Arachidonic Acid Pathways in Nociception
Howard S. Smith, MD, FACP


nflammation may release or generate a diverse population of proinflammatory and/or pronociceptive mediators, including bradykinins, serotonin, histamine, nitric oxide, prostaglandins, and cytokines. These and other substances contribute to the classic clinical picture of redness, heat, swelling, soreness, and diminished function associated with inflammation and may produce pain, hyperalgesia, or allodynia. Among the major substances that play a pivotal role in both inflammation and pain are the metabolites of arachidonic acid. These metabolites include both enzymatically generated products (thromboxanes, prostaglandins, leukotrienes, lipoxins, and epoxyeicosatrienoic acids [EETs]) and non-enzymatically produced substances (isoprostanes and cyclopentenone prostaglandins).1,2

Abstract The metabolism of arachidonic acid may follow multiple, interrelated pathways, leading to the generation or release of a wide variety of biologically active substances (including bradykinins, serotonin, histamine, prostaglandins, and cytokines) that produce pain and/or inflammation. Therapeutic agents that directly affect one particular pathway, such as cyclooxygenase inhibitors (typically, nonsteroidal anti-inflammatory agents), may indirectly affect one or more other pathways, as well as the resolution of inflammation. Rather than taking the traditional approach to treating multiple types of pain by inhibiting a single pathway, future treatments of pain and inflammation may target specific pathways and pain mechanisms and/or address two or more pathways simultaneously. A thorough understanding and appreciation of the mechanisms contributing to various pain and inflammatory states, the metabolic fates of arachidonic acid, the functions of its many metabolites, and the interrelatedness of the various metabolic pathways involved in nociception may lead to more rational and optimal approaches to addressing patient suffering.

Arachidonic Acid Metabolism
As shown in Figure 1, arachidonic acid metabolism generally occurs via one of four major avenues3: • the cyclooxygenase (COX) pathway, which produces prostanoids; • the lipoxygenase pathway, which produces leukotrienes and lipoxins; • non-enzymatic lipid peroxidation, which produces isoprostanes; and • the cytochrome P450 monooxygenase pathway, which produces EETs and other substances. Oxidation reactions include epoxidation, allylic oxidation, and omega hydroxylation. In addition, arachidonic acid can undergo autooxidation to hydroperoxy acids. Inflammation leads to the rapid biosynthesis
Manuscript submitted March 29, 2005; accepted November 30, 2005. Correspondence to: Howard S. Smith, MD, FACP Albany , Medical Center, 43 New Scotland Avenue, Albany, NY 12208; telephone: (518) 262-4461; e-mail: smith@mail.amc.edu
J Support Oncol 2006;4:277–287 © 2006 Elsevier Inc. All rights reserved.

of lipid mediators generated de novo from arachidonic acid in response to multiple stimuli, such as mechanical trauma, cytokines, and growth factors. In most cells, arachidonic acid may be released at the endoplasmic reticulum and nuclear membrane, predominantly via the translocation of type IV cytosolic phospholipase A2 (PLA2). Arachidonic acid is subsequently metabolized to prostaglandin H2, or PGH2 (an intermediate arachidonic acid metabolite), by the action of prostaglandin H synthase (PGHS; also referred to as COX). Two distinct active catalytic sites exist on COX: the cyclooxygenase active site (CAS), which converts arachidonic acid to prostaglandin G2 (PGG2), and the peroxidase active site (PAS), which transforms PGG2 to PGH2. PGH2 may then be acted upon by various enzymes to yield multiple prostanoids. The prostanoid that has received the most attention—since it is thought to play the most important role in nociceptive processes—is prostaglandin E2 (PGE2). PGH2 is acted upon by PGE synthase (PGES) to yield PGE2. A sequence of three enzymatic reactions (PLA2 → COX → PGES) leads to generation of PGE2 from the cell membrane.

Dr. Smith is the Academic Director of Pain Management, Department of Anesthesiology, Albany Medical College, Albany, New York.


JUNE 2006



HPETE = hydroxyperoxyeicosatetraenoic acid. and calcium-independent PLA2 (iPLA2). LT = leukotriene. 9−11. concentrating these enzymes into particular membrane compartments. cPLA2 functions intracellularly. PGF2α. membrane remodeling. leukotriene C4 (LTC4). where they lead to the release of arachidonic acid adjacent to perinuclear arachidonic acid–metabolizing enzymes. cytosolic PLA2 (cPLA2). and shows little fatty acid specificity. 12-KETE = 12-ketoeicosatetraenoic acid.4 The three main classes of PLA2 are secretory PLA2 (sPLA2).6 Glypican is a glycosylphosphatidylinositolanchored HSPG that facilitates the “sorting. cPLA2α appears to play a key role in the evolution of various lipid mediators in certain immune cells. Each major class contains multiple family members. leukotriene B4 (LTB4). 15 EETs PGH2 Cyclooxygenase PGE2. has a high molecular weight (40–110 kDa). LOX = lipoxygenase. which carry out similar reactions but are regulated by different mechanisms.net THE JOURNAL OF SUPPORTIVE ONCOLOGY . requires millimolar concentrations of calcium for catalytic activity. macrophages obtained from cPLA2α knockout mice do not give rise to significant levels of PGE2. and cPLA2γ.Arachidonic Acid Pathways in Nociception Isoprostanes Nonenzymatic lipid peroxidation 5. producing various pathways for phospholipid degradation. cPLA2α. cPLA2β.5 cPLA2 appears to be especially important in regulating the release of arachidonic acid in human immune cells. requires micromolar levels of calcium for membrane translocation. and eicosanoid biosynthesis. exhibits a definite preference for the sn-2 arachidonic acid position. FLAP = 5-lipoxygenase-activating protein. 20HETEs 20-COOH-AA Lipoxygenase 5-LOX FLAP 5-HPETE LTA4 LTB4 LTC4 LTD4 LTE4 12-LOX 15-LOX 12-HPETE 12-HETE 12-KETE 15-HPETE 15-HETE Lipoxins Hepoxilins Figure 1 Four Major Pathways of Arachidonic Acid Metabolism Abbreviations: EETs = epoxyeicosatrienoic acids. PGD2 TXA2 PGI2 Diols Arachidonic acid Cytochrome P450 monooxygenase 19-. Compared with wild-type macrophage cells.5 In the heparin sulfate proteoglycan (HSPG)–shuttling pathway. sPLA2 is generally released extracellularly. Different PLA2 enzymes may act on different substrates. of sPLA2s into caveolae/raft-dependent vesicular routes.SupportiveOncology. or platelet-activating 278 www. TXA2 = thromboxane A2 PHOSPHOLIPASE A 2 (PLA) There are three main classes of PLA2. has a low molecular weight (14–18 kDa). and is phosphorylated by mitogen-activated protein kinases (MAPKs).6 Cytosolic PLA2.5 Secretory PLA2. group II subfamily sPLA2s may bind to glypican in activated cells. PG = prostaglandin.” or trafficking. HETEs = hydroxyeicosatetraenoic acids. 12−14. such as COX-2 and 5-lipoxygenase. 6−8.5 The cPLA2 family consists of three isoenzymes.

