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)

Sixty-two hemiplegic subjects were treated with the Bobath approach for a period of three months. During this time they were evaluated on three occasions. The testing battery consisted of a Bobath evaluation, the Brunnstrom scale, the Fugl-Meyer test, the Upper Extremity Functional Test (UEFT) and the Present Pain Intensity (PPI) of the McGill pain questionnaire. A Friedman analysis of variance showed that, except for pain, all the protocols used disclosed significant progress (p less than 0.001) over time in terms of motor recovery. Except for pain, the results of the Bobath evaluation were significantly correlated (Spearman's Rho, p less than 0.001) with the results of the other testing procedures. It is concluded that the new Bobath evaluation proposed in a previous paper is as sensitive in depicting progress in motor recovery over time as are the other testing procedures used. Furthermore, this new evaluation seems to be measuring similar properties to the other tests. However, pain (PPI) appears not to be an important dependent variable.
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PMID:An evaluation of the hemiplegic subject based on the Bobath approach. Part III. A validation study. 341 50

Persistent nociceptive input increases neuronal excitability and induces a program of gene expression in the dorsal spinal cord. The alteration in gene expression commences with phosphorylation and induction of immediate early genes and proceeds to target genes. Only a few target genes have been identified as yet. The present report uses a polymerase chain reaction-based subtraction cloning procedure to obtain an "anatomically focused" complementary DNA library enriched in transcripts related to sensory spinal cord (rat dorsal horn minus ventral horn). A subset of clones from this library (n=158) was screened to verify dorsal horn enrichment and to identify those regulated by carrageenan-induced peripheral inflammation. Molecular classes which displayed enriched expression included a proto-oncogene not previously associated with sensory processes, two regulators of the Rho/Rac pathway which controls cell shape, and three genes involved in cytoskeletal regulation and scaffolding. Additional transcripts coded for proteins involved in intercellular communication or intracellular function. Within the set of 158 transcripts, one known and two unknown genes were induced by persistent noxious input. The known gene codes for the secreted cysteine proteinase inhibitor, cystatin C, suggesting that modulation of extracellular proteolytic activity occurs. Since it is secreted, cystatin C may also provide a cerebrospinal fluid bio-marker for persistent pain states. Using a combined anatomical and functional approach, we have extended the molecular repertoire of genes expressed and induced in second-order neurons or supporting glial cells in several new directions, with particular emphasis on regulation of cell morphology and plasma membrane dynamics. Some of these proteins reveal new pathways for information signaling in the sensory half of the spinal cord and require further research to understand their role in the adult spinal cord. The induced genes may provide new molecular targets for therapeutic development and provide new probes for investigating the dynamic state of cellular activity that occurs during persistent pain states.
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PMID:Spinal cord genes enriched in rat dorsal horn and induced by noxious stimulation identified by subtraction cloning and differential hybridization. 1124 63

Achilles tendinosis is a degenerative overuse tendinopathy involving the primary ankle plantarflexors, namely the soleus and gastrocnemius muscles forming the tendo Achilles. The Orthopaedic Research Institute-Ankle Strength Testing System (ORI-ASTS) was designed to record objective measurements of force generated with a resisted ankle plantarflexion test. Testing normal subjects (n=6) was used to establish the reliability of the ORI-ASTS for measuring ankle plantarflexion force. Testing patients with Achilles tendonitis (n=5) over time and comparing Achilles tendon analogue pain scores to ankle plantarflexion force measurements was used to assess the validity of the ORI-ASTS for monitoring progression of Achilles tendinopathy. Inter-rater reliability of the ORI-ASTS with normal subjects was excellent, with single measure intraclass correlation coefficients (ICC) for right mean peak force of 0.92, left mean peak force of 0.96, right mean total force of 0.89, left mean total force of 0.91. The ORI-ASTS also had excellent intra-rater reliability for normal subjects with the following single measure ICC scores: right mean force 0.96, left mean force 0.92, right mean total force 0.97, left mean total force 0.92. The relative technical errors of measurement were calculated from these results, and ranged from 1.0% to 2.7%. Testing patients with Achilles tendinosis (n=5), and comparing analogue activity pain scores to ORI-ASTS testing demonstrated a strong negative relationship between the two parameters (Spearman Rho -0.87 to -1.0, Kendall tau b -0.82 to -1.0). The relationship was statistically significant at the p=0.01 level for two of the five patients. The ORI-ASTS shows excellent reliability for testing ankle plantarflexor force, and appears valid for objectively assessing and monitoring patients with Achilles tendinosis.
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PMID:The Orthopaedic Research Institute-Ankle Strength Testing System: inter-rater and intra-rater reliability testing. 1185 30

Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.
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PMID:Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. 1519 86

Dorsal rhizotomy results in primary deafferentation of the dorsal horn with concomitant sprouting of spared intraspinal monoaminergic axons. Because descending monoaminergic systems are thought to mitigate nociceptive transmission from the periphery and because dorsal rhizotomy can result in neuropathic pain, we sought to determine whether the rhizotomy-induced sprouting response could be further augmented. Because myelin-derived molecules mask endogenous plasticity of CNS axons and because myelin-inhibitory signaling occurs through the Rho-GTPase pathway, we inhibited Rho-pathway signaling after cervical dorsal rhizotomy in rats. An increase in the density of serotonergic- and tyrosine hydroxylase-positive fibers was seen in the dorsal horn 1 week after septuple rhizotomy, and axon density continued to increase for at least 1 month. One week after septuple rhizotomy, administration of intrathecal Y-27632, an antagonist of Rho-kinase (ROCK), increased the density of both fiber types over vehicle-treated controls. To examine behavioral effects of both cervical rhizotomy and ROCK inhibition, we examined responses to evoked pain: mechanical and thermal allodynia and cold hyperalgesia in the forepaw were examined after single, double, and quadruple rhizotomies of dorsal roots of the brachial plexus. The most notable behavioral outcome was the development of cold hyperalgesia in the affected forepaw after rhizotomies of the C7 and C8 dorsal roots. Application of Y-27632 both attenuated cold hyperalgesia and induced monoaminergic plasticity after C7/8 rhizotomy. Thus, inhibition of Rho-pathway signaling both promoted the sprouting of intact supraspinal monoaminergic fibers and alleviated pain after dorsal rhizotomy.
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PMID:Rho-kinase inhibition enhances axonal plasticity and attenuates cold hyperalgesia after dorsal rhizotomy. 1557 30

Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major in vivo substrate for protein kinase C in the brain and has been implicated in cellular processes associated with cytoskeletal restructuring such as synaptic trafficking and neurotransmitter release. A phosphorylation-site specific antibody against Ser159-phospho-MARCKS (pS159-Mar-Ab) revealed that MARCKS is phosphorylated at Ser159 by Rho-kinase and that its phosphorylation is inhibited by the Rho-kinase specific inhibitor H-1152. Since the function of MARCKS is regulated by phosphorylation at multiple sites, here we examined the involvement of Rho-kinase in relation to phosphorylation of MARCKS at Ser159 in inflammatory and neuropathic pain by H-1152. When intrathecally administered 10 min before s.c. injection of formalin, H-1152 at 10 and 100 ng attenuated the second-phase, but not the first-phase, pain-like behaviors in the formalin test. Neuropathic pain induced by selective L5 spinal nerve transection was also relieved by intrathecal injection of H-1152. Nitric oxide synthase activity visualized by NADPH diaphorase histochemistry increased in the superficial layer of the spinal cord 30 min after formalin injection and 7 days after nerve transection, which were blocked by H-1152. Phosphorylation of MARCKS at Ser159 was detected in the spinal cord by pS159-Mar-Ab and the level of phosphorylation increased in the superficial layer after nerve transection. In contrast, immunoreactivities of neuronal nitric oxide synthase and MARCKS did not change significantly in the spinal cord before and after nerve transection. Taken together, the present study demonstrates that Rho-kinase is involved in inflammatory pain and the maintenance of neuropathic pain through phosphorylation of MARCKS at Ser159.
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PMID:Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS). 1570 90

Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.
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PMID:Rho kinase, a promising drug target for neurological disorders. 1586 68

Prostaglandin E2 (PGE2), the principal pro-inflammatory prostanoid, is known to play versatile roles in pain transmission via four PGE receptor subtypes, EP1-EP4. We recently demonstrated that continuous production of nitric oxide (NO) by neuronal NO synthase (nNOS) following phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) and NMDA receptor NR2B subunits is essential for neuropathic pain. These phosphorylation and nNOS activity visualized by NADPH-diaphorase histochemistry were blocked by indomethacin, a PG synthesis inhibitor. To clarify the interaction between cyclooxygenase and nNOS pathways in the spinal cord, we examined the effect of EP subtype-selective agonists on NO production. NO formation was stimulated in the spinal superficial layer by EP1, EP3, and EP4 agonists. While the EP1- and the EP4-stimulated NO formation was markedly blocked by MK-801, an NMDA receptor antagonist, the EP3-stimulated one was completely inhibited by H-1152, a Rho-kinase inhibitor. Phosphorylation of MARCKS and NADPH-diaphorase activity stimulated by the EP3 agonist were also blocked by H-1152. These results suggest that PGE2 stimulates NO formation by Rho-kinase via EP3, a mechanism(s) different from EP1 and EP4.
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PMID:Rho-kinase mediates spinal nitric oxide formation by prostaglandin E2 via EP3 subtype. 1618 27

It is projected that in 2005, approximately 220 900 men will be newly diagnosed with carcinoma of the prostate (CaP). Men who are diagnosed with locally advanced or metastatic disease undergo androgen ablation therapy and most will relapse and progress within 18 months. Metastasis to bone is the major clinical concern during CaP progression, as it is associated with intractable pain, bone fracture and paralysis resulting from spinal cord compression. Therefore, an understanding of the key mechanisms involved in CaP cell bone metastasis is vital to development of novel treatments. The Rho GTPases are molecular switches involved in cell survival, motility and invasion. Increased expression of RhoC GTPase is linked to enhanced metastatic potential in multiple cancers; however, the role of RhoC GTPase in CaP metastasis has not been addressed. In the current study, we demonstrate that RhoC GTPase is expressed and active in PC-3 CaP cells. RhoC inhibition, either pharmacologically with C3 exotransferase or molecularly through expression of a dominant-negative RhoC, promotes IGF-I stimulated random motility but decreases in vitro invasion and experimental metastases. Inhibition of RhoC activity results in drastic morphologic changes and alterations in the expression and distribution of focal adhesion-related proteins. These data suggest that RhoC inhibition leads to activation of other GTPases involved in nondirected motility and that expression of active RhoC is required for the invasive phenotype of PC-3 cells.
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PMID:RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility. 1631 38

After a CNS injury in the adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Here, we show that the nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal. Similar to Rho and Rock inhibitors C3 transferase or Y27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], both NSAID drugs stimulate a significant neurite growth in the cultured dorsal root ganglion neurons exposed to the inhibitory substrates. Systemic administration of ibuprofen to spinal cord-lesioned rodents reverses the active RhoA signal around injury area measured via Rho-GTP binding assay. Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma. In contrast, the non-RhoA-inhibiting NSAID naproxen does not have the axon growth-promoting effects on cultured or lesioned neurons. These studies demonstrate the therapeutic potential of RhoA-inhibiting NSAIDs in treating CNS injuries characterized by axonal disconnection including spinal cord injury.
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PMID:Nonsteroidal anti-inflammatory drugs promote axon regeneration via RhoA inhibition. 1742 93


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