Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An intracellular signalling pathway in the dorsal root ganglion (DRG) and spinal neurons is a popular target in pain research that is relevant to the neuroplastic changes that occur during chronic pain conditions. First, we examined the phosphorylation of ERK in DRG neurons after peripheral inflammation and sciatic nerve transection without any stimulation to the receptive field. We found an activation of ERK in different populations of DRG neurons after peripheral inflammation and axotomy, which developed from alterations in target-derived nerve growth factor (NGF). We observed that the ERK signalling regulates the brain-derived neurotrophic factor (BDNF) expression in DRG neurons in both conditions. We also demonstrated that very rapid phosphorylation of ERK occurred in DRG neurons that were involved in the transmission of various noxious signals under normal conditions. Further, we examined the pERK labelling after the mechanical stimuli into the inflamed tissue and found that the pERK labelling occurred through the P2X3 receptors in the terminals. This activity-dependent activation of the ERK signal pathway may be useful for identifying which DRG neurons are involved in transmission of noxious stimuli under normal and pathological conditions.
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PMID:Changes in DRG neurons and spinal excitability in neuropathy. 1546 46

Phosphorylation of the cyclic AMP response element-binding protein (CREB) in the spinal dorsal horn may critically contribute to chronic pain following peripheral nerve injury. We employed inhibitors and activators of protein kinase A (PKA), protein kinase C (PKC), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and calcium/calmodulin-dependent kinase II (CaMKII) to examine whether these kinases individually or in concert mediate the increase in CREB phosphorylation that is evident as early as 2 h after loose ligation of the sciatic nerve. Specific inhibitors of each kinase significantly attenuated the ligation-associated CREB phosphorylation when compared to saline-treated animals. Combined application of the ERK1/2 and CaMKII inhibitors also attenuated the ligation-associated CREB activation but not to a greater extent than either inhibitor alone. Specific activators of PKA, PKC and ERK1/2 elicited significant increases in CREB phosphorylation 2 h after drug application in the spinal dorsal horn of control, peripherally uninjured animals. Pre-treatment of animals with the ERK1/2 inhibitor abolished the increases elicited by either the PKA or the PKC activator. Significant increases in ERK1/2 phosphorylation were also detected 2 h after sciatic ligation confirming a role for the ERK pathway in injury-related responses in the dorsal horn. Each kinase inhibitor significantly attenuated the ligation-associated activation of ERK1/2 as well. These data suggest that early, sciatic ligation-elicited phosphorylation of CREB in the spinal dorsal horn is mediated by multiple kinase pathways, and that PKA, PKC and CaMKII activate CREB at least in part by way of the ERK pathway.
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PMID:Multiple kinase pathways mediate the early sciatic ligation-associated activation of CREB in the rat spinal dorsal horn. 1588 94

The role of the ERK1/2 signal transduction pathway and related transcription factors in the regulation of gene expression and pain behavior following excitotoxic spinal cord injury (SCI) was examined. Specifically, phosphorylation of ERK1/2, activation of transcription factors NF-kB, ELK-1, and CREB, and gene expression of the neurokinin-1 receptor and NMDA receptor subunits NR1 and NR-2A were investigated. Excitotoxic injury was produced by intraspinal injection of quisqualic acid (QUIS) in male Sprague-Dawley rats. Western blots were used to evaluate phosphorylation and activation of ERK1/2 and transcription factors using phospho-specific or total antibodies. Real-time PCR was used to evaluate gene expression of NK-1R, NR-1, and NR-2A. Assessment of excessive grooming behavior was used to evaluate the presence of spontaneous pain behavior. Excitotoxic spinal injury resulted in: (1) increased phosphorylation of ERK1/2; (2) increased activation of NF-kB and phosphorylation of ELK-1; and (3) increased gene expression for the NK-1 receptor and NR1 and NR-2A subunits of the NMDA receptor. Blockade of the ERK cascade with the MEK inhibitor PD98059 inhibited phosphorylation of ELK-1, activation of NF-kB and gene expression of NR1, NR-2A and NK-1R, and prevented the development of excessive grooming behavior. The results have shown that excitotoxic spinal injury leads to the injury-induced activation of the ERK-->ELK-1 and NF-kB signaling cascades and transcriptional regulation of receptors important in the development of chronic pain. Blockade of this intracellular kinase cascade prevented the onset of injury-induced pain behavior.
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PMID:Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury. 1592 85