NUMBER 6 ■ JUNE 2006 www. exhibits enhanced activity with ATP and seems to have a role in regulating intracellular . peripheral COX-2 is expressed to any physiologically significant degree only after tissue injury is induced secondary to inflammation. calcium.13 However. to facilitating the release of nociceptive neuropeptides. COX-2 is known to be upregulated during inflammation. the expression of which is upregulated by various neurotransmitters. myocardial ischemia. where it is activated/stabilized by phosphorylation of serine residues and/or binding to anionic phospholipids with subsequent “lid” removal. Its physiologic role remains uncertain. in a time.13 The clinical significance of the various isoforms remains incompletely appreciated.and laminar-dependent manner. suggested that both COX-1 and COX-2 are important in the neuropathic pain that may emerge after neural insult. iPLA2 may play a key role in pain states associated with high oxidative stress. for example.18. it appears that COX-1 and COX-2 are two distinct prostanoid biosynthetic systems with separate biological functions for their products. growth factors.5 It is conceivable that an ionic intracellular trigger to activation of iPLA2 may be a drop in the intracellular concentration of potassium. not gray-matter glia. the majority of neurons and radial glia in the spinal cord (ie. calcium homeostasis. COX-2 is twice as abundant at the nuclear envelope than within the endoplasmic reticulum. Calcium-independent PLA2.20 The development of allodynia associated with neural insult may be partly due to spinal prostaglandins synthesized by COX-1 as well as COX-2.SupportiveOncology. denoted COX-3 (a variant of COX-1). the clinical significance of the COX-3 isoform in humans is unclear.net 279 . suggested that COX-1 expression in the spinal cord is not static and changes. lipopolysaccharides.11 Therefore. in part. after nerve injury.21–25 This finding is in contrast to the predominant role of COX-2 in inflammatory pain. At 2 and 4 weeks following partial sciatic nerve ligation (PSNL). leading to hyperalgesia.26 The constitutive COX-2 in the spinal cord is important in generating PGE2. COX-1 produces prostaglandins constitutively for secretion as extracellular mediators. thereby exposing the active catalytic site resulting in the generation of arachidonic acid. however. has been identified in brain tissue. iPLA2 occurs intracellularly.8 Therefore. such as neural insult. studies reveal that mice deficient in COX-2 yield normal inflammatory responses with exogenous arachidonic acid but exhibit an increased incidence of suppurative peritonitis. such as microglia astrocytes and oligodendrocytes) express significant. whereas the concentration of COX-1 is equal at both locations. proinflammatory cytokines. Ma and Eisenach24 provided morphological and pharmacological evidence of the role of peripheral prostaglandins in the pathogenesis of neuropathic pain.12. such as kidney and nerve tissue. During conditions when expression of cPLA2 and sPLA2 is suppressed. however. Zhu and Eisenach. detectable levels of constitutive COX-2.10. COX-1 functions predominantly in the endoplasmic reticulum and COX-2 mostly in the nucleus.6 Differences in COX isoforms. iPLA2 generally has little acyl specificity. exists in multiple isoforms. however.6 Calcium binding to the C2 domain of cPLA2α promotes its translocation to the phosphatidylcholine-rich perinuclear region. since ibuprofen was better at reversing allodynia than SC-560.17 A third isoform. It has been purported to represent the long sought-after acetaminophen-sensitive COX activity that may play a key role in fever regulation9.12. COX-1 is expressed constitutively. COX-1 expression can be induced under certain conditions.9 COX-1 and COX-2 share 60% amino acid sequence homology. and COX-2 produces prostaglandins predominantly within the nuclear fat. from primary afferent fibers with increased spinal dynorphin. arachidonic acid levels in myocardium (iPLA2[myocardium]) and macrophages (iPLA2[macrophages]). iPLA2 appears to have unique functional roles in apoptosis. these authors suggested that spinally administered specific COX-1 inhibitors may be useful in preventing and treating neuropathic pain. such as substance P and calcitonin gene-related peptide (CGRP).Smith factor (PAF) in the A23187-induced immediate arachidonic acid response. due. whereas an increase in intracellular calcium may trigger activation of cPLA2. Hefferan and colleagues 21 found that spinal prostaglandins synthesized by COX-1 in the early period (4–8 hours) after neural insult appear to be important in the development of allodynia in rats.23 working with partial sciatic nerve transsection and L5-L6 spinal-nerve ligation models in male rats.7 as well as in the induction of arachidonic acid release by reactive oxygen species. Convenient simplifications depict COX-1 as a homeostatic continuous regulator that is expressed constitutively and COX-2 as being an inducible enzyme.6 and postsynaptic modulation of neurotransmission. has a high molecular weight (45–80 kDa). and small peptide hormones. iPLA2 may function as the primary arachidonic acid hydrolyzing phospholipase. Lashbrook et al28 suggested that spinal prostanoids generated via both the COX-1 and COX-2 pathways may play a role in the hyperalgesia/allodynia seen in nerve-injured rats. The resulting overproduction of prostaglandins appears to contribute to the central plasticity and maintenance of neuropathic pain after nerve insult. In much of the peripheral nervous system. express COX-2 constitutively. which converts arachidonic acid to endoperoxidecontaining intermediates to produce prostaglandins and thromboxanes. Both enzymes are membrane bound.26 Ghilardi et al27 suggested that blocking constitutive spinal COX-2 before tissue injury may diminish sensitization (both peripheral and central) following tissue injury. dramatic increases in COX-2 immunoreactive cell profiles were observed VOLUME 4. These researchers compared the effects of intrathecal administration of SC-560 (a selective COX-1 inhibitor) with that of S(+)-ibuprofen (which inhibits both COX-1 and COX221) and. CYCLOOXYGENASE (COX) PATHWAY COX. and exhibits activity that appears to be independent of calcium concentration. Further. Ma and Eisenach19 have demonstrated (primarily in infiltrating macrophages) that COX2 is universally upregulated following various types of peripheral nerve injury.13–16 and various tissues. Relation to neuropathic pain.13 However. the glia in the white matter.

