Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Voltage-gated K(+) channel alpha subunits Kv 4.2 and Kv 4.3 are the major contributors of somatodendritic A-type K(+) currents in many CNS neurons. A recent hypothesis suggests that Kv 4 subunits may be involved in pain modulation in dorsal horn neurons. However, whether Kv 4 subunits are expressed in dorsal horn neurons remains unknown. Using immunohistochemistry, we found that Kv 4.2 and Kv 4.3 immunoreactivity was concentrated in the superficial dorsal horn, mainly in lamina II. Both Kv 4.2 and Kv 4.3 appeared on many rostrocaudally orientated dendrites, whereas Kv 4.3 could be also detected from certain neuronal somata. Kv 4.3(+) neurons were a subset of excitatory inerneurons with calretinin(+)/calbindin(-)/PKCgamma(-) markers, and a fraction of them expressed micro-opioid receptors. Kv 4.3(+) neurons also expressed ERK 2 and mGluR 5, which are molecules related to the induction of central sensitization, a mechanism mediating nociceptive plasticity. Together with the expression of Kv 4.3 in VR 1(+) DRG neurons, our data suggest that Kv C4 subunits could be involved in pain modulation.
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PMID:Expression of A-type K channel alpha subunits Kv 4.2 and Kv 4.3 in rat spinal lamina II excitatory interneurons and colocalization with pain-modulating molecules. 1617 57

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

Although migraine is more common in women than men and often linked to the menstrual cycle, few studies have investigated the biological basis of hormonal influences on the trigeminovascular system. In the present study we investigated the effect of physiological levels (10(-9) m) oestrogen on female rat trigeminal ganglia in vitro. Immunocytochemical analysis demonstrated the presence of oestrogen receptor-alpha in a predominantly cytoplasmic location and in neurites. Microarray analysis demonstrated that oestrogen treatment regulates several genes with potential relevance to menstrual migraine. The genes that were upregulated included synapsin-2, endothelin receptor type B, activity and neurotransmitter-induced early gene 7 (ania-7), phosphoserine aminotransferase, MHC-1b, and ERK-1. Down-regulated genes included IL-R1, bradykinin B2 receptor, N-tropomodulin, CCL20, GABA transporter protein, fetal intestinal lactase-phlorizin hydrolase, carcinoembryonic antigen-related protein, zinc finger protein 36, epsin 1 and cysteine string protein. Protein activity assays demonstrated that exposure of the cultured neurons to oestrogen leads to activation of ERK, which has been linked to inflammatory pain. Immunocytochemistry demonstrated that activated ERK was present in neurons containing peripherin, a marker of nociceptive neurons. Several of the genes in the present study may provide potential targets for understanding the association of oestrogen with migraine and other hormone-related orofacial pain.
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PMID:Effects of oestrogen on trigeminal ganglia in culture: implications for hormonal effects on migraine. 1639 64

The phosphorylated Extracellular Signal-regulated Kinase (pERK) and Fos expression and masticatory muscle activity were analyzed in rats with capsaicin-induced acute inflammation of the tooth pulp in order to clarify the role of the spinal trigeminal nucleus and upper cervical spinal cord in tooth pulp pain. Digastric and masseteric muscle activities were significantly increased following capsaicin injection into the molar tooth pulp but not after vehicle treatment. The pERK-like immunoreactive (LI) neurons were observed in the subnuclei interpolaris-caudalis transition (Vi/Vc) zone, the paratrigeminal nucleus (Pa5) and the superficial laminae of the caudal Vc/C2 zone. The pERK expression was detected as early as 2 min and peaked at 5 min after capsaicin or vehicle injection. The pERK expression in the Vi/Vc zone and Pa5 was bilateral, whereas it was predominantly ipsilateral in the caudal Vc/C2 zone. The capsaicin treatment of the whisker pad produced pERK expression in the rostro-caudal middle portion of the ipsilateral Vc, but small number of pERK-LI cells were observed after vehicle treatment. The pERK expression was similar in the Vi/Vc zone following capsaicin injection into the upper or lower molar tooth pulp, whereas the pERK expression was in the lateral portion of the caudal Vc/C2 zone after upper molar injection and restricted to the medial portion of the Vc/C2 zone after the lower molar capsaicin. These data were confirmed with Western blots. There were differences in the distribution of Fos protein-like immunoreactive (LI) cells and pERK-LI cells following tooth pulp stimulation. After capsaicin application into the upper molar tooth pulp, no pERK-LI cells were observed in the ventral part of the Vi/Vc zone, whereas many Fos protein-LI cells were expressed in this region. The difference in the distribution pattern of pERK- and Fos protein-LI cells in the Vi/Vc zone suggests their differential temporal expression profiles after capsaicin. The present findings suggest that tooth-pulp-driven neurons in the spinal trigeminal nucleus are involved in tooth pulp pain through activation of the intracellular signal transduction pathway that involves earlier ERK phosphorylation and subsequent Fos expression.
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PMID:Phosphorylation of Extracellular Signal-Regulated Kinase in medullary and upper cervical cord neurons following noxious tooth pulp stimulation. 1644 86