The cognitive-behavioral, fear-avoidance (FA) model of chronic pain (Vlaeyen JWS, Kole-Snijders AMJ, Boeren RGB, van Eek H. Fear of movement/(re)injury in chronic low back pain and its relation to behavioral performance. Pain 1995a;62:363-72) has found broad empirical support, but its multivariate, predictive relationships have not been uniformly validated. Applicability of the model across age groups of chronic pain patients has also not been tested. Goals of this study were to validate the predictive relationships of the multivariate FA model using structural equation modeling and to evaluate the factor structure of the Tampa Scale of Kinesiophobia (TSK), levels of pain-related fear, and fit of the FA model across three age groups: young (< or =40), middle-aged (41-54), and older (> or =55) adults. A heterogeneous sample of 469 chronic pain patients provided ratings of catastrophizing, pain-related fear, depression, perceived disability, and pain severity. Using a confirmatory approach, a 2-factor, 13-item structure of the TSK provided the best fit and was invariant across age groups. Older participants were found to have lower TSK fear scores than middle-aged participants for both factors (FA, Harm). A modified version of the Vlaeyen JWS, Kole-Snijders AMJ, Boeren RGB, van Eek H (Fear of movement/(re)injury in chronic low back pain and its relation to behavioral performance. Pain 1995a;62:363-72.) FA model provided a close fit to the data (chi(2)(29)=42.0, p>0.05, GFI=0.98, AGFI=0.97, CFI=0.99, RMSEA=0.031 (90% CI 0.000-0.050), p close fit=0.95). Multigroup analyses revealed significant differences in structural weights for older vs. middle-aged participants. For older chronic pain patients, a stronger mediating role for pain-related fear was supported. Results are consistent with a FA model of chronic pain, while indicating some important age group differences in this model and in levels of pain-related fear. Longitudinal testing of the multivariate model is recommended.
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PMID:The fear-avoidance model of chronic pain: validation and age analysis using structural equation modeling. 1651 74

C-fos is an immediate-early gene whose expression in the spinal cord has been extensively used as a marker of peripheral noxious stimulation. The Fos protein accumulates in the nuclei of spinal neurons, reaching detectable levels 2 h after stimulation. The ERK pathway is an important signalling pathway in spinal cord neurons. ERK is activated upon phosphorylation on specific amino acid residues. Its activation in the spinal cord, following noxious stimulation, has been shown to contribute to the establishment and maintenance of long-term neuronal alterations associated with chronic pain. Phosphorylated ERK can target several cellular elements, including transcription factors, which indicates that ERK participates in the regulation of gene expression. The relation between ERK and c-fos is at present still unclear. Some in vitro studies have reached the conclusion that ERK contributes to c-fos regulation whereas others have provided evidence of ERK-independent c-fos expression. In fact, in the spinal cord the occurrence of c-fos expression in the absence of ERK phosphorylation has been reported. In this study we investigated in vivo the contribution of ERK to c-fos expression in the spinal cord. By inhibiting spinal ERK activation with intrathecal administration of PD98059, we verified that ERK phosphorylation does contribute to regulate c-fos expression upon noxious bladder stimulation.
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PMID:The activation of the ERK pathway contributes to the spinal c-fos expression observed after noxious bladder stimulation. 1755 19

Chronic pain is very common in all European countries, with musculoskeletal problems predominating. About 1% of the adult population develops a syndrome of chronic muscle pain, fibromyalgia (FMS), characterized by multiple tender points, back or neck pain, and a number of associated problems from other organs, including a high frequency of fatigue. Evidence points to central sensitization as an important neurophysiological aberration in the development of FMS. Importantly, these neurological changes may result from inadequately treated chronic focal pain problems such as osteoarthritis or myofascial pain. It is important for health professionals to be aware of this syndrome and to diagnose the patients to avoid a steady increase in diagnostic tests. On the other hand, patients with chronic widespread pain have an increased risk of developing malignancies, and new or changed symptoms should be diagnosed even in FMS. In rheumatology practice it is especially important to be aware of the existence of FMS in association with immune inflammatory diseases, most commonly lupus and rheumatoid arthritis. Differential diagnoses are other causes of chronic pain, e.g. thyroid disease. The costs of this syndrome are substantial due to loss of working capability and direct expenses of medication and health-system usage. Fibromyalgia patients need recognition of their pain syndrome if they are to comply with treatment. Lack of empathy and understanding by healthcare professionals often leads to patient frustration and inappropriate illness behavior, often associated with some exaggeration of symptoms in an effort to gain some legitimacy for their problem. FMS is multifaceted, and treatment consists of both medical interventions, with emphasis on agents acting on the central nervous system, and physical exercises.
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PMID:Chronic widespread pain in the spectrum of rheumatological diseases. 1760 90

Spinal cord injury (SCI) results in the generation and amplification of pain caused in part by injury-induced changes in neuronal excitability at multiple levels along the sensory neuraxis. We have previously shown that activated microglia, through an ERK (extracellular signal-regulated kinase)-regulated PGE(2) (prostaglandin E(2)) signaling mechanism, maintain neuronal hyperexcitability in the lumbar dorsal horn. Here, we examined whether microglial cells in the thalamus contribute to the modulation of chronic pain after SCI, and whether microglial activation is governed by spinally mediated increases in the microglial activator cysteine-cysteine chemokine ligand 21 (CCL21). We report that CCL21 is upregulated in dorsal horn neurons, that tissue levels are increased in the dorsal horn and ventral posterolateral (VPL) nucleus of the thalamus 4 weeks after SCI, and that the increase can be differentially reduced by spinal blockade at T1 or L1. In intact animals, electrical stimulation of the spinothalamic tract induces increases in thalamic CCL21 levels. Recombinant CCL21 injected into the VPL of intact animals transiently activates microglia and induces pain-related behaviors, effects that could be blocked with minocycline. After SCI, intra-VPL antibody-mediated neutralization of CCL21 decreases microglial activation and evoked hyperexcitability of VPL neurons, and restores nociceptive thresholds to near-normal levels. These data identify a novel pathway by which SCI triggers upregulation of the neuroimmune modulator CCL21 in the thalamus, which induces microglial activation in association with pain phenomena.
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PMID:Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. 1769 71