Local injection of ketorolac. whereas COX-2 is located predominantly in the perinuclear envelope.42 These changes in ion influx result in decreased firing thresholds. If this work is validated in human studies. which leads to enhanced.26 Microsomal (mPGES) is a membrane-associated enzyme that exists in two isoforms.32 Hematopoietic PGD synthase (a cytosolic terminal enzyme) translocates to the endoplasmic reticulum as the immediate response to stimulation with A23187 (where it is preferentially coupled with COX-1) and translocates to the perinuclear envelope as the delayed response to cytokine stimulation (where it is preferentially coupled with COX-2).32 whereas PGES (complexed with cytosolic proteins [Hsp90 and casein kinase 2]) is coupled with COX-1. intradermal PGE2 is largely responsible for hyperalgesia in the peripheral nervous system) but also appears to be involved in a wide variety of other functions.24 In addition. which have restricted patterns of expression and receptor-specific actions.33 Trebino and coworkers.37 PGE2 is not only thought to play a key role in nociception (eg. PROSTAGLANDIN E SYNTHASE (PGES) perinuclear membrane. Although the mice retained normal nociceptive responses. Cytosolic PGES (cPGES) is constitutively expressed in many tissues and is functionally coupled to COX-1.SupportiveOncology.32 “Traditional” nonselective COX inhibitors and COX-2– specific inhibitors not only block the formation of individual prostaglandins but also may knock out other “bystander” eicosanoids that may be needed to maintain homeostasis or may have the effect of “shunting” arachidonic acid metabolism toward other metabolic pathways. locations.41 Mode of action.net THE JOURNAL OF SUPPORTIVE ONCOLOGY . a nonselective COX inhibitor.” has received the most attention among prostaglandins because of its contribution to nociception and inflammation. Activation of MAPK induces increased expression of the transcription factor Egr-1 and subsequently activates Egr-1 (via phosphorylation). Additionally. such as prostacyclin (PGI2) synthase and mPGES-1. known as EP1 to EP4. including vasodilation. the pain hypersensitivity produced by this model is not significantly COX-2 dependent. in the setting of neural insult. clinical correlates may translate into the preferred use in certain subpopulations of traditional nonsteroidal anti-inflammatory agents that inhibit both COX-1 and COX-2 (perhaps with partial COX-1 selectiveness over COX-2) in situations where the potential for the development of neuropathic pain exists (eg. inhibition of voltage-dependent potassium currents. which promotes transcriptional activation of the mPGES-1 gene. The most widely accepted explanation for the effects of prostaglandins on nociception relates to the activation of the adenyl cyclase/cAMP/protein kinase A (PKA) pathway sparked by the binding of PGE2 to the EP2 receptor. tend to be selectively coupled with COX-2.36 Activated Egr-1 binds to the proximal GC box in the mPGES-1 promoter. . without knocking out bystanders). PKA activated via PGE2/EP2 binding may selectively block in- 280 www. substance P CGRP and nitric oxide. an increased number of COX-1 immunoreactive cell profiles were observed in the epidermis of the ipsilateral foot pad of PSNL rats.31 Coexpression studies utilizing both COX enzymes with certain terminal prostaglandin synthases have shown that synthases near the PGE2. As with PLA2 and COX. and functions. the “original prostaglandin.38–40 PGE2 induces different cellular responses via interaction with specific receptors. and increased voltage-dependent calcium influx in nociceptive afferent fibers. within the nanomolar to micromolar range) tissueand cell type–selective actions. PGE2 stereospecifically exerts potent (ie.24 Broom et al25 reported similar results using the rat spared nerve injury model of neuropathic pain. suggesting that PGE2 produced by mPGES-1 is involved in neuropathic pain. altered microvascular permeability. Distinct subcellular localization with colocalization of terminal prostaglandin synthases affects enzyme functions and coupling. it would appear reasonable to utilize agents that inhibit both COX-1 and COX-2 in order to diminish and/or prevent neuropathic pain. have defined the contributions of mPGES-1 and PGE2 in chronic inflammation and pain. PGES facilitates the conversion of PGH2 to PGE2. Mabuchi et al29 studied a neuropathic pain model created by L5 spinal nerve transection in mPGES-1 knockout (mPGES-1) mice. and febrile responses. and the release of excitatory amino acids. multiple forms of PGES exist with different enzymatic qualities.29 Kamei et al. they did not exhibit mechanical allodynia or thermal hyperalgesia for over a week following transection.35 PROSTAGLANDINS As mentioned earlier. They concluded that although COX-2 plays a key role in the development of inflammatory hypersensitivity induced by injection of complete Freund adjuvant into the rat hind paw. provided evidence that mPGES-1 plays a pivotal role in the production of PGE2 involved in pain hypersensitivity and inflammation.34 studying the pathogenesis of collagen-induced arthritis in mPGES-1–deficient mice. The clinical implications of these findings translate into the appropriate selection of selective COX-2 inhibitors for inflammatory pain—preferably one that crosses the blood-brain barrier reasonably well. before treatment with vincristine).8). the . suggesting that agents that block mPGES-1 may be comparable in efficacy to COX-2 inhibitors against pain and inflammation but may be better tolerated and have fewer unfavorable side effects (eg.35.Arachidonic Acid Pathways in Nociception at the injured site and in the adjacent region. tetrodotoxin-resistant sodium currents (probably via phosphorylation of NaV 1. COX-1 is more enriched in the endoplasmic reticulum than in the perinuclear envelopes. mPGES-1 and mPGES-2. into the ipsilateral plantar side or into the injured region of the sciatic nerve reversed the mechanical allodynia induced by PSNL for more than 5 days and suppressed the PSNL-induced increase in the phosphorylation of a transcription factor cAMP (cyclic adenosine monophosphate) response element-binding protein in the ipsilateral spinal cord dorsal horn of L4 and L5.30 also using mPGES-1 knockout mice. However. increased firing rates.

