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)

The microenvironment of the brain requires tight regulation for proper neuronal function. Protecting the central nervous system (CNS) from the varying concentrations of ions, proteins, and toxins in the periphery is the dynamically regulated blood-brain barrier (BBB). Recent studies have demonstrated significant modulation of the BBB in a number of diseases and physiological states, including pain. This study expands on previous explorations of acute and chronic pain-induced effects on the function and molecular cytoarchitecture of the barrier. It describes the role of cyclooxygenase (COX) up-regulation by blocking with diclofenac (30 mg/kg, i.p.), and it examines the variation in BBB regulation through various brain regions. Edema and hyperalgesia were induced by lambda-carrageenan and attenuated by the additional administration of diclofenac. Examination of unidirectional [14C]sucrose permeability with multitime in situ perfusion studies demonstrated that lambda-carrageenan significantly increased cerebral permeability and decreased brainstem permeability. There were no significant changes in any of the other brain regions examined. These permeability changes correlated with up- and down-regulation of the tight junction (TJ) protein claudin-5 in the cerebrum and brainstem, respectively. Diclofenac administration attenuated the cerebral permeability uptake as well as the claudin-5 up-regulation. In addition, diclofenac reversed the lowered permeability in the brainstem, but it did not attenuate TJ protein expression. These studies demonstrate the complex regulation of the BBB occurring during inflammatory pain and the role of COX in this process. An understanding of BBB regulation during pain states is critically important for pharmacotherapy, and it holds great promise for new therapies to treat central nervous system pathologies.
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PMID:Diclofenac attenuates the regional effect of lambda-carrageenan on blood-brain barrier function and cytoarchitecture. 1830 16

L5/L6 spinal nerve ligation (SNL) in rodents induces behavioral signs similar to the symptoms of neuropathic pain in humans. L5/L6 SNL in rats has been well characterized so far, but there have been few studies using mice. In this study, we established an L5/L6 SNL model in mice and examined the effects of known antinociceptive drugs in the model. We also analyzed the changes in gene expression in dorsal root ganglions with special reference to those which are known to change in a neuropathic pain state to validate the model. Mechanical allodynia in the ipsilateral side paw was observed beginning on day 1 and lasted for at least 2 months following surgery. Diclofenac showed no significant effect on the mechanical allodynia. Gabapentin and pregabalin completely reversed allodynia, but they also caused a decrease in locomotor activity. Duloxetine caused a partial recovery of the threshold. Mexiletine completely reversed allodynia, but it also caused sedation or motor impairment. Morphine caused a partial recovery of the threshold and hyper-locomotion. This mouse L5/L6 SNL model represents a robust mechanical allodynia, which shows a similar pharmacological response to that reported in rats and human patients with neuropathic pain. The pattern changes in gene expression also resembled those reported in rats. This model will therefore be useful for investigation of the effects of novel antinociceptive compounds and the mechanisms of neuropathic pain.
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PMID:Pharmacological characterization and gene expression profiling of an L5/L6 spinal nerve ligation model for neuropathic pain in mice. 1840 Apr 11

The aim of the study was to compare treatment with diclofenac sodium (Voltaren 3 x 50 mg) to occlusal splint therapy in a randomized, single-blind controlled trial of patients with a diagnosis of temporomandibular joint (TMJ) osteoarthritis (OA) in accordance with Research Diagnostic Criteria for temporomandibular disorders. Patients with general joint disorders or restrictions against medication with non-steroidal anti-inflammatory drug were not included. Twenty-seven females and two males (aged 36-76 years) included, answered a standardized questionnaire and were clinically examined and they underwent TMJ tomography. The treatment was randomized to either splint (n = 15) or diclofenac (n = 14). The temperatures over the TMJs were determined. The patients were re-examined 1 week, 1 month and 3 months after the start of treatment. A 1-year follow-up was carried out using questionnaires. After 1 week of treatment with diclofenac, significant reductions of pain and discomfort, TMJ tenderness and joint pain on jaw movements were noted. The splint therapy gave a significant reduction of reported symptoms after 1 month of treatment. Both treatments gave few adverse effects and were on an equal level. Estimation of the degree of inflammation by measuring the surface temperature over the TMJ was not reliable. Structural changes of the symptomatic TMJs were radiographically found in 82%, the contralateral, symptom-free TMJ had changes in 36%. There was a discrepancy between the clinical and the radiographical findings. Diclofenac gave a more rapid improvement, but both treatments gave a significant reduction of symptoms of TMJ OA within 3 months which remained at the one-year follow-up.
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PMID:Diclofenac sodium and occlusal splint therapy in TMJ osteoarthritis: a randomized controlled trial. 1848 50

