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Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system?
Prostaglandins, Leukotrienes and Essential Fatty Acids 68 (2003) 219–224
Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system? Haim Shapiro* Wolfson Medical Center, 62 Lochamim Street, Holon 58220, Israel Received 30 June 2002; accepted 30 July 2002
Abstract The intake of n-3 polyunsaturated fatty acids (PUFAs) in many industrialized countries is relatively low and its increased consumption has protective and modifying effects on such diverse conditions as atherosclerosis, ventricular arrhythmias, multiple sclerosis, major depression and inflammatory and autoimmune diseases. In addition, n-3 PUFAs have been shown to alleviate pain in patients with rheumatoid arthritis, inflammatory bowel disease and in a number of other painful conditions. This has been attributed to the inhibition of pro-inflammatory eicosanoid and cytokine production by peripheral tissues. n-3 PUFAs have also been shown to inhibit eicosanoid production in glial cells, block voltage-gated sodium channels (VGSCs), inhibit neuronal protein kinases and modulate gene expression. They also appear to have mood-stabilizing and sympatholytic effects. The present article explores the possibility that, based on what is known about their neural and non-neural effects, n-3 PUFAs directly attenuate the neuronal and glial processes that underlie neuropathic and inflammatory pain. r 2003 Elsevier Science Ltd. All rights reserved.
1. n-3 PUFAs in health and disease Fatty acids are classified as saturated or mono- or polyunsaturated, depending on the number of double bonds. PUFAs are further categorized according to the position of the first double bond from the n-terminal of the molecule, such as the n-3 (or omega-3) and n-6 PUFAs. Ingested PUFAs are incorporated into the phospholipid membrane of cells throughout the body, including those of the central and peripheral nervous system [1,2]. In addition to their effect on membrane stability and fluidity, certain n-3 and n-6 PUFAs serve as eicosanoid precursors, molecules which modulate many physiological processes such as inflammation,
Abbreviations: PUFA: polyunsaturated fatty acid; VGSC: voltagegated sodium channel; EPA: eicosapentaenoic acid; DHA: docosahexanoic acid; NSAID: non-steroidal anti-inflammatory drug; MI: myocardial infarction; VGCC: voltage-gated calcium channel; DRG: dorsal root ganglion; DH: dorsal horn; IL: interleukin; TNF: tumor necrosis factor; CNS: central nervous system; PKC: protein kinase C; MAPK: mitogen-activated protein kinase. *Corresponding author. 6 Bar Kochba Street, Jerusalem 97875, Israel, Tel.:+972 2 5322698 ; fax: +972 2 5400497. E-mail address: haim [email protected] (H. Shapiro).
hemostasis and vascular tone. Eicosanoids produced from the n-3 PUFA eicosapentaenoic acid (EPA) are less pro-inflammatory and pro-thrombotic than those derived from n-6 PUFAs [3]. Production of proinflammatory cytokines is attenuated in the presence of EPA and the other important fish-derived n-3 PUFA, docosahexanoic acid (DHA) [3]. A number of other cellular processes are beneficially modulated by n-3 PUFAs, but not by n-6 PUFAs. These include the function of certain ion channels, receptors and signal conduction molecules, as well as gene expression [3,4]. A typical European and American diet contains more n-6 PUFAs and less n-3 PUFAs than the typical Greek diet, and this is thought to contribute to the development of a number of diseases common to the industrialized world [5]. Epidemiological studies and clinical trials show that increased n-3 PUFA intake attenuates or helps to prevent ischemic heart disease [6], sudden cardiac death [7], stroke [8], multiple sclerosis [9], other autoimmune [10] and chronic inflammatory diseases [11], and major depression [12]. The attempt to increase n-3 PUFA consumption has become a major health issue [5,13]. Further mention of n-3 PUFAs in this article refers to the fish-derived n-3 PUFAs, EPA and DHA.