These receptors signal via Gs-mediated increases in intracellular cAMP via adenylate cyclase.43 This PGE2-induced “disinhibition” may facilitate transmission of nociceptive input to higher areas of the central nervous system. • A 39-year-old woman with pancreatic cancer and a chronic inflammatory lower extremity lesion. PGI2 may contribute to hyperalgesia under certain circumstances. a selective COX-1 inhibitor. Utilizing EP1 and EP3 receptor knockout mice. NUMBER 6 ■ JUNE 2006 www. which leads to facilitation (ie. and PGI2 is thought to contribute to pain and inflammation because IP knockout mice show a reduction in pain and edema. EP1. EP2. with resultant activation of PKA and phosphorylation of sodium channels. • A 73-year-old man returns to his oncologist with lung cancer and metastatic invasion into the right brachial plexus. Epoprostenol therapy. Case Examples The following are some hypothetical clinical vignettes that illustrate the potential utility of the preceding discussion in medical decision-making regarding targeted treatments for analgesia. and a combined-adenosine receptor antagonist/p38 MAPK/PDE4 inhibitor. . and capsaicin.42 The primary mode of prostaglandin action is through specific G-protein–coupled receptor superfamilies of seven transmembrane-spanning proteins. Her physician feels that she may have disturbances in the processes involved with the resolution of inflammation and prescribes lipoxin A4. At low doses of PGE2.44 Differences in prostaglandin receptors. known as . His physician suggested potent opioids.Smith hibitory (strychnine-sensitive) glycinergic neurotransmission onto superficial dorsal horn neurons.44 The EP3 receptor is considered an inhibitory receptor that signals through Gi-mediated decreases in cAMP formation. a lipoxygenase inhibitor. it appears that spinal EP3 receptors may play a key role in PGE2-induced hyperalgesia.44 Although the mechanisms by which eicosanoids contribute to or facilitate nociception remain uncertain. such as glycine. Glycine-mediated inhibition of the actions of neurons normally occurs when an agonist. and an LTB4 receptor antagonist. which waxes and wanes in its severity. PGE2 disinhibits the spinal transmission of nociceptive input from the spinal cord to higher brain areas via PKA-dependent phosphorylation and inhibition of GlyR α3.46 Nanomolar concentrations of PGE2 reduce the responsiveness of postsynaptic inhibitory glycine receptors in the superficial layers of the spinal cord dorsal horn43 and may also directly depolarize deep dorsal horn neurons. Harvey and coworkers50 demonstrated that mice deficient in GlyR α3 lack the normally seen inhibition of glycinergic neurotransmission caused by spinal injection of PGE2 or peripheral inflammation. antioxidants. and different subtypes could be activated depending upon the amount of agonist present.42 GLYCINE RECEPTORS An international team50 has discovered that the glycine receptor subtype α3 (GlyR α3) may be the receptor that spinal prostaglandins utilize to produce central inflammatory pain sensitization. referred to as “relaxant” receptors. or domains. and EP4 are considered one group. that signal through Gq-mediated increases in intracellular calcium. PGF2α has been shown to lead to allodynia via its effects on large-diameter (myelinated) fibers. with resultant right brachial plexopathy and severe right upper extremity pain.42 Further. FP and TP are considered a second group. with subsequent binding to neurokinin-1 receptors on smalldiameter primary afferent fibers. PGI2 and other prostaglandins.47 Ueno et al48 implicated IP and EP3 receptors in mediating the enhanced acetic acid–induced writhing response in mice previously exposed to lipopolysaccharide. is on high-dose opioid therapy and complaining of abdominal and leg pain. “contractile” receptors. VOLUME 4. Minami et al46 demonstrated that spinal EP1 receptors contribute to PGE2-induced allodynia (apparently upstream from N-methyl. PGI2 levels are elevated in the central nervous system during the early phase of carrageenan-induced paw edema. being a member of the chemoattractant receptor subgroup. bradykinin. Although PGE2 appears to be the key prostaglandin involved in nociceptive processes. Prostaglandins also facilitate membrane currents and the release of substance P and CGRP induced by protons. This receptor may therefore represent an important potential therapeutic target in attempts to provide analgesia. • An 83-year-old woman with breast cancer and an ischemic left lower extremity is complaining of severe pain in the extremity despite taking high doses of potent opioids.net 281 .D-aspartate receptor activation and resultant nitric oxide generation). however.51 The addition of phosphate to GlyR α3 impedes or blocks chloride ion influx. it is apparent that both peripheral and central nervous system processes seem to be involved. Bradykinin-evoked increases in excitability in isolated nodose neurons demonstrated the dependence on PGI2 in the neuronal membrane. a 5-LOX inhibitor.42 DP effects have also been implicated in antagonizing PGE2-induced allodynia. binds to the GlyR α3 receptor and triggers the movement of chloride ions into the neuron. greater sensitivity may be mediated by increased numbers of EP receptors. They concluded that during inflammatory pain states. The DP2 receptor is an exception. and isoprostane antagonists are added to her pharmacotherapy.49 PGD2 may lead to hyperalgia via DP effects on substance P release. A complex interplay of receptor subtypes may be involved in various hypersensitivity states. disinhibition) of neuronal activity and nociceptive input. It appears that in certain situations.SupportiveOncology. The receptors IP DP1. thereby facilitating the development of central thermal and mechanical hypersensitivity.45 Ma and Eisenach24 found a dramatic increase in immunoreactivity for EP1–EP4 in injured nerve of PSNL rats and suggested that PGE2 may be overproduced in injured nerve and facilitate upregulation of EP receptors. since inhibi- tors of PGI2 synthesis negated the effect of bradykinin.

