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Peroxynitrite: a strategic linchpin of opioid analgesic tolerance
Review
Peroxynitrite: a strategic linchpin of opioid analgesic tolerance Daniela Salvemini1 and William L. Neumann2 1 2
Department of Internal Medicine, Saint Louis University, St Louis, MO 63110, USA Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, IL 62026, USA
Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, partly because the reduced analgesic effectiveness accompanying chronic opiate therapy (i.e. tolerance) leads to escalating doses and distressing side effects. Accordingly, there is major interest in new approaches to maintain opiate efficacy during repetitive dosing without engendering tolerance or causing unacceptable side effects. Recent mounting evidence implicates nitroxidative stress caused by the presence of superoxide (O2S), nitric oxide (NO) and subsequently peroxynitrite (ONOOS) in opiate analgesic tolerance. Here, we provide a pharmacological basis for developing inhibitors of ONOOS biosynthesis and/or ONOOS scavengers as potent adjuncts to opiates in the management of chronic pain, addressing an issue of major clinical and socio-economic importance while laying the basis for interventions with strong therapeutic potential. Introduction Opioid analgesics are the primary treatment for moderate to severe pain but their clinical utility is often compromised by the development of both analgesic tolerance and de novo painful hypersensitivity to innocuous and noxious stimuli [1–3]. Morphine tolerance often necessitates escalating doses to achieve equivalent pain relief [4], even though morphine-induced hypersensitivity eventually subverts the therapeutic impact of such dose increases [1–3]. This complex pathophysiological cycle contributes to decreased quality of life in the growing population of subjects with chronic pain because of oversedation, reduced physical activity, respiratory depression, constipation, potential for addiction and other side effects [4]. Accordingly, there is substantial interest in new approaches to maintain opiate efficacy during repetitive dosing for chronic pain, without engendering tolerance or unacceptable side effects. Although opioid analgesic tolerance is clearly not a monolithic phenomenon, there are substantial data now implicating the overproduction of peroxynitrite (ONOO ) under neuroinflammatory conditions as a key linchpin for its development. The intricate biological chemistry of reactive oxygen and reactive nitrogen species has been extensively reviewed elsewhere [5]. Herein it is instructive to present the basic pathways for the formation of ONOO Corresponding authors: Salvemini, D. ([email protected])
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and its subsequent biological reaction manifolds, within the context of affecting the mechanisms of opiate antinociceptive tolerance (Box 1). Although a host of oxidative and nitrative modifications of cellular targets has been identified, the nitration of proteins and the subsequent alteration of their functions continue to be important indicators of, and contributors to, pathological states encompassing cardiovascular diseases, inflammation, neurodegeneration and diabetes [6]. Here, we focus on ONOO as a potent pro-inflammatory and proapoptotic species, and the ONOO -derived nitration and modification of protein functions essential for normal neuronal homeostasis, as key disrupting factors that contribute to the mechanisms of opioid tolerance and hyperalgesia. In addition, we review the current antioxidant and ONOO -decomposition therapeutic strategies that have shown promise for the prevention and reversal of antinociceptive tolerance. Protein nitration and the O2S/NO/ONOOS balance Nitration of mitochondrial manganese superoxide dismutase A key component of O2 /NO balance governing ONOO homeostasis is the loss of activity accompanying the posttranslational nitration of mitochondrial manganese superoxide dismutase (MnSOD). In the neuroinflammatory setting, the increased production of both O2 and NO to afford ONOO can generate several possible activated species that nitrate tyrosine-34 of MnSOD and deactivate the enzyme [7]. This process favors the unchecked accumulation of ONOO , which, in turn, nitrates and alters additional proteins and receptors (Figure 1), thereby perpetuating and extending the initial damage [8]. In confirmatory experiments, it has recently been shown that repeated administration of morphine leads to nitration and enzymatic inactivation of MnSOD in the spinal cord. Furthermore, these studies have determined that prevention of ONOO formation (either by inhibition of NO synthase [NOS], scavenging of O2 or decomposing ONOO ), blocks nitration, restores the activity of the enzyme and attenuates tolerance [9]. Another study has shown that formation of NO-derived ONOO in neurons subsequent to neuronal activation by cytokines (such as tumor necrosis factor-a [TNF-a] released from activated glial cells) nitrates MnSOD leading to neuronal cell death [10].
0165-6147/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2008.12.005 Available online 2 March 2009
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Box 1. Formation and fate of neuronal ONOOS Neuronal NO is generated from L-arginine and molecular oxygen by a Ca2+/calmodulin-activated NO synthase (nNOS) in response to Ca2+ influx mediated by the NMDA receptor [7]. O2 is generated primarily by uncoupling of mitochondrial electron transport and as a product of cytosolicoxidases such as NADPH oxidase and xanthineoxase [8]. nNOS is also capable of producing O2 in addition to NO under lowarginine conditions constituting a ‘ONOO -synthase’ activity [5]. The fate of ONOO in vivo can been visioned as resulting from two main categories of highly reactive entities: (i) The ONOOH–ONOO acid– base conjugate pair and (ii) the fallout from reaction of ONOO with CO2 (Figure I). The ONOO ion can exert its cytotoxic effects either by direct or metal-mediated oxidation reactions or through homolysis of
its protonated conjugate acid to form nitrogen dioxide and hydroxyl radical [9]. Alternatively, the reaction of ONOO with CO2 (present in biological systems at 1–2 mM concentrations) leads to the formation of nitrogen dioxide and carbonate radical via the initial homolysis of nitrosoperoxy carbonate adduct [10,11]. A vast body of evidence is now in support of the ONOO -driven post-translational tyrosine nitration and consequent modification of protein function [6,13,14]. The biological importance of post-translational nitration is thus underscored by numerous reported studies linking this phenomenon to a number of diseases driven by the overproduction of ONOO [15– 26]. Most recently, ONOO has been implicated as a pivotal component of pain and opiate antinociceptive tolerance [18–20,27].
Figure I. The peroxynitrite reactivity manifold.