In the present study, we investigated the role of phosphorylated calcium/calmodulin-dependent protein kinase II (pCaMK-II) and phosphorylated extracellular signal-regulated protein kinase (pERK) in nociceptive processing at the spinal and supraspinal levels in the formalin subcutaneous induced mouse pain model. In the immunoblot assay, subcutaneous (s.c.) injection with formalin increased the pERK and pCaMK-IIalpha level in the spinal cord, and an immunohistochemical study showed that the increase of pERK and pCaMK-IIalpha immunoreactivity mainly occurred in the laminae I and II areas of the spinal dorsal horn. At the supraspinal level, although pERK was not changed in the hippocampus induced by formalin s.c. injection, pCaMK-IIalpha was increased in the hippocampus and hypothalamus by s.c. formalin injection, and an increase of pCaMK-IIalpha immunoreactivity mainly occurred in the pyramidal cells and the stratum lucidum/radiatum layer of the CA3 region of hippocampus and paraventricular nucleus of the hypothalamus. Moreover, pERK immunoreactivity in the hypothalamic paraventricular nucleus was also increased. The second phase of nociceptive behavior induced by formalin administered either i.t. or intracerebroventricularly (i.c.v.) was attenuated by PD98059 (ERK inhibitor) as well as KN-93(a CaMK-II inhibitor). On the other hand, the first phase of nociceptive behavior induced by formalin s.c. injection was not affected by i.t. KN-93. Our results suggest that pERK and pCaMK-II located at both the spinal cord and supraspinal levels are an important regulator during the nociceptive processes induced by formalin administered s.c. respectively.
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PMID:Involvement of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse formalin pain model. 1686 46

Chronic inflammation of the urinary bladder generates hyperalgesia and allodynia. Growing evidence suggests a role of ERK in mediating somatic and visceral pain processing. In the present studies, we characterized and compared the activation of two ERK isoforms, ERK1/2 and ERK5, in micturition pathways, including the urinary bladder, lumbosacral dorsal root ganglia (DRG), and spinal cord in adult female and male rats before and after cyclophosphamide (CYP)-induced bladder inflammation. Results showed differential activation of ERK1/2 and ERK5 in these regions following cystitis. The level of phospho-ERK1/2 but not phospho-ERK5 was increased in the urinary bladder; the level of phospho-ERK5 but not phospho-ERK1/2 was increased in DRG; and the level of phospho-ERK1/2 but not phospho-ERK5 was increased in lumbar spinal cord following cystitis compared with control. Cystitis-induced upregulation of phospho-ERK1/2 and phospho-ERK5 was time dependent and showed similar patterns in female and male rats. The level of phospho-ERK1/2 in bladder was increased at 2 and 8 h after CYP injection; the level of phospho-ERK5 in DRG was increased at 8 and 48 h after CYP injection; and the level of phospho-ERK1/2 in lumbar spinal cord was increased at 48 h after CYP injection. The result that phospho-ERK5 was exclusively increased in DRG neurons, while phospho-ERK1/2 was increased in the spinal cord and the urinary bladder after cystitis, suggests a region-specific effect of neurotrophins on micturition pathways following bladder inflammation.
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PMID:Region-specific changes in the phosphorylation of ERK1/2 and ERK5 in rat micturition pathways following cyclophosphamide-induced cystitis. 1711 May 31

Serotonin (5-HT) derived from bulbo-spinal projection is released by nociceptive input into the spinal dorsal horn. Here we report that formalin injection in the paw produced pain behavior (flinching) and phosphorylation of spinal ERK1/2 (P-ERK1/2, indicating activation) in rats. Depletion of spinal 5-HT by intrathecal (IT) 5,7-DHT, a serotonergic neurotoxin, profoundly reduced formalin evoked flinching and the increase in P-ERK1/2. Ondansetron (a 5-HT3 receptor antagonist) at IT doses that inhibited flinching also attenuated spinal ERK activation. These findings reveal that primary afferent-evoked activation of spinal ERK requires the input from an excitatory 5-HT descending pathway.
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PMID:Descending serotonergic facilitation of spinal ERK activation and pain behavior. 1711 81