demonstrated that 8-isoprostaglandin E2 (8-iso PGE2) lowers nociceptive thresholds to mechanical and thermal stimuli. and 5.3-bis-methoxyphenyl]-thiophen-5-yl) butanamide. showing that 10 µM 8-iso PGE2 stimulates peptide release directly from sensory neurons. in part via downregulation of PGE2 and LTB4. interleukin 1β. it may exert potent antiplatelet effects due to inhibition of COX-1 activity.2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2. epinephrine and PGE2) at or downstream of PKA and PKCε.58 LTB4 is a rapidly synthesized neutrophil chemoattractant and activator of inflammatory cells (which also appears to mediate T-cell recruitment59.and 15(S)hydroperoxyeicosatetraenoic acids.72 using isolated rat sensory neurons. whereas treatment with 1 µM 8-iso PGE2 augments the release of transmitters 282 www.70. tumor necrosis factor. She states that she has essentially no money or medical coverage to obtain medications and wonders if there are any other options. a 5-LOX inhibitor.55 Aley and Levine56 demonstrated in animal models that nordihydroguaiaretic acid (NDGA. Two isoforms of 15-LOX exist: 15-LOX type 1 and 15-LOX type 2.and 15(S)-hydroxyeicosatetraenoic acids directly activate TRV1 in isolated membrane patches of sensory neurons. a 12-lipoxygenase inhibitor).71 Evans et al. BLT-1 receptor activation may result in IP3-mediated calcium release initially from intracellular stores and later via influx through cell-membrane channels with subsequent activation of PKA pathways and/or protein tyrosine kinase pathways. since it functions as a selective COX-1 inhibitor and may ameliorate any potential exacerbation of neuropathic pain. with type 1 providing anti-inflammatory effects.66 including S 19812 (Nhydroxy-N-methyl 4-[2.64 These results have excited investigators in the pain arena as well as in oncology. 12-hydroperoxyeicosatetraenoic acid. 12(S).56 They suggested that products of the 5-LOX and 12-LOX pathways contribute to peripheral hyperalgesia induced by agents that act directly on primary afferent nociceptors (eg. 12-lipoxygenase (12-LOX). Singh and colleagues64 induced mechanical and thermal hyperalgesia by autologous nucleus pulposus in rat sciatic nerves. and perhaps analgesic effects via reduced expression of various cytokines (eg. The LOX products LTB4.SupportiveOncology.61 LTB4 may play a role as a nociceptive mediator under certain circumstances.63 Dual 5-LOX/COX-2 inhibition.3-dihydro-1H-pyrrolizine-5-yl]-acetic acid). Her physician tells here to take a baby aspirin daily. and growth factors)53.65 Such dual inhibitors would be especially useful in situations with leukotriene-mediated nociception. Licofelone is a competitive inhibitor of 5-LOX. aggravating bone loss).64 Coadministration of zileuton and indomethacin enhanced the antihyperalgesic effects of zileuton. arachidonic acid can be metabolized via three major lipoxygenases: 5-lipoxygenase (5-LOX). COX-1. suggesting that leukotrienes and prostaglandins may both play a significant role in hyperalgesia induced by autologous nucleus pulposus in rats—and that dual inhibition of the LOX and COX pathways may provide a useful treatment approach under certain conditions. and COX-2. LIPOXYGENASE PATHWAY In human tissues. a nonselective lipoxygenase inhibitor). and 5(S). baicalein (BAIC. Zileuton (Zyflo). Dual inhibition of 5-LOX and COX-2 (which may produce an efficacy similar to that of glucocorticoids but without their adverse effects) may yield synergistic effects. cell-surface G protein-coupled receptor BLT-1. decreasing both leukotriene and prostaglandin expression with presumed low gastrotoxicity. LTB4 does not induce pain itself but lowers the pain threshold for other stimuli. NDGA and 5. multiple dual 5-LOX/COX-2 inhibitors are under development. CAS 181308-68-9)67 and licofelone ([2.54 and type 2 yielding opposing effects (eg. significantly decreased mechanical as well as thermal hyperalgesia in a dose-dependent (25–100 mg/kg) manner when compared with the nucleus pulposus group.62. however. vincristine.52 The two isoforms may have antagonistic effects.68 NONENZYMATIC LIPID PEROXIDATION PATHWAY Isoprostanes (stereoisomers of prostaglandins) are formed in vivo primarily via nonenzymatic in situ peroxidation of arachidonic acid by reactive oxygen species. and prednisone) regimen. and 15-lipoxygenase (15-LOX).56 Leukotriene B4.53 Bradykinin (acting at B2 bradykinin receptors) activates transient receptor potential vanilloid receptor-1 (TRV1) via an intracellular second messenger pathway involving mobilization of arachidonic acid by PLA2 and generation of a lipoxygenase product. As a result of this interest. LTB4 and PGE2 may act synergistically to promote inflammation57 and possibly nociception as well.60) that signals primarily its high-affinity. where inhibition of COX2 may lead to shunting of arachidonic acid metabolism toward the leukotriene pathway. LTB4 can act on neutrophils through the LBT1 receptor to elicit chemotaxis.net THE JOURNAL OF SUPPORTIVE ONCOLOGY .Arachidonic Acid Pathways in Nociception Case Examples (continued) • A 79-year-old woman with breast cancer and a preexisting peripheral neuropathy is about to undergo chemotherapy with vincristine as part of the CHOP (cyclophosphamide.69 Studies in animal models suggest that licofelone may impede the progression of osteoarthritis without increasing the frequency or severity of gastrointestinal side effects when co-administered with lowdose aspirin69.68 in an effort to provide novel therapeutic agents for the treatment of pain and inflammation. The most widely appreciated leukotriene involved in nociceptive processes may be the 5-LOX product LTB4.6-dehydroarachidonic acid inhibited PGE2-induced hyperalgesia mediated via PKA. protection against bone loss. She is concerned about an exacerbation of neuropathic pain and asks her physician if there is any medication she could take prior to and throughout her chemotherapy to abort or lessen any potential exacerbation of her symptomatic peripheral neuropathy. doxorubicin.6-dehydroarachidonic acid (a 5-lipoxygenase inhibitor) inhibited epinephrine-induced hyperalgesia and ψεRACK (a selective activator of protein kinase Cε [PKCε])-induced hyperalgesia.