Disruption of glutamate homeostasis Glutamate is the most important excitatory neurotransmitter in the brain and spinal cord activating several ionotropic and metabotropic glutamate receptors. The excitatory phase of glutamate-mediated neurotransmission is terminated by the uptake of glutamate by glutamate transporters (GTs) and subsequent conversion to glutamine by glutamine synthase (GS). These functions are collectively known as the glutamatergic pathway. Dysfunction of the glutamatergic pathway is a key component of nociception [2,11]. ONOO alters glutamate homeostasis through post-translational nitration and modification of key proteins involved in maintaining a normal glutamate balance. Indeed, research in fields other than opiate tolerance or pain, including amyotrophic lateral sclerosis and septic shock, has demonstrated that ONOO nitrates and inactivates N-methyl-D-aspartic acid (NMDA) receptors and sodium-dependent, high-affinity glutamate GTs and GS, which are proteins of central importance in glutamate homeostasis [12–14], Glutamate neurotransmission, in particular that which is mediated via NMDA receptors under chronic pain conditions, is fundamentally involved in the development of opioid tolerance, especially tolerance arising from m-opioid receptor stimulation [15].
Glutamate, a primary endogenous ligand for the NMDA receptor, is not metabolized by extracellular enzymes and has to be removed from the synaptic cleft by cellular uptake. The homeostasis of extracellular glutamate is tightly regulated by GTs in the plasma membranes of both neurons and glia [17]. Three glutamate transport protein subtypes isolated in the spinal cord (GLAST and GLT-1 associated with glial cells, and EAAC1 associated with neurons [18,19]) are considered to be essential to maintain low resting levels of glutamate (<1 mM) and to prevent overstimulation of GTs [17]. Thus, several studies indicate that GTs have a crucial role in the prevention of glutamate neurotoxicity under both physiological and pathological conditions [17]. In brain regions, decreases in GLT-1 mRNAs have been observed after naloxone (a competitive m receptor antagonist)-precipitated morphine withdrawal [20]. In addition, the activity of GTs decreases during morphine tolerance and this is associated with spinal apoptosis [21]. GT inhibitors or activators such as MS135 increase and decrease, respectively, the development of spinal apoptosis, hyperalgesia and tolerance [21,22]. Finally, it has been shown that nitration of GLT-1 by ONOO inhibits its GT capacity leading to excitotoxicity [12] (Figure 1).
Nitration of the NMDA receptor and GTs ONOO interacts with the NMDA receptor leading to nitration of the tyrosine residues present on the NMDA receptor subunits. This event is an irreversible reaction that leads to a constant potentiation of the synaptic currents and calcium influx and ultimately excitotoxicity [16] (Figure 1).
Nitration of GTs further incapacitates neuronal antioxidant defense In addition to regulating synaptic levels of glutamate, GTs have a crucial role in the uptake of cysteine and, thus, contribute to the overall thiol redox state of cells regulated by intracellular levels of glutathione (GSH). This endogen195
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Figure 1. ONOO formation and opioid analgesic tolerance. Hyperalgesia, excitotoxicity and chronic pain associated with morphine tolerance are mediated, in part, by the accumulation of glutamate within the synaptic cleft between nociceptors and dorsal horn cells. The resulting prolonged glutamate NMDA activation results in the removal of the Mg2+ plug in the Ca2+ channels. Ca2+ flux in to the cell activates protein kinase C, which primes NOS for the synthesis of NO. The co-existing state of neuroimmune glial cell activation results in upregulation of the inflammatory cascade and a large flux of O2 , which rapidly combines with NO to form ONOO . The activated nitrating and oxidizing species formed via the ONOO reactivity manifold nitrates and inactivates the NMDA receptor, GTs, GS and several other crucial targets perpetuating the intractable pain state [19].
ous cysteine-containing tripeptide antioxidant is essential in both protecting cells from oxidative stress and maintaining the thiol redox state. GSH depletion enhances oxidative stress leading to neuronal degeneration as shown in several studies [23]. In neurons, cysteine is the ratelimiting substrate for GSH synthesis [24], and in neurons 90% of total cysteine uptake is mediated by GTs (such as EAAC1) [25]. Recent studies have shown that ONOO -mediated nitration of EAAC1 in neurons reduces the uptake capacity of cysteine leading to a depletion of intracellular GSH and neuronal cell death [26] (Figure 1). In the tolerance setting, excitotoxicity driven by increased synaptic concentrations of glutamate and a decrease in neuronal antioxidant defenses can be correlated to decreased intracellular levels of cysteine and, thus, GSH. Nitration of GS Under normal neuronal housekeeping conditions glutamate is removed from the synapses by glial cell uptake (mediated by EAAT1 and EAAT2) and converted into nontoxic glutamine by the enzyme GS [27]. Studies have shown that in glutamatergic areas the distribution of both glial glutamate receptors and glial transporters parallels the location of GS, indicating a functional coupling between the two systems to prevent damage from gluta196
mate-derived excitotoxicity [28]. Furthermore, through feedback regulation, a decrease in the activity of GS can reduce the activity of GTs [28]. Therefore, a dysfunctional glutamate–glutamine, glial–neuronal shuttle can also contribute to antinociceptive tolerance [22,29,30]. Recent results in support of this conclusion show that post-translational tyrosine nitration of both spinal GTs (i.e. GLT-1) and GS by ONOO contributes to the development of antinociceptive tolerance to morphine [9] (Figure 1). Increased levels of glutamate can be decreased by reducing the production of cytokines such as TNF-a and interleukin (IL)-6, which have been shown to be important in the inhibition of glutamate uptake [31]. Because ONOO increases cytokine production (see later) it is likely that ONOO also modulates glutamate homeostasis via the cytokine signaling pathway. Thus, ONOO -mediated protein nitration interferes with the crucial glutamatergic pathway from postsynaptic NMDA receptor nitration to GT and GS nitration impairing the glial cell to presynaptic processing of the glutamate–glutamine neuronal shuttling systems. ONOOS and neuroimmune activation ONOO is also a potent pro-inflammatory species, and a role for inflammation at the level of the spinal cord has been well documented. Chronic administration of mor-
