linoleic-acid and Pain

Various fatty acyl lipid mediators are derived from dietary polyunsaturated fatty acids (PUFAs) and modulate nociception. The modern diet is rich in linoleic acid, which is associated with nociceptive hypersensitivities and may present a risk factor for developing pain conditions. Although recommendations about fatty acid intake exist for some diseases (e.g. cardiovascular disease), the role of dietary fatty acids in promoting pain disorders is not completely understood. To determine how dietary linoleic acid content influences the accumulation of pro- and anti-nociceptive fatty acyl lipid mediators, we created novel rodent diets using custom triglyceride blends rich in either linoleic acid or oleic acid. We quantified the fatty acyl lipidome in plasma of male and female rats fed these custom diets from the time of weaning through nine weeks of age. Dietary fatty acid composition determined circulating plasma fatty acyl lipidome content. Exposure to a diet rich in linoleic acid was associated with accumulation of linoleic and arachidonic acid-derived pro-nociceptive lipid mediators and reduction of anti-nociceptive lipid mediators derived from the omega-3 PUFAs. Our findings provide mechanistic insights into exaggerated nociceptive hypersensitivity associated with excessive dietary linoleic acid intake and highlight potential biomarkers for pain risk stratification.

Topics: Animals; Arachidonic Acid; Diet; Dietary Fats; Eicosanoids; Fatty Acids; Fatty Acids, Unsaturated; Female; Linoleic Acid; Linoleic Acids; Male; Oleic Acid; Pain; Rats; Triglycerides

Inflammation is a primary defense and immune response. However, under pathological conditions, the inflammation processes always become uncontrolled and lead to chronic diseases. Bufotenine, as a natural component from toad venom, showed great potential for development as a novel anti-inflammation and analgesia agent. This study aimed to investigate the therapeutic effects of bufotenine against inflammation and pain on animal models with a focus on lipid metabolism. In pharmacological studies, bufotenine significantly inhibited the swelling rates on formalin-induced paw edema model, and increased paw withdrawal mechanical thresholds (PWMTs) in von Frey test and thermal pain thresholds (TPTs) in hot-plate test. High-sensitivity lipidomics analysis revealed the effects might be related to the down-regulation of inflammatory mediators from cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP450), linoleic acid (LA), docosahexaenoic acid (DHA) and other pathways. The activities might result from the binding of bufotenine and its receptors, including sigma-1 receptor and 5-Hydroxytryptamine receptor 3A, thus regulating lipid metabolism pathway. The research provided a systemic evidence for the actions and mechanism of bufotenine. It suggested that the natural compound might be a potential candidate for reducing inflammatory pain disorders.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Bufotenin; Cyclooxygenase 2; Cytochrome P-450 Enzyme System; Docosahexaenoic Acids; Edema; Female; Linoleic Acid; Lipid Metabolism; Lipoxygenase; Male; Mice, Inbred ICR; Molecular Docking Simulation; Pain; Receptors, Serotonin; Receptors, sigma; Sigma-1 Receptor; Signal Transduction

Oxaliplatin, a platinum-based chemotherapeutic drug, which is used as first-line treatment for some types of colorectal carcinoma, causes peripheral neuropathic pain in patients. In addition, an acute peripheral pain syndrome develop in almost 90% of patients immediately after oxaliplatin treatment, which is poorly understood mechanistically but correlates with incidence and severity of the later-occurring neuropathy. Here we investigated the effects of acute oxaliplatin treatment in a murine model, showing that male and female mice develop mechanical hypersensitivity 24 h after oxaliplatin treatment. Interestingly, we found that the levels of several lipids were significantly altered in nervous tissue during oxaliplatin-induced acute pain. Specifically, the linoleic acid metabolite 9,10-EpOME (epoxide of linoleic acid) as well as the lysophospholipids lysophosphatidylcholine (LPC) 18:1 and LPC 16:0 were significantly increased 24 h after oxaliplatin treatment in sciatic nerve, DRGs, or spinal cord tissue as revealed by untargeted and targeted lipidomics. In contrast, inflammatory markers including cytokines and chemokines, ROS markers, and growth factors are unchanged in the respective nervous system tissues. Importantly, LPC 18:1 and LPC 16:0 can induce Ca

Topics: Animals; Antineoplastic Agents; Calcium Signaling; Chemokines; Cytokines; Female; Hyperalgesia; Linoleic Acid; Lipidomics; Lysophosphatidylcholines; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Oxaliplatin; Pain; Peripheral Nervous System Diseases; TRPM Cation Channels; TRPV Cation Channels

