Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In chemical terms the mediators of inflammation can be divided in amines (histamine, serotonine), peptides (ECF-A, bradykinin), proteins (lysosomal enzymes), and lipids. They mainly act at three levels: 1.) They induce vascular reactions and are responsible for the classical symptoms of inflammation, 2.) they define and modulate the cellular response towards the inflammatory stimulus such as the morphology of the tissue infiltrate, 3.) they act on haemostasis by interaction with platelets. While in the past investigations on classical mediators have dominated research, recently the biological role of lipid mediators has been appreciated. They can be detected only in minute quantities; they often have a short half-life and are not preformed within the cells. The most common precursor of the lipid mediators is arachidonic acid. This unsaturated fatty acid is generated from phospholipids after phospholipase activation of cells and is transformed by the enzyme cycloxygenase to a series of compounds such as the prostaglandins. They induce the classical signs of inflammation such asvescular dilatation, increase in permeability, pain, hyperalgesia etc. By the same process, the thromboxanes and prostacycline are generated which mainly act on the coagulation system. Various products are obtained from arachidonic acid via lipoxygenase activation. To these belong a factor chemically not completely defined with classical SRS-A activity; there is strong evidence that PAF and ECF are formed on the same line. Experiments in recent years have supported the idea that neutrophils and mononuclear cells are by far the main producers of lipid mediators, thus indicating the cellular interdependence during the inflammatory process.
 ...
PMID:[Origin and biological role of lipid mediators during inflammation (author's transl)]. 12 Mar 7

Bradykinin is one of several pro-inflammatory, pain-inducing substances produced during inflammation--the body's response to injury. In previous work we have shown that bradykinin and guanosine-5'-O-3-thiotriphosphate increase excitability in a subpopulation of cultured neonatal rat dorsal root ganglion neurons. We now describe experiments in which the mechanism underlying the stimulatory action of these two substances has been examined in more detail. Using the whole-cell voltage-clamp technique, bradykinin-sensitive cells were distinguished by their response to a 1-s depolarizing voltage-pulse which evoked more than one inward current during the step command. The secondary inward currents are likely to represent action potentials generated at the poorly clamped neurites of these cells. Bradykinin- and guanosine-5'-O-3-thiotriphosphate-induced changes in excitability were measured indirectly by a change in the number of inward currents recorded during the 1-s depolarizing voltage-step. The effect of activators and inhibitors of protein kinase C, arachidonic acid metabolism, G-protein activation and release of intracellular Ca2+ were examined on this response. In the presence of extracellular staurosporine (1.0 microM) or nordihydroguaiaretic acid (10 microM), these excitatory effects were reduced but not abolished, whilst indomethacin (20 microM) had no effect. Intracellular application of guanosine-5'-O-2-thiodiphosphate (10 mM) or ryanodine (100 microM) substantially reduced the effect of bradykinin. The excitatory effect of internal guanosine-5'-O-3-thiotriphosphate (500 microM) occurred gradually over time, and this was mimicked by internal application of myo-inositol 1,4,5-trisphosphorothioate (1.0 microM). From the results, it is proposed that G-protein activation is an essential component of the bradykinin response, which may also require a Ca(2+)-activated conductance modulated by protein kinase C and lipoxygenase metabolites of arachidonic acid.
 ...
PMID:G-protein mediation in nociceptive signal transduction: an investigation into the excitatory action of bradykinin in a subpopulation of cultured rat sensory neurons. 140 41

The derivatives of arachidonic acid are generally called by the term eicosanoid. Arachidonic acid is a starting material for a series of biologically highly active metabolites that are formed either through cyclooxygenase, e.g., the prostaglandins (PG), or through various lipoxygenase ways, e.g., hydroxyarachidonic acids (HETE), leukotriene (LT), and peptide-LT. Eicosanoids also take part in menstrual bleeding; in dysmenorrhea also cyclooxygenase inhibitors, e.g., indomethacin have been proven to fight pain in addition to spasmolytics and the preventive action of hormonal contraceptives. PGs and peptide-LT could be shown in relative high concentrations in the endometrium of dysmenorrheic women. An analytic method in which menstrual blood was used as test material was developed. Women were given standardized tampons and holders filled with acidified alcohol. The holders were weighed for determination of the amount of blood. A special high performance liquid chromatography separation system was developed for purification, and radioimmunoassay was subsequently used for analysis of 60keto-PGF1alpha, and PGE2. 103 tampons of 14 subjects from 24 menstrual cycles were evaluated in 4 groups; no hormonal contraceptive use, contraceptive use, no pain, and pain. The taking of a pill significantly affected the blood volume; it was only 1/2 as much as in the control group without the taking of a pill. In the control group with a pill and pain 12 HETE was quantitatively the most important eicosanoid with a 60% share. F2alpha dominated among PGs. In patients with pain without pill use the average values of 6-keto, PGE2, 12-HETE, and LTB 4 were 50% higher. After pill use PG concentrations dropped significantly by 80% compared with controls. 12-HETE and PGF2alpha were the main metabolites of arachidonic acid in menstrual blood, in pain some metabolites were higher, and OCs reduced eicosanoid excretion significantly.
 ...
PMID:[Effect of hormonal contraceptives on eicosanoid content of menstrual blood]. 179 Sep 85

