ERK2 as well as maintaining the capacity of beta-alanine to elevate intracellular [Ca(2+)], which was reduced in magnitude and slowed in response with increasing times of expression of rMrgD in isolation. Associated with these effects, the presence of rMrgE restricted beta-alanine-induced internalization of rMrgD. This is the first report of heterodimeric interactions between members of the Mas-related gene (Mrg) receptor family and indicates that interactions between rMrgD and rMrgE modulate the function of rMrgD. Because the Mrg receptors are potential therapeutic targets in pain, these results suggest that efforts to understand the function and regulation of individual Mrg family receptors may require coexpression of relevant pairs.
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PMID:Interactions between the Mas-related receptors MrgD and MrgE alter signalling and trafficking of MrgD. 1628 20


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