Review phine promotes neuroimmune activation as evidenced by activation of spinal cord glial cells, production of proinflammatory cytokines such as TNF-a, IL-1b and IL-6 and spinal sensitization [32]. Thus, inhibitors of glial cell metabolism and/or anti-cytokine approaches block morphine-induced antinociceptive tolerance and hyperalgesia [32]. In addition, other anti-inflammatory agents including dexamethasone [29], neurosteroids [33], non-steroidal anti-inflammatory drugs (NSAIDs) [34], IL-10 [35], NOS inhibitors [36] p38 kinase inhibitors [37] and superoxide dismutase (SOD) mimetics [38] have been shown to inhibit morphine-induced antinociceptive tolerance and hyperalgesia. The possible mechanisms for chronic morphineinduced glial cell activation are not known with certainty but it is clear that morphine primes glial cells for enhanced production of pro-inflammatory cytokines [39]. In inflammation, ONOO induces endothelial cell damage and increased microvascular permeability; activates redox-sensitive transcription factors including nuclear factor-kB and activator protein-1 that in turn regulate genes encoding various pro-inflammatory and pronociceptive cytokines such as IL-1b, TNF-a and IL-6; upregulates adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and P-selectin to recruit neutrophils at sites of inflammation; auto-catalyzes the oxidative destruction of neurotransmitters and hormones such as norepinephrine and epinephrine; and induces lipid peroxidation and oxidation (for review, see Ref. [40]). Thus, it is clear that anti-inflammatory strategies leading to the downregulation or destruction of ONOO can effectively inhibit opioid analgesic tolerance. ONOOS and spinal neuronal apoptosis ONOO is a potent proapototic species and a role for spinal neuronal apoptosis in morphine antinociceptive tolerance is established [21,41]. Mitochondria are key sites of cellular death and constitute a primary locus for the intracellular formation and reactions of ONOO [42]. ONOO -mediated inactivation of mitochondrial MnSOD in the vicinity of a functional NOS that resides at the inner surface of the inner mitochondrial membrane favors an autocatalytic surge in ONOO formation; this results in positive feedback processes that promote mitochondrial dysfunction and the triggering of apoptotic signaling of cell death, including poly (ADP-ribose) polymerase (PARP) and caspase activation [7,43]. Previous reports have implicated apoptosis in antinociceptive tolerance and associated hypersensitivity. Indeed, chronic morphine exposure causes apoptosis in the spinal cord dorsal horn [21,41,44]. Caspase-3 inhibitors that block apoptosis prevent the development of morphine hyperalgesia and antinociceptive tolerance [21,41,44]. Thus, ONOO is generated in the mitochondrion in response to chronic opioid treatment, is associated with mitochondrial dysfunction leading to apoptotic pathways, and apoptosis is a key element in opioid tolerance. Targeting ONOOS or destruction to address opioid tolerance A strong pharmacological basis has now been provided for developing inhibitors of ONOO biosynthesis and/or
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ONOO scavengers as adjuncts to opioids for the prevention of analgesic tolerance. There are essentially three distinct strategies for the therapeutic attenuation of ONOO levels in response to chronic pain and tolerance. (i) The first indirect strategy is to prevent the formation of ONOO (from the rapid combination of O2 and NO) by cutting off O2 or NO at the sources. This process could be accomplished either through the downregulation of proinflammatory mediators that lead to elevated O2 levels or through direct inhibition of NOS isoforms. (ii) The second indirect strategy would be to scavenge O2 effectively enough to prevent its combination with NO. (iii) The only direct strategy would be to scavenge or decompose ONOO itself before harmful biological nitration and oxidation reactions can take place. Strategy 1: cyclooxygenase and NOS inhibition It is now well established that NSAIDs can synergize with opioids providing analgesia at dosages at which some adverse events are minimal. For example, combinations of NSAIDS and morphine have been used to manage terminal cancer patient pain in the clinic with maximized analgesia and somewhat lessened side effects [45]. Studies in animals have confirmed that neuronal cyclooxygenase (COX) activity contributes to the expression of opioid tolerance and that certain COX inhibitors can be used for the prevention, and even the reversal, of morphine tolerance [46]. It has also been established that NOS inhibitors can effectively attenuate opioid tolerance [36]. Given that COX-II activity is upregulated as a component of the neuroinflammatory conditions that lead to the generation of more O2 and that NOS activity and subsequent elevated NO levels have been shown to contribute to the development of opioid tolerance, it might be suggested that the resulting overproduction of ONOO is the true linchpin. Unfortunately, each of these two inhibitor strategies has its drawbacks. On the one hand, selective COX-II inhibitor use has been associated with side effects including increased risks of heart attack and stroke, which prompted the withdrawal of Vioxx (rofecoxib) from the market in 2004 and the removal of Bextra (valdecoxib) and a black-box warning label change for Celebrex (celecoxib) in 2005 [47]. On the other hand, potent NOS inhibition might indeed prevent ONOO formation but would also interfere with many crucial NO-mediated cellular signaling processes [40]. Stategy 2: organic antioxidant scavengers Endogenous and exogenous ONOO -decomposition agents and the current understanding of their mechanisms of stoichiometric or catalytic action have been the subject of several recent excellent reviews [48–51]. Herein we restrict our discussion to those compounds that have shown promise in further addressing the contribution of ONOO toxicity within the framework of opioid analgesic tolerance (Figure 2). Many of these antioxidants are capable of scavenging multiple free radical species (O2 and ONOO derived) but, owing to the rapid kinetics involved, the formation of ONOO and its subsequent decomposition pathways are likely to be the most relevant in biological systems. 197
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Figure 2. Stoichiometric scavengers of ONOO . Ascorbic acid (a), a highly water soluble antioxidant reacts slowly with ONOO but avidly with the chemical fallout of the peroxynitrosocarbonate pathway [53]. Mega doses have been reported to prevent morphine tolerance [52]. Ascorbic acid is also a key co-reductant for the detoxification of ONOO [67]. Trolox (b), a water soluble vitamin E analogue reduces ONOO effectively at pH = 7 (k105 M 1 s 1) [55]. Vitamin E analogues (c) such as g-tocopherol (R = H) have been shown to inhibit protein nitration under conditions of inflammation [54]. Melatonin (d) is a potent antioxidant species and a naturally occurring hormone that is found in most animals and in humans. Melatonin has been shown to inhibit tyrosine nitration under conditions of inflammation and to attenuate antinociceptive tolerance to d opioid receptor agonists [59]. Ebselen (e), a low-molecular-weight glutathione peroxidase mimic rapidly detoxifies ONOO (k106 M 1s 1). The resulting melatoninselenoxide can then be reduced back to ebselen in the presense of GSH and/or thioredoxin reductase and NADPH, converting this stoichiometric system to one that is catalytic [9]. Flavonoids comprise a large class of polyphenolic antioxidants that can effectively intercept CO3 and NO2 and, thus, protect against ONOO - and/or peroxynitrosocarbonate-derived toxicity. Quercetin (f) has been shown to attenuate morphine-induced tolerance [56]. Genistein (g) and epicatechin (h) are effective in preventing tyrosinenitration [57].