Agonists of protease-activated receptor 2 (PAR(2)) evoke hyperexcitability of dorsal root ganglia (DRG) neurons by unknown mechanisms. We examined the cellular mechanisms underlying PAR(2)-evoked hyperexcitability of mouse colonic DRG neurons to determine their potential role in pain syndromes such as visceral hyperalgesia. Colonic DRG neurons were identified by injecting Fast Blue and DiI retrograde tracers into the mouse colon. Using immunofluorescence, we found that DiI-labelled neurons contained PAR(2) immunoreactivity, confirming the presence of receptors on colonic neurons. Whole-cell current-clamp recordings of acutely dissociated neurons demonstrated that PAR(2) activation with a brief application (3 min) of PAR(2) agonists, SLIGRL-NH(2) and trypsin, evoked sustained depolarizations (up to 60 min) which were associated with increased input resistance and a marked reduction in rheobase (50% at 30 min). In voltage clamp, SLIGRL-NH(2) markedly suppressed delayed rectifier I(K) currents (55% at 10 min), but had no effect on the transient I(A) current or TTX-resistant Na(+) currents. In whole-cell current-clamp recordings, the sustained excitability evoked by PAR(2) activation was blocked by the PKC inhibitor, calphostin, and the ERK(1/2) inhibitor PD98059. Studies of ERK(1/2) phosphorylation using confocal microscopy demonstrated that SLIGRL-NH(2) increased levels of immunoreactive pERK(1/2) in DRG neurons, particularly in proximity to the plasma membrane. Thus, activation of PAR(2) receptors on colonic nociceptive neurons causes sustained hyperexcitability that is related, at least in part, to suppression of delayed rectifier I(K) currents. Both PKC and ERK(1/2) mediate the PAR(2)-induced hyperexcitability. These studies describe a novel mechanism of sensitization of colonic nociceptive neurons that may be implicated in conditions of visceral hyperalgesia such as irritable bowel syndrome.
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PMID:Mechanisms of protease-activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon. 1728 84

The phosphorylation of extracellular signal-regulated kinase (pERK) in DRG and dorsal horn neurons is induced by the C-fiber electrical stimulation to the peripheral nerve. The present study was designed to investigate the expression and modulation of pERK in the rat dorsal horn neurons produced by repetitive electrical stimulation, and its involvement in the electrophysiological activity of dorsal horn neurons. Electrical stimulation of C-fiber intensity at different frequencies was applied to the sciatic nerve; the stimuli-induced pERK expression and the activity in dorsal horn neurons were studied by immunohistochemistry and extracellular recording, respectively. Electrical stimulation of C-fibers (3 mA) induced pERK expression in dorsal horn neurons in a frequency-dependent manner, indicating that the frequency of electrical stimulation is an important factor which activates the intracellular signal pathway in the spinal cord. To demonstrate the underlying mechanism of this frequency-dependent pERK expression, an NMDA receptor antagonist, MK-801, and a voltage sensitive calcium channel antagonist, nifedipine, were administrated intrathecally before the stimulation. We found that high frequency (0.5 Hz and 10 Hz) but not low frequent (0.05 Hz) stimulus-evoked pERK was partially inhibited by MK-801. Both high and low frequency stimulus-evoked pERK were inhibited by the nifedipine treatment. The extracellular single unit activities were recorded from the laminae I-II and V of the L4-5 dorsal horn, and we found that blockage of the intracellular ERK signal suppressed the wind-up responses in a dose-dependent manner. In contrast, any change in the mechanically evoked responses was not observed following the administration of ERK inhibitor. These observations indicate that ERK activation plays an important role in the induction of the wind-up responses in dorsal horn nociceptive neurons.
Mol Pain 2007 Jul 16
PMID:Frequency-dependent ERK phosphorylation in spinal neurons by electric stimulation of the sciatic nerve and the role in electrophysiological activity. 1763 90

Current therapies to treat skeletal fracture pain are extremely limited. Some non-steroidal anti-inflammatory drugs have been shown to inhibit bone healing and opiates induce cognitive dysfunction and respiratory depression which are especially problematic in the elderly suffering from osteoporotic fractures. In the present report, we developed a closed femur fracture pain model in the mouse where skeletal pain behaviors such as flinching and guarding of the fractured limb are reversed by 10mg/kg morphine. Using this model we showed that the administration of a monoclonal antibody against nerve growth factor (anti-NGF) reduced fracture-induced pain-related behaviors by over 50%. Treatment with anti-NGF reduced c-Fos and dynorphin up-regulation in the spinal cord at day 2 post-fracture. However, anti-NGF treatment did not reduce p-ERK and c-Fos expression at 20 and 90 min, respectively, following fracture. This suggests NGF is involved in maintenance but not the acute generation of fracture pain. Anti-NGF therapy did not inhibit bone healing as measured by callus formation, bridging of the fracture site or mechanical strength of the bone. As the anti-NGF antibody does not appreciably cross the blood-brain barrier, the present data suggest that the anti-hyperalgesic action of anti-NGF therapy results from blockade of activation and/or sensitization of the CGRP/trkA positive fibers that normally constitute the majority of sensory fibers that innervate the bone. These results demonstrate that NGF plays a significant role in driving fracture pain and that NGF sequestering therapies may be efficacious in attenuating this pain.
Pain 2007 Dec 15
PMID:Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture. 1769 23


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