The present study was designed to assess the antinociceptive efficacy and gastroprotective activity of the mixture of diclofenac and misoprostol and its comparison with celecoxib in rats. The effect of diclofenac/misoprostol and celecoxib was assessed in the 1% formalin test. Female Wistar rats were fasted 12 hr before experiments and diclofenac (10 and 50 mg/kg), misoprostol (100 microg/kg), celecoxib (30 and 100 mg/kg), saline and the combination of diclofenac (50 mg/kg) plus misoprostol (25, 50 and 100 microg/kg) were administered orally. Nociceptive behavior was assessed during the following hr. Diclofenac and celecoxib dose-dependently reduced formalin-induced nociception reaching similar maximal effects. Moreover, misoprostol did not produce antinociception, but increased diclofenac-induced antinociception. Animals were sacrificed 3 hr following drug administration and stomachs examined to assess gastric damage. Misoprostol did not produce any damage to the stomach. However, diclofenac, but not celecoxib, produced significant gastric damage (number of stomach ulcers) in a dose-dependent fashion. Misoprostol dose-dependently reduced diclofenac-induced ulcers. Data show that diclofenac and celecoxib lead to similar antinociception, with diclofenac being more active to produce gastric damage. However, diclofenac-induced gastric damage can be markedly reduced by misoprostol. In addition to its gastroprotective effect, misoprostol showed a synergic effect on diclofenac-induced anti-nociception. Considering the cardiovascular effects of COX-2 selective inhibitors, the combination of diclofenac and misoprostol could represent a safer and effective alternative for patients with pain.
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PMID:Comparison of antinociceptive efficacy and gastroprotection between celecoxib and diclofenac plus misoprostol in rats. 1860 34

Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.
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PMID:Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone. 1884 62

The clinical utility of diclofenac potassium, a nonsteroidal anti-inflammatory drug, may be lessened by inconsistent gastrointestinal absorption. Diclofenac potassium liquid filled soft-gelatin capsule (DPSGC) is an investigational formulation that uses ProSorb dispersion technology to facilitate rapid and consistent gastrointestinal absorption. In this study, the pharmacokinetic (PK) properties of DPSGC are investigated and compared with a commercially available oral diclofenac potassium tablet in patients after primary unilateral first metatarsal bunionectomy. In an open-label, randomized study, 53 patients received ProSorb-D 12.5 mg (the liquid equivalent of DPSGC), DPSGC 25 mg, DPSGC 50 mg, or immediate-release diclofenac potassium 50-mg tablet administered every 8 hours for a 24-hour inpatient period followed by 7 days of outpatient dosing. Diclofenac steady-state PK was evaluated over an 8-hour sampling period 4 days after surgery. Delayed and/or multiple peaks in the diclofenac plasma concentration-time course profiles occurred more frequently with the commercially available oral diclofenac potassium 50-mg tablet than with the other DPSGC formulations. PK data for ProSorb-D 12.5-mg liquid, DPSGC 25 mg, DPSGC 50 mg, and diclofenac potassium 50-mg tablet revealed mean peak plasma concentrations (Cmax) of 302, 749, 1006, and 902 ng/mL, respectively, whereas area under the plasma concentration curve values were 316, 595, 1029, and 1166 ng-hour/mL, respectively. Mean times to Cmax (tmax) were 0.49, 0.63, 0.95, and 1.26 h, respectively. When compared with absorption characteristics of diclofenac potassium 50-mg tablet, DPSGC was more rapidly and consistently absorbed after bunionectomy. These characteristics should be advantageous when rapid pain relief is desired.
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PMID:A pharmacokinetic analysis of diclofenac potassium soft-gelatin capsule in patients after bunionectomy. 1953 31

The article deals with an investigation of therapeutic efficiency combined with applications of biological preparations and special medical-improving gymnastic exercises at treatment of a vertebral cervical osteochondrosis on the one hand, traditional means on the other hand. 76 patients aged 31-62 have taken part in the given research. The basic group was made by 47 patients and the control group - by 29. The patients of the basic group applied a special complex of medical-improving gymnastic exercises, and also paravertebral injections of biological preparations Traumeel S, Neuralgo-Rheum-Injeel. The patients of the control group received traditional therapy of a vertebral osteochondrosis. Injections of Voltaren (Diclofenac) intramuscularly, MIG400 (Ibuprophen) tablets, phonophorez with Indometacin ointment, a traditional complex of physiotherapy exercises. Duration of the treatment in all groups has made 28 days. Obtained data testify that by the end of treatment full knocking over of a pain syndrome in the basic group is noted at 71,2 % of patients, in control group only in 41,4 % of patients the pains have completely disappeared in a cervical spine. Thus, therapy by biological preparations in a combination to a complex of special medical-improving gymnastic exercises allows to reduce terms of knocking over of sharp clinical displays of an osteochondrosis of a cervical spine, to raise efficiency of restoration of sensitive, vascular, muscular-tonic frustration, and also allows to avoid neuro-surgical intervention at patients with hernias interspine disks.
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PMID:[The complex approach to treatment of pain syndrome of cervical vertebral osteochondrosis]. 1955 39