Eicosanoids play a crucial role in inflammatory pain. However, there is very little knowledge about the contribution of oxidized linoleic acid metabolites in inflammatory pain and peripheral sensitization. Here, we identify 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME), a cytochrome P450-derived linoleic acid metabolite, as crucial mediator of thermal hyperalgesia during inflammatory pain. We found 12,13-DiHOME in increased concentrations in peripheral nervous tissue during acute zymosan- and complete Freund's Adjuvant-induced inflammatory pain. 12,13-DiHOME causes calcium transients in sensory neurons and sensitizes the transient receptor potential vanilloid 1 (TRPV1)-mediated intracellular calcium increases via protein kinase C, subsequently leading to enhanced TRPV1-dependent CGRP-release from sensory neurons. Peripheral injection of 12,13-DiHOME in vivo causes TRPV1-dependent thermal pain hypersensitivity. Finally, application of the soluble epoxide hydrolase (sEH)-inhibitor TPPU reduces 12,13-DiHOME concentrations in nervous tissue and reduces zymosan- and CFA-induced thermal hyperalgesia in vivo. In conclusion, we identify a novel role for the lipid mediator 12,13-DiHOME in mediating thermal hyperalgesia during inflammatory pain and propose a novel mechanism that may explain the antihyperalgesic effects of sEH inhibitors in vivo.

Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Female; Freund's Adjuvant; Hot Temperature; Humans; Hyperalgesia; Inflammation; Linoleic Acid; Male; Mice; Oleic Acids; Oxidation-Reduction; Pain; Phenylurea Compounds; Piperidines; Protein Kinase C; Sensory Receptor Cells; TRPV Cation Channels; Zymosan

Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-

Topics: Adult; Aged; Aged, 80 and over; Animals; Case-Control Studies; Female; Humans; In Vitro Techniques; Inflammation; Linoleic Acid; Male; Mice; Middle Aged; Nociceptors; Pain; Pruritus; Psoriasis; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin Gene-Related Peptide; Sensory Receptor Cells; Skin; Systems Analysis

Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes.. Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues.. The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes.

Topics: Animals; Autacoids; Dietary Fats; Fatty Acids, Omega-3; Linoleic Acid; Male; Nociception; Organ Specificity; Oxylipins; Pain; Rats, Inbred F344; Syndrome

The TWIK-related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo.

Topics: Analgesics; Animals; Caffeic Acids; Cinnamates; Esters; Male; Mice; Models, Molecular; Pain; Potassium Channels, Tandem Pore Domain; Quantitative Structure-Activity Relationship; Xenopus

Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [eg, cytochrome P450 (CYP)] are up-regulated after inflammation in the rat. However, it is not known whether such agonists are elevated in human inflammatory pain conditions. Because TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal vs inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues evoked significant inward currents in trigeminal ganglia neurons and were blocked by pretreatment with the TRPV1 antagonist IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in trigeminal ganglia neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of 2 CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicate that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.

Topics: Animals; Biopsy; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dental Pulp; Enzyme Inhibitors; Humans; Immunohistochemistry; Inflammation; Isoenzymes; Ketoconazole; Linoleic Acid; Male; Microscopy, Confocal; Oxidation-Reduction; Pain; Patch-Clamp Techniques; Rats; Sensory Receptor Cells; Toothache; TRPV Cation Channels

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24h after thermal injury, with allodynia being maintained for up to 7d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C(14)]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1.

Topics: Animals; Behavior, Animal; Benzothiazoles; Burns; Chromatography, High Pressure Liquid; Hot Temperature; Hyperalgesia; Immunohistochemistry; Ketoconazole; Linoleic Acid; Lipids; Male; Nerve Fibers; Neutrophil Infiltration; Oxidation-Reduction; Pain; Pain Measurement; Pyrimidines; Rats; Rats, Sprague-Dawley; Skin; TRPV Cation Channels

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous agonists to the transient receptor potential V1 (TRPV1) receptor. Although TRPV1 mediates inflammatory heat hyperalgesia, it is not known if the OLAMs contribute to the peripheral activation of this receptor during tissue inflammation. In the present study, we evaluated whether the OLAM system is activated during inflammation and whether cytochrome P450 enzymes mediate OLAM contributions to heat hyperalgesia using the complete Freund's adjuvant (CFA) model of inflammation.. Our results demonstrate that the intraplantar (ipl) injection of anti-OLAM antibodies significantly reversed CFA-induced heat hyperalgesia. Moreover, application of lipid extracts from inflamed rat skin to cultured sensory neurons triggered a significant release of iCGRP that is blocked by co-treatment with I-RTX, a TRPV1 antagonist. To determine the role of CYP enzymes in mediating OLAM effects, we used a broad spectrum CYP inhibitor, ketoconazole. Pretreatment with ketoconazole inhibited the release of TRPV1 agonists in lipid extracts from inflamed skin and significantly reversed CFA-induced heat hyperalgesia by a peripheral mechanism of action. Moreover, the ipl injection of linoleic acid to rats 24 hr after CFA evoked spontaneous nocifensive behaviors that were significantly reduced by capsazepine, by knockout of the TRPV1 gene, or by pretreatment with either anti-OLAM antibodies or ketoconazole.. Taken together, our data suggests that OLAMs contribute to inflammatory nociception in the periphery and that cytochrome P450 enzymes play a crucial role in mediating OLAM contributions to inflammatory heat hyperalgesia.