0952-3278/03/$ - see front matter r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0952-3278(02)00273-9
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2. n-3 PUFAs alleviate different types of pain A number, but not all, observational and clinical studies have shown that a higher intake of n-3 PUFAs, either dietary or as a supplement, is associated with reduced pain in rheumatoid arthritis [14], inflammatory bowel disease [15], dysmenorrhea [16,17] and musculoskeletal injury [18]. In some trials, n-3 PUFAs exhibited an NSAID- or steroid-sparing effect [14,15]. A high n-3 PUFA diet inhibited the sickness response (i.e. anorexia, cachexia, fever and lethargy) to subcutaneous injection of turpentine in mice [19], an animal model of inflammatory pain. These findings are attributed to n-3 PUFAs’ inhibition of inflammatory mediators by peripheral (outside the nervous system) cells, that contribute to the pain and other symptoms characteristic of the above conditions. Finally, rats fed a diet with a high n-3/n-6 PUFA ratio exhibited higher thermal pain thresholds than controls [20]. The explanation for this phenomenon is not clear. In short, n-3 PUFAs have been shown to reduce a variety of forms of pain but their direct action on pain and analgesic pathways of the nervous system have not been evaluated. In the present article we explore the possibility that, based on what is presently known about their physiological and therapeutic effects, n-3 PUFAs attenuate nervous system changes underlying neuropathic and inflammatory pain.
3. n-3 PUFAs block VGSCs in the heart and hippocampus, preventing electrical hyperexcitability Dietary supplementation of n-3 PUFAs significantly lowers mortality in post-myocardial infarction (MI) patients [7]. This is attributed mainly to n-3 PUFAs’ antiarrhythmic properties, which reduce the incidence of post-MI Ventricular Fibrillation [21]. Unesterified n-3 PUFAs potently and reversibly bind to and block the current through VGSCs and voltage-gated calcium channels (VGCC), in a concentration- and voltagedependent manner. Their electrophysiological effects on VGSCs are similar to those of type Ib antiarrhythmics, except that n-3 PUFAs do not exhibit use-dependent (frequency-dependent) blockade [22]. Yet they only block the function of VGSCs in hyperexcitable, ischemic myocytes, sparing the function of the healthy myocardium. Leaf [21] proposed a hypothesis to account for this finding: Ischemia causes local dysfunction of the Na+/K+ ATPase, extracellular K+ accumulation and partial depolarization of neighboring myocytes. The latter are thus hyperexcitable, their membrane potential becoming closer to the VGSCs’ activation threshold. In the presence of n-3 PUFAs, myocytes have to be hyperpolarized before their VGSCs return to their closed resting state. Ischemic myocytes do not reach
this negative potential and a sufficient number of VGSCs remain in an inactivated state to prevent a ventricular tachyarrhythmia. Non-ischemic myocytes are able to produce an action potential, and their rhythmicity is maintained. Some of the n-6 PUFAs have also been shown to block VSGCs in vitro, but their metabolites are proarrhythmic [22]. Indeed, a high dietary n-6 to n-3 PUFA ratio may increase the risk of sudden cardiac death [23]. n-3 PUFAs had a similar effect on VGSCs in CA1 neurons from the rat hippocampus, albeit higher concentrations were required than in cardiomyocytes [24]. They also raised the electrical threshold for seizure activity in a rat model of epilepsy (cortical stimulation) [25]. In a small, uncontrolled study, increased n-3 PUFA intake reduced the frequency and severity of convulsions in epileptic patients [26]. Another interesting finding is that although cardiomyocytes exposed to the type Ib antiarrhythmic mexiletine upregulated VGSC expression, co-treatment with n-3 PUFAs prevented this event [27]. n-3 PUFAs also blocked L-type VGCCs in cardiomyocytes [21] and CA1 neurons [24], similarly to their effect on VGSCs. In addition, they inhibited the release of Ca2+ from cardiomyocyte intracellular compartments [21]. Their effect on N-type VGCCs, which are more pertinent than the L-type to analgesia [28], has not been assessed.
