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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory mediators produced in the injured nerve have been proposed as contributing factors in the development of neuropathic pain. Prostaglandins (PGs) are probably included in these important inflammatory mediators. In the present study, 2 and 4 weeks following partial sciatic nerve ligation (PSNL), we observed a dramatic increase in the prostaglandin synthesizing enzyme cyclooxygenase (COX)2-immunoreactive (IR) cell profiles in the injury site and adjacent region. Some of these COX2-IR cells were identified as macrophages because they coexpressed ED1. None of these COX2-IR cell profiles coexpressed the Schwann cell marker S100. In the contralateral sciatic nerve and sciatic nerve from normal rats, we failed to observe any of these COX-IR cell profiles. We also observed COX1-IR cell profiles (presumably Langerhans cells) in the epidermis of the footpad of both normal and PSNL rats. Interestingly, a greater number of COX1-IR cell profiles were observed in the epidermis of the ipsilateral footpad of PSNL rats. Local injection of ketorolac, a nonselective COX inhibitor, into the ipsilateral plantar side or into the injury site of the sciatic nerve, effectively reversed the tactile allodynia induced by PSNL for > 5 days. Intraperitoneal or intramuscular injection of ketorolac had a similar but shorter antiallodynic effect. Intraplantar or peri-neural injection of ketorolac dramatically suppressed the PSNL-induced increase in the phosphorylation of a transcription factor cAMP response element binding protein (CREB) in the ipsilateral dorsal horn of L4 and L5 spinal cord of PSNL rats. Intraplantar or peri-neural injection of ketorolac at the time of lesion did not prevent mechanical hypersensitivity but reduced it with a slow onset 3 weeks after lesion. Our data suggest that PSNL induces over-production of PGs in peripheral tissues and that PGs probably sensitize nociceptors and are involved in central plasticity and sensitization at the spinal cord level, thus contributing to the maintenance of tactile allodynia.
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PMID:Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain. 1191 52

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

Inflammation proximal to a peripheral nerve injury may be responsible for ectopic discharge and/or death of sensory neurones, factors thought to contribute to the development and/or maintenance of neuropathic pain. Here, ED1+, ED2+ and major histocompatibility complex class II (MHC II)+ macrophages in dorsal root ganglia (DRGs) and spinal nerve roots have been compared quantitatively in adult rats following transection of one sciatic or one spinal nerve, using double labelling immunohistochemistry. In control DRGs, all ED2+ cells expressed ED1 and some also MHC II. One week after either lesion, the ED2+ cells changed negligibly, except that all expressed MHC II. ED1+ and MHC II+ cell density increased markedly, with cells expressing MHC II alone (the majority), ED1/MHC II or rarely ED1 alone. In the spinal roots, ED1+ and MHC II+ cell density increased less after sciatic than after spinal nerve transection when ED1+ foamy cells were prominent. All ED2- macrophages were aggregated with T lymphocytes around blood vessels at 1 week or around isolated somata at later stages. ED1+ cell density declined more rapidly than MHC II+ cell density. Within the DRG, the debris of retrogradely labelled neurones appeared in ED2+ cells and a small proportion of MHC II+ cells that contained ED1. The data suggest that (i) resident ED2+ macrophages do not proliferate but are phagocytic and (ii) of ED1+ and MHC+ monocytes invading from the blood, only ED1+/MHC II+ cells are phagocytic. Four functional subtypes of macrophage within the DRGs were distinct from ED1+ foamy cells that phagocytosed myelin after spinal nerve transection.
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PMID:Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat. 1476 52

The mechanisms underlying neuropathic pain caused by nerve injury are not well understood. Inflammatory responses in injured nerves are likely to be key contributing factors in the generation and maintenance of neuropathic pain. The pro-inflammatory cytokine interleukin-6 (IL-6) is up-regulated in invading macrophages and has been implicated in the development of neuropathic pain. We previously demonstrated that invading macrophages up-regulate cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) receptors EP1 and EP4, suggesting that PGE2 may affect macrophage function via autocrine or paracrine mechanisms. This study was undertaken to determine whether PGE2 is involved in the up-regulation of IL-6 in invading macrophages. Two weeks following partial sciatic nerve ligation, numerous IL-6 immunoreactive (IR) cell profiles were present in injured nerves. Colocalization of IL-6 with the invading macrophage marker ED1 or with COX2 was frequently observed. IL-6-IR, COX2-IR and ED1-IR cells were present only in cultures derived from injured nerve segments. PGE2 and IL-6 release from cultured cells derived from injured nerves was increased significantly compared with uninjured nerves. Non-selective and selective COX2 inhibitors suppressed PGE2 and IL-6 release. Treatment with PGE2 further enhanced IL-6 release in a concentration- and time-dependent manner. A selective EP4 receptor antagonist L-161982 was able to suppress IL-6 release, whereas an EP1 receptor antagonist, SC19220, was ineffective. Moreover, a protein kinase C inhibitor, calphostin C, dramatically suppressed IL-6 release, whereas a protein kinase A inhibitor H-89 and a Ca2+ chelator EGTA failed. Taken together, our data suggest that PGE2 is involved in mediating the up-regulation of IL-6 occurring in invading macrophages. This action is mediated through an EP4 receptor and the protein kinase C signaling pathway.
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PMID:Up-regulation of interleukin-6 induced by prostaglandin E from invading macrophages following nerve injury: an in vivo and in vitro study. 1583 25