Many studies have been published regarding the use of organic, nutritional, vitamin and drug candidate antioxidants for the attenuation of morphine tolerance. In most cases, molecules from these classes act in a stoichiometric manner, being irreversibly modified by ONOO to afford by-products that may or may not display their own toxicities. Ascorbate has been reported to suppress tolerance and dependence to morphine in humans and rodents. Even though the rate for the reaction of ascorbate with ONOO is rather slow (k 102 M 1 s 1), fairly high intracellular concentrations can be achieved (1–2 mM) and mega-dosing studies have been reported to prevent morphine tolerance [52]. In addition, ascorbate has high reactivity with NO2 and CO3S formed preferentially from ONOO and CO2 under physiological conditions [53]. To our knowledge, there have been no reports of the use of vitamin E or derivatives thereof (tocopherols) in opioid analgesic-tolerance studies. However, there is a wealth of studies concerning the successful use of vitamin E derivatives in treating various neurodegenerative disorders known to be driven by nitroxidative stress [54]. In addition, the rate constant for the reaction of trolox (a water-soluble vitamin E derivative) with NO2 is very high [55]. Taken together, these results indicate that vitamin E derivatives 198
could be effective as adjuncts to opioids for the treatment of chronic pain. There are several reports of bioflavonoids such as quercetin attenuating the development of morphine tolerance in animals [56]. Bioflavonoids are potent antioxidants with excellent scavenging reactivity toward the peroxnitrite– CO2 manifold [57]. However, quercetin and kaempferol display antinociceptive activities on their own and have been shown to interact with the opioidergic systems and NOS systems directly in addition to their scavenging properties [58]. There are also reports of melatonin attenuating antinociceptive tolerance to d receptor agonists in addition to enhancing the anti- and proconvulsant effects of morphine [59]. Although some of these effects have been attributed to the melatonin MT2 receptor subtype, contributions from the antioxidant nature of melatonin cannot be excluded and are likely. Finally, to our knowledge there are no reports of organoselenium compounds, such as ebselen, that behave as glutathione peroxidase mimics [60] in opioid tolerance. There is, however, a host of studies regarding ebselen and other organoselenium, organotellurium and organosulfur antioxidants displaying potent neuroprotective
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Figure 3. The catalytic decomposition of ONOO by metal–porphyrin complexes (M = Mn or Fe). Isomerase activity (a) can be envisioned as the reaction of ONOO with Fe(III) to afford Fe(IV) = O and NO2, followed by solvent-cage recombination of NO2 and the metal-oxo group generating Fe(III) and NO3 [49]. Reductase activity (b) can involve biological reductants to regenerate the active catalyst.
effects in addition to being effective in the detoxification of ONOO [61–63]. Strategy 3: ONOO -decomposition catalysts Many new catalytic antioxidant strategies have now been developed and offer great therapeutic potential for the management of pain and opioid tolerance. From the early work profiling iron and manganese porphyrin complexes as ONOO -decomposition catalysts [48,64–67] to the development of these systems into highly active and more druggable entities [68], it has been shown that destruction of the highly damaging ONOO is of paramount importance in restoring and in some cases potentiating the efficacy of opioid analgesics. The mechanistic chemistry and general biological impact of ONOO -decomposition catalysts has been thoroughly reviewed [48–51]. Thus, we highlight the prototypical systems that have been investigated within the framework of opioid tolerance. Various groups have shown
over the past 15 years that certain redox-active transition metal–porphyrin complexes react rapidly with ONOO and can function as ONOO reductases or isomerases (Figure 3). Either of these functions can provide a useful mechanism for the detoxification of the ONOO manifold. Manganese(III) and iron(III) porphyrin complexes such as FeTM-4-PyP5+ are active cataysts (Figure 4). It has recently been shown in mice that the coadministration of morphine with the NOS inhibitor L-NAME (1–10 mg 1kg 1d 1) or with the metalloporphyrin complexes MnTBAP3 (1–10 mg 1 kg 1d 1) or FeTM-4-PyP5+ (3–30 mg 1 kg 1d 1) over a 4-day period inhibited the development of tolerance in a dose-dependent manner. Control animals given morphine alone developed substantial antinociceptive tolerance to an acute injection of morphine on the 5th day. Remarkably, cutting off NO production with the NOS inhibitor (L-NAME; N-nitro-Larginine methyl ester) or scavenging O2 and catalytically decomposing ONOO with MnTBAP3 and FeTM-4-PyP5+
Figure 4. Catalytic antioxidants. The structures of metal porphyrins commonly used as SOD mimic (MnTBAP3 ) and peroxynitrite decomposition (FeTM-4-PyP5+) catalysts and the Mn(II)-polyazamacrocyclic complex SC-72325 developed as an SOD mimic at Monsanto-Searle [38].
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Figure 5. Conclusions and future implications.