4. VGSCs are implicated in neuropathic and inflammatory pain Following certain types of peripheral nerve injury, complex changes in the VGSC type, number and function occur. These changes are thought to cause neuronal hyperexcitability and increased membrane potential oscillations, thereby increasing the chance of spontaneous depolarization. In addition, ongoing impulse traffic in neighboring dorsal root ganglion (DRG) neurons is more likely to cause cross-depolarizations in hyperexcitable neurons than in normal neurons. Such stimuli-independent activity probably contributes to neuropathic pain [29,30]. Type Ib antiarrhythmics that are or have been used to treat ventricular tachyarrhythmias have also been shown to reduce ectopic discharges in experimental neuromas [31,32]. These agents are often used in the treatment of neuropathic pain, but their clinical use is limited because of the side effects appearing at plasma levels that do not produce sufficient analgesia [28]. Still, these findings suggest some degree of cross-reactivity of cardiac and pain neuron VGSCs to different sodium channel blockers, and that n-3 PUFAs may block pain neuron VGSCs which underlie neuropathic pain. Indeed, the gene encoding one of the nociceptor-specific VGSCs, SNS/ PN3, shares a very similar genomic structure with the
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human cardiac VGSC gene [33]. Although SNS/PN3 expression appears to be downregulated in neuropathic pain [29], evidence suggests that attenuation of their activity could relieve such pain [34]. As opposed to type Ib antiarrhythmics, n-3 PUFAs are safe as long as the PUFAs supply less than 10% of the total energy intake and the diet contains an adequate amount of Vitamin E [35,36]. Changes in the location, type, number and function of peripheral pain neuron VGSCs also occur in inflammatory pain. SNS/PN3 expression is up-regulated, and its activity is enhanced via second messenger-activated protein kinases [37]. Inhibition of its expression and function should attenuate inflammatory pain [34].
5. n-3 PUFAs inhibit the formation of pro-inflammatory molecules such as eicosanoids and cytokines in cells throughout the body
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Ca2+/Calmodulin protein kinase, and mitogen-activated protein kinase (MAPK). In addition, n-3 PUFAs prevented serotonin receptor-induced activation of MAPK in hippocampal preparations [44,45]. Different isoforms of PKC are activated in peripheral-pain neurons following injury and inflammation and contribute to changes in VGSC function and expression [46]. MAPK appears to regulate central sensitization in both inflammatory and neuropathic pain [47]. There is evidence that activation of a PKC isoform in the dorsal horn contributes to central sensitization and morphine tolerance [48]. Experimental drugs that inhibit PKC have the potential to alleviate neuropathic pain but are systemically toxic, probably because they inhibit ‘‘normal’’ PKC activity [46]. n-3 PUFAs, on the other hand, are safe. Inhibition of PKC and MAPK by n-3 PUFAs might prevent downstream events that contribute to pathological pain. 6.2. Possible anti-depressant and mood stabilizing effects
Certain pro-inflammatory cytokines (IL-1b, IL-6 and TNF-a) and eicosanoids (e.g. PGE2) promote inflammatory and neuropathic pain, as well as the hyperalgesia of the sickness response, via their direct and indirect actions on central and peripheral neurons, glia, and endothelial cells [38]. Glial cells are both a source and a target of these pro-inflammatory molecules and their role in pathological pain states is now recognized [39]. Membranal EPA competes with arachidonic acid as a substrate for cyclo- and lipooxygenase, thereby reducing the production of inflammatory metabolites (PGE2, LTA4 and TXA2) and increasing the synthesis of less inflammatory eicosanoids or even anti-inflammatory ones [3,11]. This has been demonstrated in many cells throughout the body, including glial cells [40]. Numerous studies have revealed that n-3 PUFAs inhibit the in vitro production of pro-inflammatory cytokines by a number of cell types, and their in vivo synthesis in healthy adults and those with autoimmune diseases [3,11,41,42]. In addition, n-3 PUFAs may protect the brain from the deleterious effects of the pro-inflammatory cytokines: the IL-1-induced changes in neurotransmitter release in the nucleus accumbens is attenuated in rats pre-fed n-3 PUFAs [43]. Theoretically, n-3 PUFAs could minimize the neural plasticity underlying chronic pain by antagonizing the peripheral and neural production of eicosanoids and cytokines.
