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 previously reported that cyclooxygenase 2 (COX2) is up-regulated in macrophages in injured nerve of rats with partial sciatic nerve ligation (PSNL) and that local injection of the COX inhibitor ketorolac reversed tactile allodynia (Eur. J. Neurosci. 15: 1037-1047, 2002). These findings suggest that prostaglandins (PGs) are overproduced in injured nerve and are involved in the pathogenesis of neuropathic pain. In this study, we examined whether overproduced PGs alter the expression of PGE2 receptors, EP1-EP4, in injured nerve of PSNL rats. We found that cell profiles immunoreactive (IR) for four EP receptors, EP1, EP2, EP3, and EP4, are dramatically increased in injured nerve 2 and 4 weeks after PSNL. EP4-IR cells were the most abundant among these receptor-expressing cells. Immunoreactivities of all four EP receptors were localized to the cell nucleus. These EP-IR cells were never found in uninjured nerve. More than 80% EP1- and about 30% EP4-IR cells were identified as infiltrating macrophages since they coexpressed ED1. Only 3% EP2- and 6% EP3-IR cells coexpressed ED1. These findings suggest that majority of EP2-, EP3-, and EP4-IR cells are other types of inflammatory cells than macrophages. About 48% of macrophages expressed EP1 and 45% expressed EP4. Only 3 and 6% of macrophages, respectively, expressed EP2 and EP3. Perineural injection of ketorolac reversed tactile allodynia and suppressed the up-regulation of EP1 and EP4, but not the recruitment of ED1-IR marcrophages, in injured nerve. Our data suggest that following PSNL, PGE2 is one of the possible PGs overproduced in injured nerve and PG overproduction is involved in the up-regulation of EP receptors in injured nerve.
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PMID:Four PGE2 EP receptors are up-regulated in injured nerve following partial sciatic nerve ligation. 1455 99

We previously reported that partial sciatic nerve ligation (PSNL) dramatically up-regulates cyclooxygenase 2 (COX2) in injured sciatic nerve, and local injection of the COX inhibitor, ketorolac, reverses tactile allodynia and suppresses increased phosphorylation of the transcription factor cAMP responsive element binding protein [Eur J Neurosci 15 (2002) 1037]. These findings suggest that peripheral prostaglandins (PGs) are over-produced and contribute to the central plasticity and the maintenance of neuropathic pain after nerve injury. PGs, particularly PGE2, are well known to facilitate the release of the pro-nociceptive neuropeptide substance P (SP) and calcitonin gene-related peptide (CGRP) from primary sensory afferents. Thus, suppressing peripheral PG over-production may inhibit the release of these two neuropeptides from primary afferents and thereby increase the content of these neuropeptides remaining in afferent terminals in the dorsal horn. In this study we tested this hypothesis by examining the immunoreactivities of SP and CGRP in the dorsal horn of PSNL rats intraplantarly injected with saline and ketorolac. Four weeks after PSNL, SP- and CGRP-immunoreactivities (IR) in the ipsilateral dorsal horn were not significantly different from the contralateral side. Five days following intraplantar injection of ketorolac, CGRP- and SP-IR in the ipsilateral and contralateral dorsal horn were dramatically reduced compared with saline-injected PSNL rats. Local ketorolac also suppressed PSNL-induced increase in dynorphin-IR in dorsal horn neurons. Since abundant production of PGs during inflammation is well documented, we further examined the effect of intraplantar ketorolac on neuropeptide expression in the dorsal horn following carrageenan inflammation. We observed that co-administration of ketorolac with carrageenan in the hindpaw also reduced SP- and dynorphin-IR in the ipsilateral and contralateral dorsal horn. These findings are in contrast to our hypothesis, suggesting that peripherally over-produced PGs following nerve injury and inflammation possibly contribute to the production of SP and CGRP in primary sensory neurons, to the up-regulation of dynorphin in the dorsal horn neurons, and finally to the mechanisms of neuropathic and inflammation pain.
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PMID:Intraplantar injection of a cyclooxygenase inhibitor ketorolac reduces immunoreactivities of substance P, calcitonin gene-related peptide, and dynorphin in the dorsal horn of rats with nerve injury or inflammation. 1456 28