net 283 . His physician suggested a dual 5-LOX/COX-2 inhibitor. suggesting that the actions of 8-iso PGE2 were not mediated by the production of prostaglandins via the COX pathway and that isoprostanes may be important mediators for producing or facilitating nociception in situations where oxidative stress modulates neural functions.81 The exogenous addition of 11. midchain conjugated dienols formed by LOX-like bisallylic oxidation of arachidonic acid. zileuton) and a COX-2 inhibitor. Monooxygenases generally metabolize arachidonic acid into three major classes of eicosanoid products80: 1. such as ischemic pain. The patient is having difficulty obtaining the combination medication. 11.81. selective isoprostane antagonists may be particularly useful. Cytochrome P450 epoxygenases produce four EET regioisomers: 5. EETs generated from arachidonic acid may be taken up from the cytosol and/or circulation and re-tailored into the sn-2 position of the cell membrane glycerol phospholipids. however. did not affect the sensitizing action of 8-iso PGE2 on peptide release. Node et al87 suggested that EETs may play an important nonvasodilatory role in vascular inflammation in part by the inhibition of NF-κB–mediated vascular cell adhesion molecule-1 (VCAM-1) expression. Efforts to delineate EET effects have focused largely on modulation of cardiovascular function via actions predominantly on the vasculature and in the kidneys.88 thereby potentially modulating nociception in pain states where leukocytes may facilitate nociceptive signals. cyclopentenone isoprostanes may be formed in large amounts in vivo. therefore. interleukin-6.78 Cyclopentenone isoprostanes contain highly reactive unsaturated carbonyl moieties on the prostane ring that readily adduct relevant biomolecules. Therefore. cytochrome P450 epoxygenases).72 A growing body of evidence suggests that reactive oxygen species may contribute to nociception under certain circumstances.73–77 It is conceivable that isoprostanes may facilitate nociception under conditions where reactive oxygen species are involved. and he has had significant adverse reactions to glucocorticoids. The “physician of the future” prescribes lumiracoxib. cis-EETs produced by olefin epoxidation of arachidonic acid (known as the epoxygenase reaction81).81 11. utilizing other enzymes81 already “committed” to monooxygenase pathways.79 Although the potential role of these substances as modulators of pain and/or inflammation under certain circumstances remains uncertain. C16–C20 alcohols formed by omega/omega-1 terminal hydroxylation of arachidonic acid omega-n arachidonate alcohols (known as the omega-oxygenase reaction). such as thiols. and have examined the formation of cyclopentenone isoprostane-like compounds from fatty acids. VOLUME 4.12-EET or overexpression of CYP 2J2 decreases cytokine-induced endothelial cell adhesion molecule expression. since its pKa (ionization constant) is such that it may work especially well in acidic environments. which produces persistent binding of IκB to NF-κB. MONOOXYGENASE CYTOCHROME P 450 EPOXYGENASE PATHWAY EETs are synthesized from arachidonic acid via monooxygenases (eg. EETs appear to inhibit IκB kinase (IκB kinase is the enzyme that normally functions to prevent the degradation of IκB).12-EET. NUMBER 6 ■ JUNE 2006 www. with many involving effects on ion channels and/or ion influx.79 Further. and 14. via the chemical process of Michael addition. yielding five EETs. The microenvironment at the interface of the osteoclast with the bone surface is highly acidic.Smith evoked by bradykinin or capsaicin from sensory neurons.12-EET displays inhibitory effects on the generation of PGE2. so his physician prescribes a 5-LOX inhibitor (eg.SupportiveOncology. and 3. This process may lead to an increase in LOX-like bis-allylic oxidation products and/or omega hydroxylase products. Various isomers of EETs may contribute to endogenous antipyresis.15-EET. 2. hoping that it may have a slight edge over other COX-2 inhibitors for the treatment of painful osseous metastases. although it does not appear to affect thromboxane production. thereby leading to “effective shunting” to arachidonic acid metabolic pathways. The effects of EETs on NF-κB may play a role in nociceptive processes in various pain and inflammatory states.81 and potently stimulate the release of melanocyte stimulating hormone α (MSHα). Epoprostenol therapy has been demonstrated to decrease oxidant stress.83–85 Wang et al86 provide support for EETs functioning as endothelium-derived hyperpolarizing factors that can upregulate endothelial nitric oxide synthase via activation of MAPK and protein kinase C signaling pathways. and this also decreases leukocyte adhesion to endothelial cells. Various EETs may have numerous functions. depending upon the local environment.81 play a role in neuroimmunomodulation.82 Furthermore. a PDE4 inhibitor. a COX inhibitor. since the osteoclast uses a proton pump to help it “digest” bone. and potent opioids.81 Functions of EETs.79 Unlike cyclopentenone prostaglandins.6-EET. Case Examples (continued) • A 74-year-old man with prostate cancer and painful osseous metastases comes to his physician complaining of widespread bone pain. EETs induce polymorphonuclear leukocyte aggregation. He is told that he is not a candidate for external-beam radiation therapy or radiopharmaceuticals. thereby diminishing leukocyte adhesion to the endothelial lining.79. generating six EETs. such as linolenic acid and docosahexaenoic acid. Nuclear transcription factor κB (NF-κB) is thought to play a critical role in cytokine-mediated inflammation. epoxygenases may be functionally inhibited.89 This maintains NF-κB in the inactive state and inhibits NFκB–mediated gene transcription. Pretreatment of neuronal cultures with the nonsteroidal antiinflammatory agent ketorolac. lumiracoxib may be a reasonable future choice. such as 15-A(2)isoprostanes. facilitates the release of tumor necrosis factor-α. Monooxygenases are mixed-function oxidase enzymes of the cytochrome P450 superfamily.87 Additionally. generating four EETs. in pain states with high oxidative stress. it is conceivable that they may represent a therapeutic target for future research. investigators have synthesized A-ring isoprostanes.