6. Other effects of n-3 PUFAs that are pertinent to the treatment of persistent pain 6.1. Inhibition of neuronal protein kinases n-3 PUFAs inhibit the in vitro activity of rat brain cAMP-dependent protein kinase, protein kinase C (PKC),
Many patients with a chronic medical illness suffer from major depression and the latter increases the risk of developing such illnesses [49,50]. This is believed to be at least partially due to shared pathophysiological processes that predispose to, and/or are a consequence of depression and physical diseases. Such processes include reduced n-3 PUFA intake, abnormal metabolism of lipid and phospholipid mediators, increased production of pro-inflammatory cytokines, dysregulation and dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, and immune dysfunction [49–53]. These processes are themselves inter-related. Depression is common in patients with chronic pain. Although it is difficult to determine causality [54], chronic pain and depression do share some of the pathophysiological processes mentioned above, and these may serve as common targets for treatment [55]. Interestingly, neonatal maternal deprivation and early stressful events can induce HPA axis dysfunction, depressive behavior and visceral or somatic hyperalgesia in rats [56–58]. These effects are gender- and speciesspecific. In humans, childhood abuse predisposes to HPA axis dysfunction, depression, and chronic visceral and somatic pain states [58–61]. Central nervous system (CNS) noradrenaline and serotonin modulate both affect and pain perception (albeit via different neural pathways), and agents that increase the synaptic level of these monoamines are used to treat affective and pain disorders [55]. Injection of endotoxin increases systemic and central levels of pro-inflammatory cytokines, inducing a sickness response that includes depressive behavior and hyperalgesia [38,62]. Cumulative evidence links low levels of membranal n-3 PUFAs with affective disorders. Treatment with n-3 PUFAs can enhance recovery in both unipolar [12] and
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bipolar depression [63]. It has been claimed that n-3 PUFAs alleviate depression by inhibiting production of the pro-inflammatory cytokines which induce the sickness response [64]. Other potential anti-depressive actions of n-3 PUFAs are neuronal PKC inhibition and elevation of central serotonin [4,44,65]. As mentioned above, agents used to treat unipolar depression exhibit a number of analgetic properties [55,66,] and have shown to be effective in the treatment of neuropathic pain [67]. Certain anticonvulsants ameliorate both manic depression and neuropathic pain [67,68]. Thus, n-3 PUFAs may target mechanisms common to both affective disorders and chronic pain. 6.3. Sympatholysis Analysis of heart rate variability (HRV) allows noninvasive assessment of sympatho-vagal balance. A low HRV indicates a high sympathetic tone and is a risk factor for developing a fatal ventricular fibrillation following MI [69]. Increasing n-3 PUFA intake raises HRV in post-MI patients, thereby contributing to the n-3 PUFAs’ antiarrhythmic effect [69,70]. Elevated adrenergic stimulation is involved in some forms of neuropathic pain [29]. By reducing sympathetic tone, n-3 PUFAs may also lower sympathetically-maintained pain.
7. Conclusion It is becoming evident that morbidity and mortality in the industrialized world could be lowered by increasing the intake of n-3 PUFAs. A growing number of diseases have been shown to be attenuated by n-3 PUFAs. However, the effect of n-3 PUFAs on the prevention and treatment of chronic pain has not been evaluated, despite their impact on many of the underlying pathological processes. Since n-3 PUFAs do not interfere with the pharmacodynamics or pharmacokinetics of commonly used analgetic drugs, they may act synergistically, allowing lower dosages to be used. The n-3 PUFAs may also prove to prevent chronic pain conditions, while conferring numerous additional health benefits.