both accomplish the goal of blocking morphine tolerance. In these studies, FeTM-4-PyP5+ was shown to effectively prevent the nitration and inactivation of the GT GLT-1 and GS. The coadministration of FeTM-4-PyP5+ with morphine not only attenuated the post-translational nitration of MnSOD (tyrosine-34) but also restored the activity of the enzyme. FeTM-4-PyP5+ was also shown to block the increased formation of TNF-a, IL-1b and IL-6 in the spinal cords of these animals. In addition, it was also shown that FeTM-4-PyP5+ blocked oxidative DNA damage and PARP activation and, therefore, attenuated neuronal and/or glial cell apoptosis [9]. Manganese(III)–porphyrin and iron(III)– porphyrin complexes behave in vivo as both SOD mimics and ONOO -decomposition catalysts. However, certain manganese(II) polyazamacrocyclic complexes such as SC-72325 (Figure 5) have been reported to react exclusively with O2 [69]. Although there is much to be sorted out with regard to the real in vivo selectivity of this class of molecules toward nitroxidative stress, it is clear that complexes such as SC-72325 have good in vitro SOD activities and have been shown to effectively prevent morphine analgesic tolerance [38]. Thus, we can conclude that inhibition of NOS, effective compartmental scavenging of O2 and decomposition of ONOO all lead to the prevention of morphine tolerance. Concluding remarks The formation and toxicity of ONOO in the spinal cord under neuroinflammatory conditions contributes to the nitration and inactivation of NMDA receptors and the GTs and GS. Nitration and inactivation of MnSOD by ONOO promotes an amplification of ONOO levels through a sustained unchecked O2 production and its subsequent reaction with NO, which itself is upregulated 200
under prolonged neuroexcitatory conditions. ONOO is also a proapoptotic species, and neuronal apoptosis is a component of nociceptive tolerance. Several studies have now been published that demonstrate that ONOO scavengers or decomposition catalysts can prevent or even reverse opioid analgesic tolerance. Taken together, these results not only point to ONOO as a crucial mediator of opioid antinociceptive tolerance but also validate the strategy of targeting ONOO as an adjunctive approach for reviving failing opioid therapies. Although not discussed here, ONOO -mediated nitroxidative stress has also been implicated in hyperalgesia associated with the development of acute and chronic inflammation and in response to NMDA receptor activation [70–73]. Hence, ONOO -decomposition catalysts are powerful inhibitors of inflammatory pain but the antihyperalgesic actions of these agents does not involve an interaction with the endogenous opiate system because the effects are naloxone insensitive [70,73]. Importantly, ONOO -decomposition catalysts synergize not only with the analgesic effects of opiates but also with those of nonselective COX inhibitors such as ibuprofen and those of selective COX-2 inhibitors such as NS-398 [73]. An imbalance between oxidant/antioxidant activity has also been observed in other models of inflammatory nociception. For example, increased levels of hydrogen peroxide (the dismutated product of O2 ) [74] and decreased levels of SOD activity in the spinal trigeminal nucleus coincided with facial hyperalgesia induced by a formalin injection into the lip [75]. Superoxide is also increased in dorsal horn neurons during neuropathic pain induced by spinal nerve ligation [76] and neurogenicinduced hyperalgesia induced by capsaicin [77]. Using nonselective antioxidants such as phenyl N-tert-butylnitrone (PBN) and 4-hydroxy-2,2,6,6-tetramethylpiperidine
Review 1-oxyl (TEMPOL), roles for nitro-oxidative stress in inflammatory pain [78] and neuropathic pain also have been documented [79–83]. These agents and other antioxidants have also been reported to be effective against trigeminal pain, fibromyalgia and temporomandibular joint dysfunction [75,84], chronic pancreatitis [85], post-irradiation of breast cancer fibrosis [86] and neurogenic hyperalgesia [77]. Overall implication of findings? These data collectively support a key role for nitroxidative stress in the development of pain of several etiologies including pain associated with prolonged use of narcotics. Future research aimed at preparing catalysts with optimized physiochemical attributes imparting drug-like properties will have great promise as novel non-narcotic analgesic agents for the management of pain (Figure 5). References 1 Arner, S. et al. (1988) Clinical experience of long-term treatment with epidural and intrathecal opioids – a nationwide survey. Acta Anaesthesiol. Scand. 32, 253–259 2 Mao, J. et al. (1995) Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 62, 259–274 3 Ossipov, M.H. et al. (2004) Antinociceptive and nociceptive actions of opioids. J. Neurobiol. 61, 126–148 4 Foley, K.M. (1995) Misconceptions and controversies regarding the use of opioids in cancer pain. Anticancer Drugs 6 (Suppl. 3), 4–13 5 Groves, J.T. (1999) Peroxynitrite: reactive, invasive and enigmatic. Curr. Opin. Chem. Biol. 3, 226–235 6 Pacher, P. et al. (2007) Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–424 7 MacMillan-Crow, L.A. and Thompson, J.A. (1999) Tyrosine modifications and inactivation of active site manganese superoxide dismutase mutant (Y34F) by peroxynitrite. Arch. Biochem. Biophys. 366, 82–88 8 Radi, R. et al. (2001) Unraveling peroxynitrite formation in biological systems. Free Radic. Biol. Med. 30, 463–488 9 Muscoli, C. et al. (2007) Therapeutic manipulation of peroxynitrite attenuates the development of opiate-induced antinociceptive tolerance in mice. J. Clin. Invest. 117, 3530–3539 10 Tangpong, J. et al. (2008) Tumor necrosis factor a-mediated nitric oxide production enhances manganese superoxide dismutase nitration and mitochondrial dysfunction in primary neurons: an insight into the role of glial cells. Neuroscience 151, 622–629 11 Meller, S.T. and Gebhart, G.F. (1993) Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 52, 127–136 12 Trotti, D. et al. (1999) SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat. Neurosci. 2, 848 13 Trotti, D. et al. (1996) Peroxynitrite inhibits glutamate transporter subtypes. J. Biol. Chem. 271, 5976–5979 14 Gorg, B. et al. (2005) Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat. Hepatology 41, 1065–1073 15 Trujillo, K.A. and Akil, H. (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251, 85–87 16 Zanelli, S.A. et al. (2002) Nitration is a mechanism of regulation of the NMDA receptor function during hypoxia. Neuroscience 112, 869–877 17 Mennerick, S. et al. (1999) Substrate turnover by transporters curtails synaptic glutamate transients. J. Neurosci. 19, 9242–9251 18 Arriza, J.L. et al. (1993) Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. J. Biol. Chem. 268, 15329–15332 19 Robinson, M.B. and Dowd, L.A. (1997) Heterogeneity and functional properties of subtypes of sodium-dependent glutamate transporters in the mammalian central nervous system. Adv. Pharmacol. 37, 69–115
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Peroxynitrite: a strategic linchpin of opioid analgesic tolerance Daniela Salvemini1 and William L. Neumann2 1 2
Department of Internal Medicine, Saint Louis University, St Louis, MO 63110, USA Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, IL 62026, USA
Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, partly because the reduced analgesic effectiveness accompanying chronic opiate therapy (i.e. tolerance) leads to escalating doses and distressing side effects. Accordingly, there is major interest in new approaches to maintain opiate efficacy during repetitive dosing without engendering tolerance or causing unacceptable side effects. Recent mounting evidence implicates nitroxidative stress caused by the presence of superoxide (O2S), nitric oxide (NO) and subsequently peroxynitrite (ONOOS) in opiate analgesic tolerance. Here, we provide a pharmacological basis for developing inhibitors of ONOOS biosynthesis and/or ONOOS scavengers as potent adjuncts to opiates in the management of chronic pain, addressing an issue of major clinical and socio-economic importance while laying the basis for interventions with strong therapeutic potential. Introduction Opioid analgesics are the primary treatment for moderate to severe pain but their clinical utility is often compromised by the development of both analgesic tolerance and de novo painful hypersensitivity to innocuous and noxious stimuli [1–3]. Morphine tolerance often necessitates escalating doses to achieve equivalent pain relief [4], even though morphine-induced hypersensitivity eventually subverts the therapeutic impact of such dose increases [1–3]. This complex pathophysiological cycle contributes to decreased quality of life in the growing population of subjects with chronic pain because of oversedation, reduced physical activity, respiratory depression, constipation, potential for addiction and other side effects [4]. Accordingly, there is substantial interest in new approaches to maintain opiate efficacy during repetitive dosing for chronic pain, without engendering tolerance or unacceptable side effects. Although opioid analgesic tolerance is clearly not a monolithic phenomenon, there are substantial data now implicating the overproduction of peroxynitrite (ONOO ) under neuroinflammatory conditions as a key linchpin for its development. The intricate biological chemistry of reactive oxygen and reactive nitrogen species has been extensively reviewed elsewhere [5]. Herein it is instructive to present the basic pathways for the formation of ONOO Corresponding authors: Salvemini, D. ([email protected])
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([email protected]); Neumann, W.L.