We previously reported the up-regulation of cyclooxygenase 2 (COX2) in injured sciatic nerve of rats with partial sciatic nerve ligation (PSNL) and the reversal of PSNL-elicited tactile allodynia by local injection of the COX inhibitor ketorolac [Eur J Neurosci 15 (2002) 1037]. We further asked whether COX2 up-regulation in injured nerve is a universal phenomenon following various types of nerve injury. In the current study, we observed that abundant COX2 immunoreactive (IR) cell profiles appeared in injured nerves of rats following spinal nerve ligation (SNL), chronic constriction injury (CCI) and complete sciatic nerve transection. Most COX2-IR cells were identified as infiltrating macrophages. Partial injury induced greater COX2 up-regulation than complete injury. COX2 up-regulation reached a peak at 2-4 weeks, evidently declined by 3 months and disappeared by 7 months postlesion. These findings suggest that up-regulation of COX2 in injured nerve is a common event during the initial several months after nerve injury. We observed that local ketorolac-elicited anti-allodynia was closely associated with the abundance of COX2-IR cells in injured nerve, varying with the type of injury and time after injury. The anti-allodynia lasted the longest when local ketorolac was given 2-4 weeks after PSNL, CCI and SNL. The duration of local ketorolac's anti-allodynia was the longest in CCI rats, which also exhibited the most abundant COX2 up-regulation. Local ketorolac's anti-allodynia lasted much shorter when given 2-3 months after lesion. Local ketorolac failed to induce anti-allodynia 7 months after lesion, a time when COX2-IR cells completely disappeared from the injured nerve except a few cells at the injury site. Our data strongly suggest that during the initial several months after nerve injury, peripherally over-produced prostaglandins play an important role in the maintenance of neuropathic pain.
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PMID:Cyclooxygenase 2 in infiltrating inflammatory cells in injured nerve is universally up-regulated following various types of peripheral nerve injury. 1456 29

1. Both clinical and preclinical models of postsurgical pain are being used more frequently in the early evaluation of new chemical entities. In order to assess the validity and reliability of a rat model of postincisional pain, the effects of different classes of clinically effective analgesic drugs were evaluated against multiple behavioural end points. 2. Following surgical incision, under general anaesthesia, of the plantar surface of the rat hind paw, we determined the time course of mechanical hyperalgesia, tactile allodynia and hind limb weight bearing using the Randall-Selitto (paw pressure) assay, electronic von Frey and dual channel weight averager, respectively. Behavioural evaluations began 24 h following surgery, and were continued for 9-14 days. 3. Mechanical hyperalgesia, tactile allodynia and a decrease in weight bearing were present on the affected limb within 1 day of surgery with maximum sensitivity 1-3 days postsurgery. Accordingly, we examined the effect of nonsteroidal antiinflammatory drugs (NSAIDs), morphine and gabapentin, on established hyperalgesia and allodynia, 1 day following plantar incision.4. In accordance with previous reports, both systemic morphine and gabapentin administration reversed mechanical hyperalgesia and tactile allodynia in the incised rat hind paw. Both drugs were more potent against mechanical hyperalgesia than tactile allodynia. 5. All of the NSAIDs tested, including cyclooxygenase 2 selective inhibitors, reversed mechanical hyperalgesia and tactile allodynia in the incised rat hind paw. The rank order of potency for both hyperalgesia and allodynia was indomethacin > celecoxib > etoricoxib > naproxen. 6. We have investigated the potency and efficacy of different classes of analgesic drugs in a rat model of postincisional pain. The rank order of potency for these drugs reflects their utility in treating postoperative pain in the clinic. As these compounds showed reliable efficacy across two different behavioural end points, the Randall-Selitto (paw pressure) assay and electronic von Frey, these methods may prove useful in the study of postsurgical pain and the assessment of novel treatments.
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PMID:Pharmacological characterisation of a rat model of incisional pain. 1459 6

Inflammation associated with nerve injury produces a number of pathogenic chemical mediators of which prostanoids are a potent component. Cyclooxygenases (Cox-1 and Cox-2) are the enzymes responsible for prostanoid production. We have investigated Cox-2 immunoreactivity (Cox-2-IR) and glial activation in human injured (n = 16) and uninjured (n = 8) nerves and in the chronic constriction injury (CCI) model of nerve injury in the rat, using immunohistological and autoradiographic methods. Tissues were immunostained with antibodies to Cox-2, CD-68 (human macrophage marker), OX42 (rat microglial marker), or incubated with tritiated PK11195 (marker of glial activation), prior to image analysis. In human nerves, Cox-2-IR was detected in cells with morphology and distribution similar to macrophages/microglia - these were increased significantly in human nerve proximal to injury (p < 0.002), reaching a peak at 4-6 weeks after injury. In the rat CCI model, at 40 days after injury, microglia-like cells with Cox-2-IR were increased significantly in the injured nerve (p < 0.004) and ipsilateral dorsal spinal cord (p < 0.008). PK11195-binding results were similar for Cox-2-IR in chronic injured human nerve and rat tissues. These findings suggest that Cox-2-immunoreactive cells could play a role in processes associated with Wallerian degeneration, nerve regeneration, and the development of persistent pain. Selection of patients 4-6 weeks after nerve injury would be more likely to show any efficacy of Cox-2 inhibitors.
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PMID:Cyclooxygenase-2 (Cox-2) in injured human nerve and a rat model of nerve injury. 1487 50