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Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system? Haim Shapiro* Wolfson Medical Center, 62 Lochamim Street, Holon 58220, Israel Received 30 June 2002; accepted 30 July 2002
Abstract The intake of n-3 polyunsaturated fatty acids (PUFAs) in many industrialized countries is relatively low and its increased consumption has protective and modifying effects on such diverse conditions as atherosclerosis, ventricular arrhythmias, multiple sclerosis, major depression and inflammatory and autoimmune diseases. In addition, n-3 PUFAs have been shown to alleviate pain in patients with rheumatoid arthritis, inflammatory bowel disease and in a number of other painful conditions. This has been attributed to the inhibition of pro-inflammatory eicosanoid and cytokine production by peripheral tissues. n-3 PUFAs have also been shown to inhibit eicosanoid production in glial cells, block voltage-gated sodium channels (VGSCs), inhibit neuronal protein kinases and modulate gene expression. They also appear to have mood-stabilizing and sympatholytic effects. The present article explores the possibility that, based on what is known about their neural and non-neural effects, n-3 PUFAs directly attenuate the neuronal and glial processes that underlie neuropathic and inflammatory pain. r 2003 Elsevier Science Ltd. All rights reserved.
1. n-3 PUFAs in health and disease Fatty acids are classified as saturated or mono- or polyunsaturated, depending on the number of double bonds. PUFAs are further categorized according to the position of the first double bond from the n-terminal of the molecule, such as the n-3 (or omega-3) and n-6 PUFAs. Ingested PUFAs are incorporated into the phospholipid membrane of cells throughout the body, including those of the central and peripheral nervous system [1,2]. In addition to their effect on membrane stability and fluidity, certain n-3 and n-6 PUFAs serve as eicosanoid precursors, molecules which modulate many physiological processes such as inflammation,
Abbreviations: PUFA: polyunsaturated fatty acid; VGSC: voltagegated sodium channel; EPA: eicosapentaenoic acid; DHA: docosahexanoic acid; NSAID: non-steroidal anti-inflammatory drug; MI: myocardial infarction; VGCC: voltage-gated calcium channel; DRG: dorsal root ganglion; DH: dorsal horn; IL: interleukin; TNF: tumor necrosis factor; CNS: central nervous system; PKC: protein kinase C; MAPK: mitogen-activated protein kinase. *Corresponding author. 6 Bar Kochba Street, Jerusalem 97875, Israel, Tel.:+972 2 5322698 ; fax: +972 2 5400497. E-mail address: haim [email protected] (H. Shapiro).
hemostasis and vascular tone. Eicosanoids produced from the n-3 PUFA eicosapentaenoic acid (EPA) are less pro-inflammatory and pro-thrombotic than those derived from n-6 PUFAs [3]. Production of proinflammatory cytokines is attenuated in the presence of EPA and the other important fish-derived n-3 PUFA, docosahexanoic acid (DHA) [3]. A number of other cellular processes are beneficially modulated by n-3 PUFAs, but not by n-6 PUFAs. These include the function of certain ion channels, receptors and signal conduction molecules, as well as gene expression [3,4]. A typical European and American diet contains more n-6 PUFAs and less n-3 PUFAs than the typical Greek diet, and this is thought to contribute to the development of a number of diseases common to the industrialized world [5]. Epidemiological studies and clinical trials show that increased n-3 PUFA intake attenuates or helps to prevent ischemic heart disease [6], sudden cardiac death [7], stroke [8], multiple sclerosis [9], other autoimmune [10] and chronic inflammatory diseases [11], and major depression [12]. The attempt to increase n-3 PUFA consumption has become a major health issue [5,13]. Further mention of n-3 PUFAs in this article refers to the fish-derived n-3 PUFAs, EPA and DHA.