P2X4 receptor (P2X4R) is an ion channel gated by adenosine 5'-triphosphate. Here we report the presence and the distribution of P2X4R in rat spinal cord by immunohistochemical analysis in an inflammatory pain model. Peripheral inflammation was induced by subcutaneous injection of 4% formalin into the rat hindpaw. Morphology, spatial localization, and activation state of P2X4R+ cells were described at 1, 5, 7, 14, and 28 days after injury. In normal and saline treated control rats, P2X4R was rarely seen. After formalin administration, an increase of P2X4R+ microglia were observed in the spinal cord dorsal horn on the side ipsilateral to the injection, reaching maximal levels by day 7, and then decreasing to normal levels by day 14. This implicates a role of P2X4R in the spinal inflammatory pain process. Furthermore, formalin-induced region-specific increase in activated microglia was confirmed by ED1 and endothelial monocytes activating polypeptide II (EMAP-II) expression. In conclusion, this is the first demonstration that P2X4R is expressed by microglia in the inflammatory pain.
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PMID:Expression of P2X4 receptor by lesional activated microglia during formalin-induced inflammatory pain. 1588 14

Immunohistochemistry was used to examine the expression of prostaglandin E(2) receptors EP1 and EP4 in sciatic nerves from the rat chronic constriction injury (CCI) model of neuropathic pain. At 21 days post-surgery the CCI rats had developed mechanical hyperalgesia on the operated side, and quantitative image analysis showed a highly significant doubling of the area occupied by EP1- and EP4-positive pixels in sections from CCI nerves when compared to sham-operated controls. Co-localisation studies with the marker ED1 revealed that 73% of the EP1-positive cells and 54% of the EP4-positive cells in the injured nerves represented infiltrating macrophages. Cells negative for ED1 and positive for either EP1 or EP4 were characterised as Schwann cells from their morphology and expression of myelin basic protein and S100 antigens. Similar EP1- and EP4-positive Schwann cell profiles were observed in sections of uninjured control nerves. Low levels of EP receptor expression were found in neurofilament-immunostained axons, but no consistent differences were observed in the levels of axonal EP staining between CCI and control tissue. These data provide further evidence of the importance of prostaglandins in the pathogenesis of neuropathic pain, and suggest that not only infiltrating macrophages but also Schwann cells may be involved in the modulation of these mediators in response to nerve injury.
Eur J Pain 2007 Aug
PMID:Localisation and modulation of prostanoid receptors EP1 and EP4 in the rat chronic constriction injury model of neuropathic pain. 1711 Jan 43

Chronic constriction injury (CCI) of the sciatic nerve in rodents produces mechanical and thermal hyperalgesia and is a common model of neuropathic pain. Here we compare the inflammatory responses in L4/5 dorsal root ganglia (DRGs) and spinal segments after CCI with those after transection and ligation at the same site. Expression of ATF3 after one week implied that 75% of sensory and 100% of motor neurones had been axotomized after CCI. Macrophage invasion of DRGs and microglial and astrocytic activation in the spinal cord were qualitatively similar but quantitatively distinct between the lesions. The macrophage and glial reactions around neurone somata in DRGs and ventral horn were slightly greater after transection than CCI while, in the dorsal horn, microglial activation (using markers OX-42(for CD11b) and ED1(for CD68)) was greater after CCI. In DRGs, macrophages positive for OX-42(CD11b), CD4, MHC II and ED1(CD68) more frequently formed perineuronal rings beneath the glial sheath of ATF3+ medium to large neurone somata after CCI. There were more invading MHC II+ macrophages lacking OX-42(CD11b)/CD4/ED1(CD68) after transection. MHC I was expressed in DRGs and in spinal sciatic territories to a similar extent after both lesions. CD8+ T-lymphocytes aggregated to a greater extent both in DRGs and the dorsal horn after CCI, but in the ventral horn after transection. This occurred mainly by migration, additional T-cells being recruited only after CCI. Some of these were probably CD4+. It appears that inflammation of the peripheral nerve trunk after CCI triggers an adaptive immune response not seen after axotomy.
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PMID:Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. 1718 59