It is widely accepted that prostaglandin (PG) E2 is the principal pro-inflammatory prostanoid and plays an important role in inflammatory pain. However whether PGE2 is involved in neuropathic pain remains unknown. PGE2 is produced from arachidonic acid via PGH2 by at least three PGE synthases (PGES), cytosolic PGES (cPGES), and membrane-associated PGES (mPGES)-1 and -2. In the present study, to clarify the involvement of PGE2 and identify PGES mediating neuropathic pain, we applied a neuropathic pain model prepared by L5 spinal nerve transection to mPGES-1 knockout (mPGES-1-/-) mice. Whereas they retained normal nociceptive responses, mPGES-1-/- mice did not exhibit mechanical allodynia and thermal hyperalgesia over a week. These results demonstrate that PGE2 produced by mPGES-1 is involved in neuropathic pain.
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PMID:Membrane-associated prostaglandin E synthase-1 is required for neuropathic pain. 1519 60

Pruritus associated with intrathecal opioid administration is particularly common in pregnancy. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the severity of this pruritus but have undesirable side effects. The recent development of drugs that can specifically inhibit the cyclooxygenase 2 isoenzyme have become an attractive alternative. This study was designed to evaluate the efficacy of such a drug (celecoxib) in reducing intrathecal opioid-induced pruritus in a randomised double-blinded study of 60 women undergoing Caesarean section. All of them received spinal anaesthesia with 3 ml of 0.5% hyperbaric bupivacaine and 0.3 mg preservative-free morphine. After delivery of the baby, they received either oral celecoxib 200 mg or placebo. Visual analogue scores for pain and pruritus were measured at 30 min, 2, 4, 8, and 24 h. There was no difference in the severity and onset of pain and pruritus between the two groups. Timing of administration, inadequate dosing and possible altered pharmacokinetics in pregnancy may explain the lack of efficacy.
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PMID:The effect of celecoxib on intrathecal morphine-induced pruritus in patients undergoing Caesarean section. 1531 Mar 50

Administration of formalin in rat paws results in stimulation of nociceptive pathways, which leads to an increase in the excitability of neurons present in dorsal horn. This increased neuron excitability, described as central sensitization, may result in development of inflammatory pain at a distant site of injury application, known as secondary hyperalgesia. The aim of the present study was to verify whether formalin injection in rat paws would lead to secondary hyperalgesia development, as measured by the tail-flick test. We also aimed to investigate whether celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, would affect secondary hyperalgesia. Formalin injected into the rat paws significantly reduced the latency for a flick response in the rat tail, which characterized development of secondary hyperalgesia. In addition, formalin-induced secondary hyperalgesia was locally prevented by pre-but not post-celecoxib treatment. However, celecoxib administered spinally inhibited formalin-induced secondary hyperalgesia, either administered previously or following formalin. In contrast, piroxicam, an unspecific COX inhibitor which displays an increased selectivity towards COX-1, only prevented secondary hyperalgesia to formalin at a high dose following spinal administration. Taken together, these results suggest that COX-2 plays an important role both in the central and in the peripheral nerve sensitization following formalin administration in rat paws. They also suggested that once central sensitization starts it can no longer be blocked by a specific COX-2 inhibitor administered locally. Notwithstanding, spinal administration of a specific COX-2 inhibitor still blocks ongoing sensitization and prevents maintenance of central sensitization.
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PMID:Prevention by celecoxib of secondary hyperalgesia induced by formalin in rats. 1546 32

With the ever-developing role of nurses in pain management and the increasing responsibilities for nurse prescribers, it is important for nurses to be aware of the current evidence base for practice in this area. This article considers some of the latest research surrounding Cox-2 drugs and guidance on their use.
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PMID:Do Cox-2 inhibitors have the potential to improve postoperative pain control? 1546 79

Arthritis urica is one of the most frequent forms of arthritis in Switzerland. On one hand it can mimic septic arthritis, on the other hand it may progress into chronic polyarticular disease. Age, sex and initial clinical presentation lead to the suspicion of crystal arthropathy. The diagnosis, however, has to be proven by microscopic analysis of synovial fluid. Functional ultrasound may be extremely helpful in collecting minute amounts of liquid in small joints. This approach enables definite diagnosis and at the same time crystalline glucocorticoids together with local anesthetics can be injected intra-articularly in order to interrupt the inflammatory process and to kill pain. Other conventional treatment modalities include non-steroidal anti-inflammatory drugs (including Cox-2 inhibitors) which should be started immediately and at maximal doses as well as glucocorticoids at moderate doses for a few days. Serum uric acid levels should be normalized in order to prevent recurrence of arthritis.
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PMID:[Gout and its differential diagnosis]. 1549 16


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