and its subsequent biological reaction manifolds, within the context of affecting the mechanisms of opiate antinociceptive tolerance (Box 1). Although a host of oxidative and nitrative modifications of cellular targets has been identified, the nitration of proteins and the subsequent alteration of their functions continue to be important indicators of, and contributors to, pathological states encompassing cardiovascular diseases, inflammation, neurodegeneration and diabetes [6]. Here, we focus on ONOO as a potent pro-inflammatory and proapoptotic species, and the ONOO -derived nitration and modification of protein functions essential for normal neuronal homeostasis, as key disrupting factors that contribute to the mechanisms of opioid tolerance and hyperalgesia. In addition, we review the current antioxidant and ONOO -decomposition therapeutic strategies that have shown promise for the prevention and reversal of antinociceptive tolerance. Protein nitration and the O2S/NO/ONOOS balance Nitration of mitochondrial manganese superoxide dismutase A key component of O2 /NO balance governing ONOO homeostasis is the loss of activity accompanying the posttranslational nitration of mitochondrial manganese superoxide dismutase (MnSOD). In the neuroinflammatory setting, the increased production of both O2 and NO to afford ONOO can generate several possible activated species that nitrate tyrosine-34 of MnSOD and deactivate the enzyme [7]. This process favors the unchecked accumulation of ONOO , which, in turn, nitrates and alters additional proteins and receptors (Figure 1), thereby perpetuating and extending the initial damage [8]. In confirmatory experiments, it has recently been shown that repeated administration of morphine leads to nitration and enzymatic inactivation of MnSOD in the spinal cord. Furthermore, these studies have determined that prevention of ONOO formation (either by inhibition of NO synthase [NOS], scavenging of O2 or decomposing ONOO ), blocks nitration, restores the activity of the enzyme and attenuates tolerance [9]. Another study has shown that formation of NO-derived ONOO in neurons subsequent to neuronal activation by cytokines (such as tumor necrosis factor-a [TNF-a] released from activated glial cells) nitrates MnSOD leading to neuronal cell death [10].
0165-6147/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2008.12.005 Available online 2 March 2009
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Box 1. Formation and fate of neuronal ONOOS Neuronal NO is generated from L-arginine and molecular oxygen by a Ca2+/calmodulin-activated NO synthase (nNOS) in response to Ca2+ influx mediated by the NMDA receptor [7]. O2 is generated primarily by uncoupling of mitochondrial electron transport and as a product of cytosolicoxidases such as NADPH oxidase and xanthineoxase [8]. nNOS is also capable of producing O2 in addition to NO under lowarginine conditions constituting a ‘ONOO -synthase’ activity [5]. The fate of ONOO in vivo can been visioned as resulting from two main categories of highly reactive entities: (i) The ONOOH–ONOO acid– base conjugate pair and (ii) the fallout from reaction of ONOO with CO2 (Figure I). The ONOO ion can exert its cytotoxic effects either by direct or metal-mediated oxidation reactions or through homolysis of
its protonated conjugate acid to form nitrogen dioxide and hydroxyl radical [9]. Alternatively, the reaction of ONOO with CO2 (present in biological systems at 1–2 mM concentrations) leads to the formation of nitrogen dioxide and carbonate radical via the initial homolysis of nitrosoperoxy carbonate adduct [10,11]. A vast body of evidence is now in support of the ONOO -driven post-translational tyrosine nitration and consequent modification of protein function [6,13,14]. The biological importance of post-translational nitration is thus underscored by numerous reported studies linking this phenomenon to a number of diseases driven by the overproduction of ONOO [15– 26]. Most recently, ONOO has been implicated as a pivotal component of pain and opiate antinociceptive tolerance [18–20,27].
Figure I. The peroxynitrite reactivity manifold.
Disruption of glutamate homeostasis Glutamate is the most important excitatory neurotransmitter in the brain and spinal cord activating several ionotropic and metabotropic glutamate receptors. The excitatory phase of glutamate-mediated neurotransmission is terminated by the uptake of glutamate by glutamate transporters (GTs) and subsequent conversion to glutamine by glutamine synthase (GS). These functions are collectively known as the glutamatergic pathway. Dysfunction of the glutamatergic pathway is a key component of nociception [2,11]. ONOO alters glutamate homeostasis through post-translational nitration and modification of key proteins involved in maintaining a normal glutamate balance. Indeed, research in fields other than opiate tolerance or pain, including amyotrophic lateral sclerosis and septic shock, has demonstrated that ONOO nitrates and inactivates N-methyl-D-aspartic acid (NMDA) receptors and sodium-dependent, high-affinity glutamate GTs and GS, which are proteins of central importance in glutamate homeostasis [12–14], Glutamate neurotransmission, in particular that which is mediated via NMDA receptors under chronic pain conditions, is fundamentally involved in the development of opioid tolerance, especially tolerance arising from m-opioid receptor stimulation [15].
Glutamate, a primary endogenous ligand for the NMDA receptor, is not metabolized by extracellular enzymes and has to be removed from the synaptic cleft by cellular uptake. The homeostasis of extracellular glutamate is tightly regulated by GTs in the plasma membranes of both neurons and glia [17]. Three glutamate transport protein subtypes isolated in the spinal cord (GLAST and GLT-1 associated with glial cells, and EAAC1 associated with neurons [18,19]) are considered to be essential to maintain low resting levels of glutamate (<1 mM) and to prevent overstimulation of GTs [17]. Thus, several studies indicate that GTs have a crucial role in the prevention of glutamate neurotoxicity under both physiological and pathological conditions [17]. In brain regions, decreases in GLT-1 mRNAs have been observed after naloxone (a competitive m receptor antagonist)-precipitated morphine withdrawal [20]. In addition, the activity of GTs decreases during morphine tolerance and this is associated with spinal apoptosis [21]. GT inhibitors or activators such as MS135 increase and decrease, respectively, the development of spinal apoptosis, hyperalgesia and tolerance [21,22]. Finally, it has been shown that nitration of GLT-1 by ONOO inhibits its GT capacity leading to excitotoxicity [12] (Figure 1).