Pain induced by a stimulus that is normally not painful is referred to as hyperalgesic pain. Inhibition of arachidonic acid metabolism and/or sympathectomy have been found to be effective treatment for this type of pain. We propose that the lowered pain threshold is induced by arachidonic acid metabolites produced in inflamed tissue or by sympathetic postganglionic neurons after nerve injury. The most extensively studied hyperalgesic mediators are prostaglandin E(2) (PGE(2)) and prostacyclin (PGI(2)), products of the cyclooxygenase pathway of arachidonic acid metabolism, whose production is inhibited by nonsteroidal antiinflammatory analgesics (NSAIAs). Recent studies, however, have demonstrated that products of the NSAIA-resistant lipoxygenase pathway of arachidonic acid metabolism are also hyperalgesic. Their production is inhibited by corticosteroids and current experimental agents.
 ...
PMID:Hyperalgesic pain: a review. 196 69

The responses of normal skin to ultraviolet (UV) irradiation are an example of inflammation. The chromophores initiating the reaction are unknown. Characteristic clinical findings are erythema, heat, swelling, and pain. Histopathologic changes include epidermal keratinocyte damage with Langerhans cell depletion and dermal edema, endothelial swelling, mast cell degranulation, and cellular infiltration with neutrophils and monocytes. Biochemical changes include release of histamine, cyclo-oxygenase, and lipoxygenase-derived products of arachidonic acid, kinins, and cytokines, probably from a range of epidermal and dermal cell types. These substances very likely assist in mediation of the reaction. The response is more pronounced in young subjects. UVB (280 to 315 nm) and UVA (315 to 400 nm) radiation both produce inflammation, but with marked qualitative and quantitative differences. UVB having more effect on the epidermis, UVA more on the dermis.
 ...
PMID:Acute effects of ultraviolet radiation on the skin. 220 37

Oxygenation of arachidonic acid is increased in inflamed tissues. In this condition products of two enzymic pathways--the cyclooxygenase and the 5-lipoxygenase producing respectively prostaglandins and leukotrienes--are elevated. Of the cyclooxygenase products, PGE2 and of the lipoxygenase products, LTB4 are the strongest candidates for mediating inflammation. Non-steroidal anti-inflammatory drugs which inhibit the cyclooxygenase, and corticosteroids are used to treat such disorders. Both types of drugs produce adverse side-effects on prolonged use. Ginger is reported in Ayurvedic and Tibb systems of medicine to be useful in rheumatic disorders. Seven patients suffering from such disorders reported relief in pain and associated symptoms on ginger administration.
 ...
PMID:Ginger (Zingiber officinale) and rheumatic disorders. 250 34

Manoalide, a non-steroidal sesterterpenoid isolated from a marine sponge, is a potent analgesic and antiinflammatory compound. Manoalide inhibits phospholipase A2 from extracellular sources (snake venoms, bee, etc.), the release of arachidonic acid from rabbit polymorphonuclear leukocytes as well as calcium mobilization. This suggests that the anti-inflamatory effect might be caused by the regulation of eicosanoid biosynthesis. The macrophage plays a major role in the immune response and the inflammatory process, it has the capacity to synthesize and secrete arachidonic acid oxygenation products derived from both cyclooxygenase and lipoxygenase catalyzed pathways, and has been used extensively to study the effect of inhibitors of phospholipases, cyclooxygenase and lipoxygenase enzymes. Our results demonstrate that Manoalide modified the release of arachidonic acid and its further metabolism into prostaglandins and leukotrienes in mouse cultured peritoneal macrophages stimulated by phorbol myristate acetate, calcium ionophore A23187 and zymosan. Since eicosanoids have been shown to cause pain, we studied the possibility that the analgesic effect of Manoalide might be correlated with a decrease of eicosanoid release in vivo. The fact that Manoalide reduced both zymosan-induced peritoneal writhing in the mouse and the synthesis of both 6-keto-prostaglandin F1 alfa and leukotriene C4 suggests that the analgesic effect of Manoalide is at least in part linked to the inhibition of eicosanoid production in vivo. Since it has been shown that eicosanoids have immunoregulatory functions, a future possibility is that a phospholipase A2 inhibitor such as Manoalide may prove useful to investigate the biological role of eicosanoid metabolites on the immune function.
 ...
PMID:[Manoalide: a new phospholipase A2 inhibitor of marine origin with potential immunoregulatory effect]. 264 Apr 87