Topics: Animals; Antibodies; Behavior, Animal; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Ketoconazole; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Mice; Mice, Inbred C57BL; Nociception; Oxidation-Reduction; Pain; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.

Topics: Animals; Fatty Acids, Unsaturated; Hot Temperature; Ligands; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Models, Biological; Oxygen; Pain; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

Bradykinin is the most potent endogenous inducer of acute pain. However, the way in which it excites nociceptive sensory nerve endings is still unclear. In an article recently published in the JCI, Liu et al. suggest a new mechanism via which bradykinin induces acute spontaneous pain. The authors report that the stimulation of B2 bradykinin receptors by bradykinin triggers the release of intracellular calcium ions from nociceptive sensory neurons of rat dorsal root ganglia. This depolarizes the sensory nerve endings by simultaneously closing M-type potassium channels and opening TMEM16A chloride channels, resulting in the production of nociceptive signals. Here, we discuss the relationship between this effect and a previously described mechanism for pain sensitization and evaluate its potential significance for therapeutic pain control. A separate study by Patwardhan et al. in this issue of the JCI identifies oxidized linoleic acid metabolites as novel mediators of thermally induced pain.

Topics: Animals; Bradykinin; Calcium; Ganglia, Spinal; Humans; Hydrolysis; Ions; Kinetics; Linoleic Acid; Models, Biological; Nociceptors; Pain; Pain Management; Potassium Channels; Rats; Receptor, Bradykinin B2

Omega-3 (n-3) fatty acids are essential for proper neuronal function, and they possess prominent analgesic properties, yet their underlying signalling mechanisms are unclear. Here we show that n-3 fatty acids interact directly with TRPV1, an ion channel expressed in nociceptive neurones and brain. These fatty acids activate TRPV1 in a phosphorylation-dependent manner, enhance responses to extracellular protons, and displace binding of the ultrapotent TRPV1 ligand [3H]resiniferatoxin. In contrast to their agonistic properties, n-3 fatty acids competitively inhibit the responses of vanilloid agonists. These actions occur in mammalian cells in the physiological concentration range of 1-10 mum. Significantly, docosahexaenoic acid exhibits the greatest efficacy as an agonist, whereas eicosapentaenoic acid and linolenic acid are markedly more effective inhibitors. Similarly, eicosapentaenoic acid but not docosahexaenoic acid profoundly reduces capsaicin-evoked pain-related behaviour in mice. These effects are independent of alterations in membrane elasticity because the micelle-forming detergent Triton X-100 only minimally affects TRPV1 properties. Thus, n-3 fatty acids differentially regulate TRPV1 and this form of signalling may contribute to their biological effects. Further, these results suggest that dietary supplementation with selective n-3 fatty acids would be most beneficial for the treatment of pain.

Topics: Animals; Binding, Competitive; Calcium; Capsaicin; Cell Line; Cell Membrane; Diterpenes; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Hydrogen-Ion Concentration; Linoleic Acid; Male; Membrane Fluidity; Membrane Potentials; Mice; Mice, Inbred C57BL; Oocytes; Pain; Rats; RNA, Complementary; TRPV Cation Channels; Xenopus laevis

Lythrum salicaria (purple loosestrife) known as "Tibbi hevhulma" in Turkish is used for its several beneficial health effects against as diarrhea, chronic intestinal catarrh, hemorrhoid and eczema in the form of a decoction or a fluid extract and to treat varicose veins, bleeding of the gums, hemorrhoid and eczema, externally. Dried herbal parts of Lythrum salicaria L. (Lythraceae) were sequentially extracted with different solvents such as petroleum ether, ethyl acetate, methanol and 50% aqueous methanol. Water extract of Lythrum salicaria was also prepared under reflux. Antioxidant, anti-inflammatory and anti-nociceptive activities of all the extracts were investigated using in vitro and in vivo methods, respectively. Free radical scavenging activity (1,1-diphenyl-2-picrylhydrazyl, DPPH* assay), iron(III) reductive activity, capacity of the inhibition of linoleic acid peroxidation and MDA formation, anti-nociceptive activity (p-benzoquinone-induced abdominal constriction test) and anti-inflammatory activity (carrageenan-induced hind paw edema model) were used for all the extracts. In addition, the content of total phenolics, flavonoids and flavonols in all the extracts were determined with spectrophotometric methods. Results were compared with reference antioxidants via ascorbic acid, butylated hydroxytoluene, and gallic acid. Qualitative and quantitative compositions of all the extracts were analysed using a HPLC-PDA system. Polar fractions were found to be rich in flavonoids such as isovitexin and isoorientin.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Edema; Flavonoids; Free Radical Scavengers; Iron; Linoleic Acid; Lipid Peroxidation; Lythrum; Male; Malondialdehyde; Medicine, Traditional; Mice; Pain; Pain Measurement; Phenols; Phytotherapy; Plant Extracts; Turkey