0952-3278/03/$ - see front matter r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0952-3278(02)00273-9
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2. n-3 PUFAs alleviate different types of pain A number, but not all, observational and clinical studies have shown that a higher intake of n-3 PUFAs, either dietary or as a supplement, is associated with reduced pain in rheumatoid arthritis [14], inflammatory bowel disease [15], dysmenorrhea [16,17] and musculoskeletal injury [18]. In some trials, n-3 PUFAs exhibited an NSAID- or steroid-sparing effect [14,15]. A high n-3 PUFA diet inhibited the sickness response (i.e. anorexia, cachexia, fever and lethargy) to subcutaneous injection of turpentine in mice [19], an animal model of inflammatory pain. These findings are attributed to n-3 PUFAs’ inhibition of inflammatory mediators by peripheral (outside the nervous system) cells, that contribute to the pain and other symptoms characteristic of the above conditions. Finally, rats fed a diet with a high n-3/n-6 PUFA ratio exhibited higher thermal pain thresholds than controls [20]. The explanation for this phenomenon is not clear. In short, n-3 PUFAs have been shown to reduce a variety of forms of pain but their direct action on pain and analgesic pathways of the nervous system have not been evaluated. In the present article we explore the possibility that, based on what is presently known about their physiological and therapeutic effects, n-3 PUFAs attenuate nervous system changes underlying neuropathic and inflammatory pain.
3. n-3 PUFAs block VGSCs in the heart and hippocampus, preventing electrical hyperexcitability Dietary supplementation of n-3 PUFAs significantly lowers mortality in post-myocardial infarction (MI) patients [7]. This is attributed mainly to n-3 PUFAs’ antiarrhythmic properties, which reduce the incidence of post-MI Ventricular Fibrillation [21]. Unesterified n-3 PUFAs potently and reversibly bind to and block the current through VGSCs and voltage-gated calcium channels (VGCC), in a concentration- and voltagedependent manner. Their electrophysiological effects on VGSCs are similar to those of type Ib antiarrhythmics, except that n-3 PUFAs do not exhibit use-dependent (frequency-dependent) blockade [22]. Yet they only block the function of VGSCs in hyperexcitable, ischemic myocytes, sparing the function of the healthy myocardium. Leaf [21] proposed a hypothesis to account for this finding: Ischemia causes local dysfunction of the Na+/K+ ATPase, extracellular K+ accumulation and partial depolarization of neighboring myocytes. The latter are thus hyperexcitable, their membrane potential becoming closer to the VGSCs’ activation threshold. In the presence of n-3 PUFAs, myocytes have to be hyperpolarized before their VGSCs return to their closed resting state. Ischemic myocytes do not reach
this negative potential and a sufficient number of VGSCs remain in an inactivated state to prevent a ventricular tachyarrhythmia. Non-ischemic myocytes are able to produce an action potential, and their rhythmicity is maintained. Some of the n-6 PUFAs have also been shown to block VSGCs in vitro, but their metabolites are proarrhythmic [22]. Indeed, a high dietary n-6 to n-3 PUFA ratio may increase the risk of sudden cardiac death [23]. n-3 PUFAs had a similar effect on VGSCs in CA1 neurons from the rat hippocampus, albeit higher concentrations were required than in cardiomyocytes [24]. They also raised the electrical threshold for seizure activity in a rat model of epilepsy (cortical stimulation) [25]. In a small, uncontrolled study, increased n-3 PUFA intake reduced the frequency and severity of convulsions in epileptic patients [26]. Another interesting finding is that although cardiomyocytes exposed to the type Ib antiarrhythmic mexiletine upregulated VGSC expression, co-treatment with n-3 PUFAs prevented this event [27]. n-3 PUFAs also blocked L-type VGCCs in cardiomyocytes [21] and CA1 neurons [24], similarly to their effect on VGSCs. In addition, they inhibited the release of Ca2+ from cardiomyocyte intracellular compartments [21]. Their effect on N-type VGCCs, which are more pertinent than the L-type to analgesia [28], has not been assessed.