Platelet-activating factor (PAF), a potent inflammatory mediator, decreases the nociceptive threshold in the rat hindpaw. Pain sensitivity, measured by the applied pressure necessary to induce vocalization, was increased maximally at 3 and 4 hr after injection of synthetic PAF. The hyperalgesic response to PAF was specifically inhibited by agents that interfere with the lipoxygenase pathway of arachidonic acid metabolism and was not affected by cyclooxygenase inhibitors. BW-755C (3-30 mg/kg, p.o.) and L-615,919 (0.01-0.3 mg/kg, p.o.) significantly reduced PAF-induced hyperalgesia, whereas indomethacin had no effect. The finding that L-615,919, a specific 5-lipoxygenase inhibitor, was a potent inhibitor of this model of hyperalgesia leads to speculation that leukotrienes are important mediators of inflammatory pain.
 ...
PMID:Pharmacological evidence for a role of lipoxygenase products in platelet-activating factor (PAF)-induced hyperalgesia. 282 47

1. Two selective inhibitors of arachidonate 5-lipoxygenase, BW A4C and BW A797C, have been studied for their effects on acute inflammatory responses following oral administration to rats and mice. 2. The concentrations of the lipoxygenase product leukotriene B4 (LTB4) in 6 h inflammatory exudates, induced in rats by the subcutaneous implantation of carrageenin-soaked polyester sponges, were reduced dose-dependently by BW A4C (ED50 = 2.6 mg kg-1) or BW A797C (ED50 = 14.3 mg kg-1). 3. BW A4C and BW A797C had little or no effect on prostaglandin E2 (PGE2) concentrations in inflammatory exudates (ED50s greater than 100 mg kg-1). 4. Doses of up to 200 mg kg-1 of either BW A4C or BW A797C had no effect on carrageenin-induced oedema in rat paws. 5. BW A4C and BW A797C had little or no effect on carrageenin-induced hyperalgesia in rats or phenyl-benzoquinone-induced writhing in mice. 6. Yeast-induced pyrexia in rats was reduced by both BW A4C (ED50 = 32 mg kg-1) and BW A797C (ED50 = 23 mg kg-1). 7. The accumulation of leucocytes in sponge exudates was reduced dose-dependently by BW A4C (ED50 = 54 mg kg-1) and BW A797C (ED50 = 16.7 mg kg-1). 8. The selective lipoxygenase inhibitors BW A4C and BW A797C do not suppress inflammatory oedema or pain although they are anti-pyretic and they do inhibit leucocyte migration. There is not, however, a close agreement between these in vivo activities and their potencies as lipoxygenase inhibitors.
 ...
PMID:Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: effects on acute inflammatory responses. 284 Jan 61

The leukotrienes (LTs) are a novel group of biologically active mediators derived from arachidonic acid via lipoxygenase enzymes. LTB4 is a potent chemotactic agent for polymorphonuclear leukocytes and in vivo may mediate inflammatory reactions by inducing leukocyte recruitment by mediating indirectly vascular permeability charges and by modulating pain responses. LTC4 and LTD4 collectively account for the biological activity known as slow-reacting substance of anaphylaxis and are potent smooth muscle contracting agents. They may mediate inflammatory reactions by producing changes in blood flow and increases in vascular permeability. Evidence for LT involvement in a number of pathological conditions including diseases such as asthma, psoriasis, ulcerative colitis, and gout is now accumulating.
 ...
PMID:Leukotrienes: their formation and role as inflammatory mediators. 298 30


1 2 3 4 5 6 7 8 9 Next >>