Nitration of the NMDA receptor and GTs ONOO interacts with the NMDA receptor leading to nitration of the tyrosine residues present on the NMDA receptor subunits. This event is an irreversible reaction that leads to a constant potentiation of the synaptic currents and calcium influx and ultimately excitotoxicity [16] (Figure 1).
Nitration of GTs further incapacitates neuronal antioxidant defense In addition to regulating synaptic levels of glutamate, GTs have a crucial role in the uptake of cysteine and, thus, contribute to the overall thiol redox state of cells regulated by intracellular levels of glutathione (GSH). This endogen195
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Figure 1. ONOO formation and opioid analgesic tolerance. Hyperalgesia, excitotoxicity and chronic pain associated with morphine tolerance are mediated, in part, by the accumulation of glutamate within the synaptic cleft between nociceptors and dorsal horn cells. The resulting prolonged glutamate NMDA activation results in the removal of the Mg2+ plug in the Ca2+ channels. Ca2+ flux in to the cell activates protein kinase C, which primes NOS for the synthesis of NO. The co-existing state of neuroimmune glial cell activation results in upregulation of the inflammatory cascade and a large flux of O2 , which rapidly combines with NO to form ONOO . The activated nitrating and oxidizing species formed via the ONOO reactivity manifold nitrates and inactivates the NMDA receptor, GTs, GS and several other crucial targets perpetuating the intractable pain state [19].
ous cysteine-containing tripeptide antioxidant is essential in both protecting cells from oxidative stress and maintaining the thiol redox state. GSH depletion enhances oxidative stress leading to neuronal degeneration as shown in several studies [23]. In neurons, cysteine is the ratelimiting substrate for GSH synthesis [24], and in neurons 90% of total cysteine uptake is mediated by GTs (such as EAAC1) [25]. Recent studies have shown that ONOO -mediated nitration of EAAC1 in neurons reduces the uptake capacity of cysteine leading to a depletion of intracellular GSH and neuronal cell death [26] (Figure 1). In the tolerance setting, excitotoxicity driven by increased synaptic concentrations of glutamate and a decrease in neuronal antioxidant defenses can be correlated to decreased intracellular levels of cysteine and, thus, GSH. Nitration of GS Under normal neuronal housekeeping conditions glutamate is removed from the synapses by glial cell uptake (mediated by EAAT1 and EAAT2) and converted into nontoxic glutamine by the enzyme GS [27]. Studies have shown that in glutamatergic areas the distribution of both glial glutamate receptors and glial transporters parallels the location of GS, indicating a functional coupling between the two systems to prevent damage from gluta196
mate-derived excitotoxicity [28]. Furthermore, through feedback regulation, a decrease in the activity of GS can reduce the activity of GTs [28]. Therefore, a dysfunctional glutamate–glutamine, glial–neuronal shuttle can also contribute to antinociceptive tolerance [22,29,30]. Recent results in support of this conclusion show that post-translational tyrosine nitration of both spinal GTs (i.e. GLT-1) and GS by ONOO contributes to the development of antinociceptive tolerance to morphine [9] (Figure 1). Increased levels of glutamate can be decreased by reducing the production of cytokines such as TNF-a and interleukin (IL)-6, which have been shown to be important in the inhibition of glutamate uptake [31]. Because ONOO increases cytokine production (see later) it is likely that ONOO also modulates glutamate homeostasis via the cytokine signaling pathway. Thus, ONOO -mediated protein nitration interferes with the crucial glutamatergic pathway from postsynaptic NMDA receptor nitration to GT and GS nitration impairing the glial cell to presynaptic processing of the glutamate–glutamine neuronal shuttling systems. ONOOS and neuroimmune activation ONOO is also a potent pro-inflammatory species, and a role for inflammation at the level of the spinal cord has been well documented. Chronic administration of mor-
Review phine promotes neuroimmune activation as evidenced by activation of spinal cord glial cells, production of proinflammatory cytokines such as TNF-a, IL-1b and IL-6 and spinal sensitization [32]. Thus, inhibitors of glial cell metabolism and/or anti-cytokine approaches block morphine-induced antinociceptive tolerance and hyperalgesia [32]. In addition, other anti-inflammatory agents including dexamethasone [29], neurosteroids [33], non-steroidal anti-inflammatory drugs (NSAIDs) [34], IL-10 [35], NOS inhibitors [36] p38 kinase inhibitors [37] and superoxide dismutase (SOD) mimetics [38] have been shown to inhibit morphine-induced antinociceptive tolerance and hyperalgesia. The possible mechanisms for chronic morphineinduced glial cell activation are not known with certainty but it is clear that morphine primes glial cells for enhanced production of pro-inflammatory cytokines [39]. In inflammation, ONOO induces endothelial cell damage and increased microvascular permeability; activates redox-sensitive transcription factors including nuclear factor-kB and activator protein-1 that in turn regulate genes encoding various pro-inflammatory and pronociceptive cytokines such as IL-1b, TNF-a and IL-6; upregulates adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and P-selectin to recruit neutrophils at sites of inflammation; auto-catalyzes the oxidative destruction of neurotransmitters and hormones such as norepinephrine and epinephrine; and induces lipid peroxidation and oxidation (for review, see Ref. [40]). Thus, it is clear that anti-inflammatory strategies leading to the downregulation or destruction of ONOO can effectively inhibit opioid analgesic tolerance. ONOOS and spinal neuronal apoptosis ONOO is a potent proapototic species and a role for spinal neuronal apoptosis in morphine antinociceptive tolerance is established [21,41]. Mitochondria are key sites of cellular death and constitute a primary locus for the intracellular formation and reactions of ONOO [42]. ONOO -mediated inactivation of mitochondrial MnSOD in the vicinity of a functional NOS that resides at the inner surface of the inner mitochondrial membrane favors an autocatalytic surge in ONOO formation; this results in positive feedback processes that promote mitochondrial dysfunction and the triggering of apoptotic signaling of cell death, including poly (ADP-ribose) polymerase (PARP) and caspase activation [7,43]. Previous reports have implicated apoptosis in antinociceptive tolerance and associated hypersensitivity. Indeed, chronic morphine exposure causes apoptosis in the spinal cord dorsal horn [21,41,44]. Caspase-3 inhibitors that block apoptosis prevent the development of morphine hyperalgesia and antinociceptive tolerance [21,41,44]. Thus, ONOO is generated in the mitochondrion in response to chronic opioid treatment, is associated with mitochondrial dysfunction leading to apoptotic pathways, and apoptosis is a key element in opioid tolerance. Targeting ONOOS or destruction to address opioid tolerance A strong pharmacological basis has now been provided for developing inhibitors of ONOO biosynthesis and/or