Peripheral nerve involvement is a frequent complication of type 1 and type 2 diabetes, and can induce major disability. Almost all types of clinical or electrophysiological disturbances may be present: mononeuropathy involving cranial nerves or a limb; multiple mononeuropathy; proximal acute radiculopathy; distal, symmetric, sensory polyneuropathy; autonomic neuropathy. Physiopathology intricates probably several mechanisms but metabolic dysregulation and ischemia are mainly involved. Despite numerous controlled clinical trials no treatment has demonstrated efficacy for peripheral neuropathy, excepting the optimization of diabetes equilibrium. However, symptomatic treatments are available, particularly for the management of neuropathic pain.

Topics: Acetates; Amines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbamazepine; Controlled Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Electrophysiology; Gabapentin; gamma-Aminobutyric Acid; Humans; Hyperglycemia; Immunoglobulins, Intravenous; Linoleic Acid; Pain; Prognosis

Ingested polyunsaturated fatty acids are postulated to lead to changes in central nervous system activity, presumably by altering the lipid composition of neuronal membranes. In support of this hypothesis, we and other investigators have previously demonstrated cognitive effects in rats fed oils that contain both alpha-linolenic acid (18:3 omega 3) and linoleic acid (18:2 omega 6), with the relative content of alpha-linolenic acid being seen as the critical variable. The present study in rats examined the effects of preparations containing different ratios of highly purified free alpha-linolenic acid to linoleic acid (about 25 mg/kg of body weight daily) on learning performance (Morris water tank), pain thresholds (heated plate), and thermoregulatory control of d-amphetamine-induced hypothermia during 4 weeks of treatment. Preparations with omega 3-to-omega 6 ratios ranging from 1:3.5 to 1:5 (specifically a ratio of 1:4) produced significant favorable effects on all of these variables. Although the specific mode of action remains to be elucidated, these results suggest that such preparations of free fatty acids should be evaluated in the treatment of memory disorders and pain conditions.

Topics: alpha-Linolenic Acid; Animals; Body Temperature Regulation; Body Weight; Dietary Fats; Energy Intake; Feeding Behavior; Learning; Linoleic Acid; Linoleic Acids; Male; Motor Activity; Pain; Rats; Sensory Thresholds

Topics: alpha-Linolenic Acid; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Dietary Fats; Female; Food, Formulated; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Pain; Potassium; Prostaglandins; Sodium; Wounds and Injuries

Hyperalgesic actions in rats of intracerebroventricularly (i.c.v.) administered arachidonic acid, prostaglandin (PG) E2 and PG F2 alpha were studied. For the analgesic assay, vocalization induced by repetitive electrical stimulation was employed. Administered i.c.v., arachidonic acid (0.1-30 micrograms/rat), PG E2 (0.001-0.3 micrograms/rat) and PG F2 alpha (0.01-3 micrograms/rat) potentiated the vocalization, in a dose-dependent manner. The maximal potentiating doses of arachidonic acid, PG E2 and PG F2 alpha were 10 micrograms/rat, 0.1 microgram/rat and 1 microgram/rat, respectively. Indomethacin and diclofenac produced much more potent analgesic effects in arachidonic acid-induced hyperalgesic rats than in normal rats and in PG E2- and PG F2 alpha-induced hyperalgesic rats, but aminopyrine, acetaminophen and morphine produced the same analgesic effect in both hyperalgesic and normal rats. Linoleic acid, linolenic acid and gamma-linolenic acid also induced a weak hyperalgesia, whereas indomethacin (4 mg/kg) failed to attenuate the vocalization in these unsaturated fatty acids-induced hyperalgesic rats. These findings indicate that the hyperalgesic actions of arachidonic acid and its metabolites are related to mediation or modulation of the central pain pathways, and the pain-relieving properties of acidic nonsteroidal antiinflammatory drugs (NSAIDs) may be, at least in part, involved in central site.

Topics: alpha-Linolenic Acid; Analgesics; Animals; Arachidonic Acid; Arachidonic Acids; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; gamma-Linolenic Acid; Injections, Intraventricular; Linoleic Acid; Linoleic Acids; Linolenic Acids; Male; Pain; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Time Factors