The application of topical analgesics to the donor site of split thickness skin grafts has been proven to be an effective method of pain management but little is known about their effects on wound reepithelialization. This study compares the effect of four analgesics on human keratinocytes and fibroblasts and whole skin explants in vitro to determine whether epithelial cell behavior is affected by topical analgesics. The effect of diclofenac, bupivacaine, lidocaine, and ketorolac was studied at concentrations between 10 mM and 1 nM. The effect on epithelial growth was measured using an ex vivo skin explant model. In addition, cell proliferation, and cytotoxicity were measured in cultured primary human keratinocytes and fibroblasts. Epithelial growth from the explant model was most inhibited by diclofenac with a significant reduction at 100 microM (p=>0.001). Diclofenac also exhibited the strongest inhibitory effect on cell proliferation especially in keratinocytes. Ketorolac was the most cytotoxic. Bupivacaine showed cytotoxicity in a dose-dependent manner with only the very highest concentrations having a significant inhibitory effect. Lidocaine showed no evidence of cytotoxicity at the concentrations tested in either the in vitro cell studies or the ex vivo explant model. Topical analgesics alter keratinocyte and fibroblast behavior and such inhibition may affect wound healing.
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PMID:The effect of topical analgesics on ex vivo skin growth and human keratinocyte and fibroblast behavior. 1966 41

Osteoarthritis (OA) is a degenerative joint disease characterized by joint pain for which there is currently no effective treatment. Previous studies have found that intra-articular injection of monosodium iodoacetate (MIA) caused a dose-dependent destruction of rat knees with concomitant increased pain. In this study, varying degrees of OA were induced by intra-articular injection of 0.1 mg, 0.3 mg and 3 mg MIA. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint and firing frequencies were determined and compared to saline-injected control joints. The analgesic effect of local application of the classic non-steroidal anti-inflammatory drug (NSAID) diclofenac (0.1 mg/0.1 ml bolus) was also determined in each group. Joint afferent firing frequency was significantly enhanced in OA knees compared to saline injected control joints and the magnitude of this sensitization showed a direct relationship with increasing dose of MIA. Diclofenac reduced nociception significantly in the 3 mg MIA treated joint, but had no effect on nerve mechanosensitivity in rats with milder OA. This study shows for the first time that MIA produces a graded sensitization of joint nociceptors making this a useful model for the study of pain mechanisms in joints with progressive OA severity. The anti-nociceptive effect of diclofenac further indicates that the MIA model offers an attractive means of objectively testing potential therapeutic agents.
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PMID:Grading of monosodium iodoacetate-induced osteoarthritis reveals a concentration-dependent sensitization of nociceptors in the knee joint of the rat. 1971 99

The analgesic mechanism underlying the efficacy of topical diclofenac in the treatment of musculoskeletal pain is incompletely understood. The present study investigated whether intramuscular injection of diclofenac (0.1mg/ml, approximately 340microM) could attenuate jaw-closer muscle nociceptor discharge and mechanical sensitization induced by activation of peripheral 5-hydroxytryptamine (serotonin) or excitatory amino acid receptors in anesthetized Sprague-Dawley rats. Diclofenac inhibited nociceptor discharge evoked by NMDA, but had no effect on nociceptor discharge evoked by 5-hydroxytryptamine or AMPA. Subsequent experiments revealed that diclofenac-mediated inhibition of NMDA-evoked nociceptor discharge was competitive. Intramuscular injection of 5-hydroxytryptamine, NMDA and AMPA also decreased nociceptor mechanical threshold, however, only the mechanical sensitization produced by NMDA was reversed by diclofenac. Co-administration of the proinflammatory prostaglandin PGE(2) did not alter the ability of diclofenac to significantly attenuate NMDA-evoked nociceptor discharge or NMDA-induced mechanical sensitization. Intramuscular injection of either diclofenac or the competitive NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (50mM) alone could elevate nociceptor mechanical threshold for a 30min period post-injection. The present study indicates that in vivo, diclofenac can exert a selective, competitive inhibition of peripheral NMDA receptors at muscle concentrations achievable after topical administration of diclofenac containing preparations. This property may contribute to the analgesic effect of topical diclofenac when used for muscle pain.
Pain 2009 Dec 15
PMID:The analgesic action of topical diclofenac may be mediated through peripheral NMDA receptor antagonism. 1979 22


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