4. VGSCs are implicated in neuropathic and inflammatory pain Following certain types of peripheral nerve injury, complex changes in the VGSC type, number and function occur. These changes are thought to cause neuronal hyperexcitability and increased membrane potential oscillations, thereby increasing the chance of spontaneous depolarization. In addition, ongoing impulse traffic in neighboring dorsal root ganglion (DRG) neurons is more likely to cause cross-depolarizations in hyperexcitable neurons than in normal neurons. Such stimuli-independent activity probably contributes to neuropathic pain [29,30]. Type Ib antiarrhythmics that are or have been used to treat ventricular tachyarrhythmias have also been shown to reduce ectopic discharges in experimental neuromas [31,32]. These agents are often used in the treatment of neuropathic pain, but their clinical use is limited because of the side effects appearing at plasma levels that do not produce sufficient analgesia [28]. Still, these findings suggest some degree of cross-reactivity of cardiac and pain neuron VGSCs to different sodium channel blockers, and that n-3 PUFAs may block pain neuron VGSCs which underlie neuropathic pain. Indeed, the gene encoding one of the nociceptor-specific VGSCs, SNS/ PN3, shares a very similar genomic structure with the
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human cardiac VGSC gene [33]. Although SNS/PN3 expression appears to be downregulated in neuropathic pain [29], evidence suggests that attenuation of their activity could relieve such pain [34]. As opposed to type Ib antiarrhythmics, n-3 PUFAs are safe as long as the PUFAs supply less than 10% of the total energy intake and the diet contains an adequate amount of Vitamin E [35,36]. Changes in the location, type, number and function of peripheral pain neuron VGSCs also occur in inflammatory pain. SNS/PN3 expression is up-regulated, and its activity is enhanced via second messenger-activated protein kinases [37]. Inhibition of its expression and function should attenuate inflammatory pain [34].
5. n-3 PUFAs inhibit the formation of pro-inflammatory molecules such as eicosanoids and cytokines in cells throughout the body
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Ca2+/Calmodulin protein kinase, and mitogen-activated protein kinase (MAPK). In addition, n-3 PUFAs prevented serotonin receptor-induced activation of MAPK in hippocampal preparations [44,45]. Different isoforms of PKC are activated in peripheral-pain neurons following injury and inflammation and contribute to changes in VGSC function and expression [46]. MAPK appears to regulate central sensitization in both inflammatory and neuropathic pain [47]. There is evidence that activation of a PKC isoform in the dorsal horn contributes to central sensitization and morphine tolerance [48]. Experimental drugs that inhibit PKC have the potential to alleviate neuropathic pain but are systemically toxic, probably because they inhibit ‘‘normal’’ PKC activity [46]. n-3 PUFAs, on the other hand, are safe. Inhibition of PKC and MAPK by n-3 PUFAs might prevent downstream events that contribute to pathological pain. 6.2. Possible anti-depressant and mood stabilizing effects
Certain pro-inflammatory cytokines (IL-1b, IL-6 and TNF-a) and eicosanoids (e.g. PGE2) promote inflammatory and neuropathic pain, as well as the hyperalgesia of the sickness response, via their direct and indirect actions on central and peripheral neurons, glia, and endothelial cells [38]. Glial cells are both a source and a target of these pro-inflammatory molecules and their role in pathological pain states is now recognized [39]. Membranal EPA competes with arachidonic acid as a substrate for cyclo- and lipooxygenase, thereby reducing the production of inflammatory metabolites (PGE2, LTA4 and TXA2) and increasing the synthesis of less inflammatory eicosanoids or even anti-inflammatory ones [3,11]. This has been demonstrated in many cells throughout the body, including glial cells [40]. Numerous studies have revealed that n-3 PUFAs inhibit the in vitro production of pro-inflammatory cytokines by a number of cell types, and their in vivo synthesis in healthy adults and those with autoimmune diseases [3,11,41,42]. In addition, n-3 PUFAs may protect the brain from the deleterious effects of the pro-inflammatory cytokines: the IL-1-induced changes in neurotransmitter release in the nucleus accumbens is attenuated in rats pre-fed n-3 PUFAs [43]. Theoretically, n-3 PUFAs could minimize the neural plasticity underlying chronic pain by antagonizing the peripheral and neural production of eicosanoids and cytokines.