Since neuropathic pain is resistant to conventional analgesics such as opiates and non-steroidal anti-inflammatory drugs, the development of new types of drugs for its treatment has been awaited. Several key molecules associated with nociception have been suggested as potential targets for new analgesics. Glial cell line-derived neurotrophic factor (GDNF) has a variety of functions affecting the survival and development of specified neural cell populations, mediated via transmission of intracellular signals through binding to its high-affinity receptor, GFR*1, and subsequent activation of a tyrosine receptor kinase, RET, neural cell adhesion molecule (NCAM), or other signaling molecules. GDNF also exhibits analgesic effects in rodent models of neuropathic pain, although the underlying mechanisms are still largely unknown, including the intracellular signal transduction involved. We report here that NCAM signaling plays a role in mediating the analgesic effect of GDNF in rats with chronic constrictive injury (CCI). We found that NCAM was expressed in intrinsic neurons in the spinal dorsal horn and in dorsal root ganglion neurons with small cell bodies. Reduction of NCAM expression by NCAM antisense oligodeoxynucleotide administration to CCI rats abolished the analgesic effect of GDNF without affecting RET signaling activation. An NCAM mimetic peptide, C3d, partially reduced the chronic pain induced by CCI. These findings suggest that NCAM signaling plays a critical role in the analgesic effect of GDNF and that development of new drugs activating GDNF-NCAM signaling may represent a new strategy for the relief of intractable pain.
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PMID:Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain. 1796 6

Opioid-like medications (OLM) are commonly used by patients with various types of chronic pain, but their long-term benefit is questionable. Electroacupuncture (EA) has been previously shown beneficial in reducing post-operative acute OLM consumption. In this pilot randomized controlled trial, the effect of EA on OLM usage and associated side effects in chronic pain patients was evaluated. After a two-week baseline assessment, participants using OLM for their non-malignant chronic pain were randomly assigned to receive either real EA (REA, n=17) or sham EA (SEA, n=18) treatment twice weekly for 6 weeks before entering a 12-week follow-up. Pain, OLM consumption and their side effects were recorded daily. Participants also completed the McGill Pain Questionnaire (MPQ), SF-36 and Beck Depression Inventory (BDI) at baseline, and at the 5th, 8th, 12th, 16th and 20th week. Nine participants withdrew during the treatment period with another three during the follow-up period. Intention to treat analysis was applied. At the end of treatment period, reductions of OLM consumption in REA and SEA were 39% and 25%, respectively (p=0.056), but this effect did not last more than 8 weeks after treatment. There was no difference between the two groups with respect to reduction of side effects and pain and the improvement of depression and quality of life. In conclusion, REA demonstrates promising short-term reduction of OLM for participants with chronic non-malignant pain, but such effect needs to be confirmed by trials with adequate sample sizes.
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PMID:The effect of electroacupuncture on opioid-like medication consumption by chronic pain patients: a pilot randomized controlled clinical trial. 1803 66

One common feature of chronic musculoskeletal pain and headaches are that they are both influenced by stress. Among these, tension-type headache (TTH), fibromyalgia (FMS) and chronic shoulder/neck pain (SNP) appear to have several similarities, both with regard to pathophysiology, clinical features and demographics. The main hypothesis of the present study was that patients with chronic pain (TTH, FMS and SNP) had stress-induced features distinguishing them from migraine patients and healthy controls. We measured pain, blood pressure, heart rate (HR) and skin blood flow (BF) during (1 h) and after (30 min) controlled low-grade cognitive stressor in 22 migraine patients, 18 TTH patients, 23 FMS patients, 29 SNP patients and 44 healthy controls. FMS patients had a lower early HR response to stress than migraine patients, but no differences were found among FMS, TTH and SNP patients. Finger skin BF decreased more in FMS patients compared to migraine patients, both during and after the test. When comparing chronic pain patients (chronic TTH, FMS and SNP) with those with episodic pain (episodic TTH and migraine patients) or little or no pain (healthy controls), different adaptation profiles were found during the test for systolic and diastolic blood pressure, HR and skin BF in the chronic group. In conclusion, these results suggest that TTH, FMS and SNP patients may share common pathophysiological mechanisms regarding the physiological responses to and recovery from low-grade cognitive stress, differentiating them from episodic pain conditions such as migraine.
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PMID:Similarities in stress physiology among patients with chronic pain and headache disorders: evidence for a common pathophysiological mechanism? 1837 56


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