docosatrienes.106 15d- 284 www. and any perturbation of various enzymes and pathways may affect other processes and pathways involved in promoting or inhibiting inflammation or its resolution.95 EETs may set in motion a series of protein phosphorylations that subsequently activate the epidermal growth factor (EGF) receptor and attract various scaffolding proteins and c-Src35 signaling transduction pathways. as well as their aspirin-triggered counterparts. It appears that EETs may have numerous effects and therefore most likely work via a number of different mechanisms.89 potential EET effects on prostaglandin production.94 Alternatively. thereby facilitating resolution of the inflammation response. it is possible that EETs may exert effects on sodium movement: Lee et al104 demonstrated that 5 µM EET reduced the open-state probability of sodium channels in rat ventricular myocardium by as much as 73% ± 5%.107–109 Some of these local autocoids exhibit potent anti-inflammatory or antineutrophil recruitment activity and may also play a significant role in the resolution of inflammation. and EET-stimulated effects on PGE2.105 Among them. which is similar to that seen with local anesthetics such as lidocaine. There is no specific prostaglandin synthase yielding 15d-PGJ2.107–109 Gilroy and colleagues110 suggested that mechanisms that “switch off” acute inflammation lead to the expression of proresolving COX-2–derived 15d-PGJ2 during “active resolution. This could occur via multiple avenues. Instead. therapies aimed at modulation of LOX pathways received less attention than those aimed at COX pathways. EETs may potentiate nociception via effects on α MSHα. LOX products and other products of arachidonic acid metabolism may represent potential therapeutic targets for pain and inflammation.91. which may be mediated in part via interaction with DP1 and DP2 receptors.90 or the abovementioned effects on NF-κB. Akt.105 15-Deoxy-∆-12.117 The development of dual COX/LOX inhibitors may eventually have clinical utility in certain pain and/or inflammation states. leukotrienes). along with certain lipoxins. lipoxins are the trihydroxytetraene-containing eicosanoids that are generated largely by transcellular biosynthesis and involved in a coordinated scheme to move from inflammation to its resolution. endogenous local mediators of resolution play a key role in controlling inflammation and its organized coordinated “active” resolution. or by covalently binding to IκK (thereby inhibiting IκK function). These proresolution mediators—including lipoxins and cyclopentenones. PGJ2 exhibits anti-inflammatory and proresolution effects.86 EET effects on signaling pathways that may be involved in nociceptive processes (eg. It is conceivable that EETs bind to a receptor (which is then linked to a cyclic AMP and PKA signal transduction pathway). as well as resolvins.87. appear to be involved in post-inflammation clean-up activities. In addition to possible inhibition of cytokine-induced inflammatory responses. EETs may also activate potassium transport84.102. possibly including phosphotidylinositol 3-kinase (PI3-K). intracellular interaction with peroxisome proliferator-activated receptors (PPARs) interfering with NF-κB DNA binding.Arachidonic Acid Pathways in Nociception Mechanisms of action.115. as well as cancer prevention. EETs and related products may contribute to the modulation of nociceptive processes under certain conditions. A failure of acute inflammation to resolve may facilitate persistence of the inflammatory response.93 and may affect calcium channels. since the melanocortin system appears to be involved in nociceptive processes. Dehydration of PGD2 yields PGJ2 and subsequently yields 15d-PGJ2. where blocking one avenue can promote beneficial effects without affecting other processes. thereby activating Gαs with subsequent cyclic AMP production and PKA activation. EETs may bind to a guanine-binding protein (G-protein). It is becoming more apparent that we can no longer think of inflammation in terms of a series of good and bad pathways. earning them the appellation “resolvins. an Resolution of Inflammation Inflammation does not simply wane as the concentration of inflammatory mediators begins to fall.SupportiveOncology. and their endogenous aspirin-triggered epimeric counterparts—could modulate nociceptive processes under certain circumstances and therefore may represent novel therapeutic targets for achieving analgesia.96 Furthermore. neuroprotectins. docosatrienes.14-prostaglandin J2 (15d-PGJ2) is a cyclopentenone that is the dehydration end product of PGD2.net THE JOURNAL OF SUPPORTIVE ONCOLOGY .”107 Resolvins. including the anti-inflammatory properties of EETs (via autocrine effects on endothelial cells).97–101 particularly in activating sensory neuron-specific receptors.105 These “stop signals” in inflammation may be involved in switching the cellular response from additional recruitment of polymorphonuclear leukocytes toward monocytes (in a non-phlogistic fashion). Future Prospects Alteration of arachidonic acid metabolism may modulate pain and inflammation and may also be involved in human carcinogenesis. thereby contributing to chronic inflammation. inflammation must be viewed as a complex. and no specific 15d-PGJ2 receptor has been identified.106 Aspirin inhibits COX-1 and converts COX-2 into an aspirin-triggered lipid mediator–generating system that produces an array of novel endogenous local autocoids from dietary omega-3 polyunsaturated fatty acids.90 as well as increased calcium influx. and extracellular signal-regulated kinase (ERK) 1/ERK 2.” which subsequently induces apoptosis of both neutrophils and macrophages. MAPK. In the past. Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of the epoxide LTA4 to the diol LTB4. Instead.92 could possibly affect various nociceptive processes under certain conditions. with subsequent effects on gene regulation. Src).103 Finally. interrelated network.111–116 Inhibiting COX pathways may lead to a “shunting” of metabolic machinery toward the production of other arachidonic acid metabolic products (eg. Bestatin. among other mechanisms. and neuroprotectins.