6. Other effects of n-3 PUFAs that are pertinent to the treatment of persistent pain 6.1. Inhibition of neuronal protein kinases n-3 PUFAs inhibit the in vitro activity of rat brain cAMP-dependent protein kinase, protein kinase C (PKC),
Many patients with a chronic medical illness suffer from major depression and the latter increases the risk of developing such illnesses [49,50]. This is believed to be at least partially due to shared pathophysiological processes that predispose to, and/or are a consequence of depression and physical diseases. Such processes include reduced n-3 PUFA intake, abnormal metabolism of lipid and phospholipid mediators, increased production of pro-inflammatory cytokines, dysregulation and dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, and immune dysfunction [49–53]. These processes are themselves inter-related. Depression is common in patients with chronic pain. Although it is difficult to determine causality [54], chronic pain and depression do share some of the pathophysiological processes mentioned above, and these may serve as common targets for treatment [55]. Interestingly, neonatal maternal deprivation and early stressful events can induce HPA axis dysfunction, depressive behavior and visceral or somatic hyperalgesia in rats [56–58]. These effects are gender- and speciesspecific. In humans, childhood abuse predisposes to HPA axis dysfunction, depression, and chronic visceral and somatic pain states [58–61]. Central nervous system (CNS) noradrenaline and serotonin modulate both affect and pain perception (albeit via different neural pathways), and agents that increase the synaptic level of these monoamines are used to treat affective and pain disorders [55]. Injection of endotoxin increases systemic and central levels of pro-inflammatory cytokines, inducing a sickness response that includes depressive behavior and hyperalgesia [38,62]. Cumulative evidence links low levels of membranal n-3 PUFAs with affective disorders. Treatment with n-3 PUFAs can enhance recovery in both unipolar [12] and
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bipolar depression [63]. It has been claimed that n-3 PUFAs alleviate depression by inhibiting production of the pro-inflammatory cytokines which induce the sickness response [64]. Other potential anti-depressive actions of n-3 PUFAs are neuronal PKC inhibition and elevation of central serotonin [4,44,65]. As mentioned above, agents used to treat unipolar depression exhibit a number of analgetic properties [55,66,] and have shown to be effective in the treatment of neuropathic pain [67]. Certain anticonvulsants ameliorate both manic depression and neuropathic pain [67,68]. Thus, n-3 PUFAs may target mechanisms common to both affective disorders and chronic pain. 6.3. Sympatholysis Analysis of heart rate variability (HRV) allows noninvasive assessment of sympatho-vagal balance. A low HRV indicates a high sympathetic tone and is a risk factor for developing a fatal ventricular fibrillation following MI [69]. Increasing n-3 PUFA intake raises HRV in post-MI patients, thereby contributing to the n-3 PUFAs’ antiarrhythmic effect [69,70]. Elevated adrenergic stimulation is involved in some forms of neuropathic pain [29]. By reducing sympathetic tone, n-3 PUFAs may also lower sympathetically-maintained pain.
7. Conclusion It is becoming evident that morbidity and mortality in the industrialized world could be lowered by increasing the intake of n-3 PUFAs. A growing number of diseases have been shown to be attenuated by n-3 PUFAs. However, the effect of n-3 PUFAs on the prevention and treatment of chronic pain has not been evaluated, despite their impact on many of the underlying pathological processes. Since n-3 PUFAs do not interfere with the pharmacodynamics or pharmacokinetics of commonly used analgetic drugs, they may act synergistically, allowing lower dosages to be used. The n-3 PUFAs may also prove to prevent chronic pain conditions, while conferring numerous additional health benefits.
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