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      Effects of NSAIDs and paracetamol (acetaminophen) on protein kinase C epsilon translocation and on substance P synthesis and release in cultured sensory neurons

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          Celecoxib, diclofenac, ibuprofen, and nimesulide are nonsteroidal anti-inflammatory drugs (NSAIDs) very commonly used for the treatment of moderate to mild pain, together with paracetamol (acetaminophen), a very widely used analgesic with a lesser anti-inflammatory effect. In the study reported here, we tested the efficacy of celecoxib, diclofenac, and ibuprofen on preprotachykinin mRNA synthesis, substance P (SP) release, prostaglandin E 2 (PGE 2) release, and protein kinase C epsilon (PKCɛ) translocation in rat cultured sensory neurons from dorsal root ganglia (DRGs). The efficacy of these NSAIDs was compared with the efficacy of paracetamol and nimesulide in in vitro models of hyperalgesia (investigated previously). While nimesulide and paracetamol, as in previous experiments, decreased the percentage of cultured DRG neurons showing translocation of PKCɛ caused by 100 nM thrombin or 1 μM bradykinin in a dose-dependent manner, the other NSAIDs tested did not have a significant effect. The amount of SP released by peptidergic neurons and the expression level of preprotachykinin mRNA were assessed in basal conditions and after 70 minutes or 36 hours of stimulation with an inflammatory soup (IS) containing potassium chloride, thrombin, bradykinin, and endothelin-1. The release of SP at 70 minutes was inhibited only by nimesulide, while celecoxib and diclofenac were effective at 36 hours. The mRNA basal level of the SP precursor preprotachykinin expressed in DRG neurons was reduced only by nimesulide, while the increased levels expressed during treatment with the IS were significantly reduced by all drugs tested, with the exception of ibuprofen. All drugs were able to decrease basal and IS-stimulated PGE 2 release. Our study demonstrates novel mechanisms of action of commonly used NSAIDS.

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          Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.

          The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.
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            Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha.

            1. Peripheral inflammation is characterized by heightened pain sensitivity. This hyperalgesia is the consequence of the release of inflammatory mediators, cytokines and growth factors. A key participant is the induction of the neurotrophin nerve growth factor (NGF) by interleukin-1 beta (IL-1 beta). 2. Tumour necrosis factor alpha (TNF alpha) has been shown both to produce hyperalgesia and to upregulate IL-1 beta. We have now examined whether the induction of TNF alpha in inflammatory lesions contributes to inflammatory sensory hypersensitivity by inducing IL-1 beta and NGF. 3. The intraplantar injection of complete Freund's adjuvant (CFA) in adult rats produced a localized inflammation of the hindpaw with a rapid (3 h) reduction in withdrawal time in the hot plate test and in the mechanical threshold for eliciting the flexion withdrawal reflex. 4. The CFA-induced inflammation resulted in significant elevation in the levels of TNF alpha, IL-1 beta and NGF in the inflamed paw. In the case of TNF alpha, an elevation was detected at 3 h, rose substantially at 6 h, peaked at 24 h and remained elevated at 5 days, with similar but smaller changes in the contralateral non-inflamed hindpaw. No increase in serum TNF alpha was detected at 24 h post CFA injection. 5. Intraplantar recombinant murine TNF alpha injections produce a short-lived (3-6 h) dose-dependent (50-500 ng) increase in thermal and mechanical sensitivity which was significantly attenuated by prior administration of anti-NGF antiserum. 6. Intraplantar TNF alpha (100-500 ng) also elevated at 6 but not 48 h the levels of IL-1 beta and NGF in the hindpaw. 7. A single injection of anti-TNF alpha antiserum, 1 h before the CFA, at a dose sufficient to reduce the effects of a 100 ng intraplantar injection of TNF alpha, significantly delayed the onset of the resultant inflammatory hyperalgesia and reduced IL-1 beta but not NGF levels measured at 24 h. 8. The elevation of TNF alpha in inflammation, by virtue of its capacity to induce IL-1 beta and NGF, may contribute to the initiation of inflammatory hyperalgesia.
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              A cascade of cytokines mediates mechanical inflammatory hypernociception in mice.

              The hypernociceptive effects of cytokines [TNF-alpha, keratinocyte-derived chemokine (KC), and IL-1beta] and their participation in carrageenan (Cg)-induced inflammatory hypernociception in mice were investigated. Nociceptor sensitization (hypernociception) was quantified with an electronic version of the von Frey filament test in WT and TNF receptor type 1 knockout mice (TNF-R1-/-). TNF-alpha-induced hypernociception was abolished in TNF-R1-/- mice, partially inhibited by pretreatment with IL-1 receptor antagonist (IL-1ra) or indomethacin and unaffected by Ab against KC (AbKC) or guanethidine. IL-1ra and indomethacin pretreatment strongly inhibited the hypernociception induced by IL-1beta, which was not altered by AbKC or guanethidine or by knocking out TNF-R1. KC-induced hypernociception was abolished by AbKC, inhibited by pretreatment with indomethacin plus guanethidine, and partially inhibited by IL-1ra, indomethacin, or guanethidine. In contrast, KC-induced hypernociception was not altered by knocking out TNF-R1. Cg-induced hypernociception was abolished by administration of indomethacin plus guanethidine, diminished in TNF-R1-/- mice, and partially inhibited in WT mice pretreated with AbKC, IL-1ra, indomethacin, or guanethidine. TNF-alpha, KC, and IL-1beta concentrations were elevated in the skin of Cg-injected paws. The TNF-alpha and KC concentrations rose concomitantly and peaked before that of IL-1beta. In mice, the cytokine cascade begins with the release of TNF-alpha (acting on TNF-R1 receptor) and KC, which stimulate the release of IL-1beta. As in rats, the final mediators of this cascade were prostaglandins released by IL-1beta and sympathetic amines released by KC. These results extend to mice the concept that the release of primary mediators responsible for hypernociception is preceded by a cascade of cytokines.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Dove Medical Press
                12 February 2013
                : 6
                : 111-120
                [1 ]Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
                [2 ]Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
                [3 ]Department of Economics and Technology, University of the Republic of San Marino, Republic of San Marino
                Author notes
                Correspondence: Vittorio Vellani, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy, Tel +39 059 2055063, Fax +39 059 2055363, Email vittorio.vellani@ 123456unimore.it
                © 2013 Vellani et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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