Huang Z.LOX inhibitors Vascular insult/disturbances Impaired resolution of inflammation Somatic inflammation Tachykinin receptor antagonists BLT-1R antagonists LTA 4 H inhibitors B(2)R antagonists Neurogenic inflammation PAIN INFLAMMATION Central inflammatory pain Central Gly R Alpha 3 agonists NMDA antagonists Peripheral neurologic insult/ disturbances P38 MAPK inhibitors ERK inhibitors COX-1/COX-2 inhibitors Peripheral tissue insult/disturbances/ inflammation High oxidation stress COX-2 inhibitors mPGES 1 inhibitors PDE4 inhibitors MAPK antagonists Selective isoprostane antagonists Figure 2 Hypothetical Analgesic and Anti-inflammatory Treatments Targeting Arachidonic Acid Metabolites and Pathways combined adenosine receptor antagonist. Drugs for Pain.Gilroy DW. Philadelphia. Different strategies to address pain or inflammation may be better suited or targeted to different pain and inflammatory states. 6. such as cilomilast and roflumilast. W i n s t e a d M V. Nature 1997. Many mechanisms are omitted. D e n n i s E A . Resolvins. LTA4H inhibitor. Specific inhibitors of phosphodiesterase type 4 (PDE4). Taheri MR. Lawrence T. et al. ed.Willoughby DA. 2005. In: Koopman WJ. Pa: Hanley and Belfus. Nonsteroidal drugs: bedside. Menard C.net 285 . Congar P. In: Smith HS.390:622–625.SupportiveOncology. 4. 3. Figure 2 is a hypothetical diagram meant only to partially illustrate the many mechanisms and avenues involved in the pathogenesis of pain and inflammation associated with arachidonic acid metabolites and to suggest potential treatment options. retain broad anti-inflammatory activity after intravenous.Anti-inflammatory lipid mediators and insights into the resolution of inflammation. at least at this stage. et al. 7. ed. Phospholipase A(2) regulation of arachidonic acid mobilization. such as CGH2466. oral. it is based only on the imagination of the author and not on any definitive studies. St-Gelais F. a References 1. Smith HS. Hong S. Serhan CN. Eicosanoids and related compounds. Baltimore. Postsynaptic injection of calcium-independent phospholipase A2 VOLUME 4.119–121 Future agents may possess multiple mechanisms aimed at combating pain and/or inflammation. Gotlinger K.73:155–172. appear not only to elevate intracellular concentrations of cAMP but also may inhibit neutrophil degranulation. NUMBER 6 ■ JUNE 2006 www. ZK-142. and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Figure 2 is certainly not intended to guide treatment choices. and PDE4 inhibitor. Prostaglandins Other Lipid Mediat 2004. interfering with second-messenger signaling may be a useful therapeutic adjunct to approaching modulation of pain and inflammation. neuroprotectins. 2003. docosatrienes.531:2–6. and there is considerable overlap among the various conditions depicted. novel omega-3-derived mediators. 2. A Textbook of Rheumatology. Native lipoxin A4 and lipoxin B4 and their synthetic analogs ATLa2.Smith Selective EET agonists 15d-PGJ2 Resolvins Lipoxins Docosatrienes Neuroprotectins Dual COX 2/5. 5 . FEBS Lett 2002. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. p38 mitogen-activated protein kinase. Md: Lippincott Williams and Wilkins. suppresses tumorigenesis in animal models of esophageal carcinoma117 and may be potentially useful (in a manner similar to BLT-1 receptor antagonists) as a therapeutic agent in certain pain and/or inflammatory states. Serhan CN. et al. Nat Rev Immunol 2002.122 Substances that promote the resolution of inflammation may potentially become useful clinical therapeutic agents. and topical administration.2:787–795. Bonventre JV. and ZK-994. Arthritis and Allied Conditions. B a l s i n d e J .118 Further.

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