Peridural scarring, or the excessive formation of scar tissue following spinal surgery, is one of the important contributing factors that result in persistent pain and disability in many individuals who have undergone elective back surgery. Treatment with anti-inflammatory agents following surgery may reduce oxidative stress and scarring, leading to a reduction in post-operative pain. We are using a surgical rat model to test the hypothesis that post-surgical inflammation and oxidative stress following laminectomy can be reduced by systemic administration of L: -2-oxo-thiazolidine-4-carboxylate (OTC) and quercetin. OTC is a cysteine precursor required for the synthesis of glutathione, an important antioxidant. Quercetin is a flavonoid with anti-oxidant properties, found in fruits and vegetables. Synchrotron FTIR microspectroscopy data has been collected on OTC, quercetin and saline (control)-treated post-surgery animals, sacrificed at 3 and 21 days (n = 6 per age and treatment group). This paper presents preliminary IR results, supported by immunocytochemistry, on the heterogeneous distribution of biological components present in the healing tissue. The data collected on animals sacrificed at 3 and 21 days post-surgery will be combined in the future with data from animals sacrificed 63 days after surgery (representing a third time point) to evaluate the efficacy of the different treatments. Initial statistical analysis of ED1 immunohistochemistry results indicates a decrease in the number of activated macrophages 21 days post-surgery in the OTC-treated animals compared with the saline controls.
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PMID:Synchrotron FTIR microspectroscopic analysis of the effects of anti-inflammatory therapeutics on wound healing in laminectomized rats. 1726 Jan 38

To investigate whether the phosphorylation of cyclic AMP response element-binding protein (CREB) is implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the change in the level of CREB phosphorylation was analyzed in the spinal cord of Lewis rats with EAE. Western blot analysis showed that the phosphorylation of CREB in the spinal cord of rats increased significantly at the peak stage of EAE compared with the controls (p<0.05) and declined significantly in the recovery stage (p<0.05). Immunohistochemistry showed that the phosphorylated form of CREB (p-CREB) was constitutively immunostained in few astrocytes and dorsal horn neurons in the spinal cord of normal rats. In the EAE-affected spinal cord, p-CREB was mainly found in ED1-positive macrophages at the peak stage of EAE, and the number of p-CREB-immunopositive astrocytes was markedly increased in the spinal cord with EAE compared with the controls. Moreover, p-CREB immunoreactivity of sensory neurons, which are closely associated with neuropathic pain, was significantly increased in the dorsal horns at the peak stage of EAE. Based on these results, we suggest that the increased phosphorylation of CREB in EAE lesions was mainly attributable to the infiltration of inflammatory cells and astrogliosis, possibly activating gene transcription, and that its increase in the sensory neurons in the dorsal horns is involved in the generation of neuropathic pain in the rat EAE model.
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PMID:Increased phosphorylation of cyclic AMP response element-binding protein in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis. 1761 86

Peripheral nerve inflammation can cause axons conducting through the inflamed site to become mechanically sensitive. Axonal mechanical sensitivity (AMS) of intact axons may explain symptoms in a diverse number of conditions characterized by radiating pain evoked by movements of the affected nerve. Because nerve inflammation also disrupts axoplasmic transport, we hypothesized that the disruption of axoplasmic transport by nerve inflammation could cause the cellular components responsible for mechanical transduction to accumulate and become inserted at the inflamed site, causing AMS. This was tested by examining AMS in C-fibre nociceptors following the application of axoplasmic transport blockers (colchicine and vinblastine) to the sciatic nerve. Both 10 mm colchicine and 0.1 mm vinblastine caused AMS to develop in 30.6% and 33.3% of intact axons, respectively (P < 0.05 compared to sham treatment). Since high doses of colchicine (> 50 mm) can damage axons, and inflammation is involved in the removal of axonal debris, experiments were performed to assess conduction across the treatment site as well as signs of inflammation. Results indicated minimal axonal loss (95% of A- and C-fibres conducting), consistent with the normal microscopic appearance of the colchicine treatment site and absence of ED1-positive (recruited) macrophages. In a separate series of experiments, the block of axoplasmic transport proximal to a localized neuritis significantly reduced inflammation-induced AMS (15.6% compared to 55.6%; P < 0.05), further supporting that the components necessary for AMS are moved by anterograde transport. In summary, nerve inflammation that causes the disruption of axoplasmic transport in patients with painful conditions may result in the accumulation and insertion of mechanosensitive elements at the inflamed site.
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PMID:Disruption of axoplasmic transport induces mechanical sensitivity in intact rat C-fibre nociceptor axons. 1832 74


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