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ONOO scavengers as adjuncts to opioids for the prevention of analgesic tolerance. There are essentially three distinct strategies for the therapeutic attenuation of ONOO levels in response to chronic pain and tolerance. (i) The first indirect strategy is to prevent the formation of ONOO (from the rapid combination of O2 and NO) by cutting off O2 or NO at the sources. This process could be accomplished either through the downregulation of proinflammatory mediators that lead to elevated O2 levels or through direct inhibition of NOS isoforms. (ii) The second indirect strategy would be to scavenge O2 effectively enough to prevent its combination with NO. (iii) The only direct strategy would be to scavenge or decompose ONOO itself before harmful biological nitration and oxidation reactions can take place. Strategy 1: cyclooxygenase and NOS inhibition It is now well established that NSAIDs can synergize with opioids providing analgesia at dosages at which some adverse events are minimal. For example, combinations of NSAIDS and morphine have been used to manage terminal cancer patient pain in the clinic with maximized analgesia and somewhat lessened side effects [45]. Studies in animals have confirmed that neuronal cyclooxygenase (COX) activity contributes to the expression of opioid tolerance and that certain COX inhibitors can be used for the prevention, and even the reversal, of morphine tolerance [46]. It has also been established that NOS inhibitors can effectively attenuate opioid tolerance [36]. Given that COX-II activity is upregulated as a component of the neuroinflammatory conditions that lead to the generation of more O2 and that NOS activity and subsequent elevated NO levels have been shown to contribute to the development of opioid tolerance, it might be suggested that the resulting overproduction of ONOO is the true linchpin. Unfortunately, each of these two inhibitor strategies has its drawbacks. On the one hand, selective COX-II inhibitor use has been associated with side effects including increased risks of heart attack and stroke, which prompted the withdrawal of Vioxx (rofecoxib) from the market in 2004 and the removal of Bextra (valdecoxib) and a black-box warning label change for Celebrex (celecoxib) in 2005 [47]. On the other hand, potent NOS inhibition might indeed prevent ONOO formation but would also interfere with many crucial NO-mediated cellular signaling processes [40]. Stategy 2: organic antioxidant scavengers Endogenous and exogenous ONOO -decomposition agents and the current understanding of their mechanisms of stoichiometric or catalytic action have been the subject of several recent excellent reviews [48–51]. Herein we restrict our discussion to those compounds that have shown promise in further addressing the contribution of ONOO toxicity within the framework of opioid analgesic tolerance (Figure 2). Many of these antioxidants are capable of scavenging multiple free radical species (O2 and ONOO derived) but, owing to the rapid kinetics involved, the formation of ONOO and its subsequent decomposition pathways are likely to be the most relevant in biological systems. 197
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Figure 2. Stoichiometric scavengers of ONOO . Ascorbic acid (a), a highly water soluble antioxidant reacts slowly with ONOO but avidly with the chemical fallout of the peroxynitrosocarbonate pathway [53]. Mega doses have been reported to prevent morphine tolerance [52]. Ascorbic acid is also a key co-reductant for the detoxification of ONOO [67]. Trolox (b), a water soluble vitamin E analogue reduces ONOO effectively at pH = 7 (k105 M 1 s 1) [55]. Vitamin E analogues (c) such as g-tocopherol (R = H) have been shown to inhibit protein nitration under conditions of inflammation [54]. Melatonin (d) is a potent antioxidant species and a naturally occurring hormone that is found in most animals and in humans. Melatonin has been shown to inhibit tyrosine nitration under conditions of inflammation and to attenuate antinociceptive tolerance to d opioid receptor agonists [59]. Ebselen (e), a low-molecular-weight glutathione peroxidase mimic rapidly detoxifies ONOO (k106 M 1s 1). The resulting melatoninselenoxide can then be reduced back to ebselen in the presense of GSH and/or thioredoxin reductase and NADPH, converting this stoichiometric system to one that is catalytic [9]. Flavonoids comprise a large class of polyphenolic antioxidants that can effectively intercept CO3 and NO2 and, thus, protect against ONOO - and/or peroxynitrosocarbonate-derived toxicity. Quercetin (f) has been shown to attenuate morphine-induced tolerance [56]. Genistein (g) and epicatechin (h) are effective in preventing tyrosinenitration [57].
Many studies have been published regarding the use of organic, nutritional, vitamin and drug candidate antioxidants for the attenuation of morphine tolerance. In most cases, molecules from these classes act in a stoichiometric manner, being irreversibly modified by ONOO to afford by-products that may or may not display their own toxicities. Ascorbate has been reported to suppress tolerance and dependence to morphine in humans and rodents. Even though the rate for the reaction of ascorbate with ONOO is rather slow (k 102 M 1 s 1), fairly high intracellular concentrations can be achieved (1–2 mM) and mega-dosing studies have been reported to prevent morphine tolerance [52]. In addition, ascorbate has high reactivity with NO2 and CO3S formed preferentially from ONOO and CO2 under physiological conditions [53]. To our knowledge, there have been no reports of the use of vitamin E or derivatives thereof (tocopherols) in opioid analgesic-tolerance studies. However, there is a wealth of studies concerning the successful use of vitamin E derivatives in treating various neurodegenerative disorders known to be driven by nitroxidative stress [54]. In addition, the rate constant for the reaction of trolox (a water-soluble vitamin E derivative) with NO2 is very high [55]. Taken together, these results indicate that vitamin E derivatives 198
could be effective as adjuncts to opioids for the treatment of chronic pain. There are several reports of bioflavonoids such as quercetin attenuating the development of morphine tolerance in animals [56]. Bioflavonoids are potent antioxidants with excellent scavenging reactivity toward the peroxnitrite– CO2 manifold [57]. However, quercetin and kaempferol display antinociceptive activities on their own and have been shown to interact with the opioidergic systems and NOS systems directly in addition to their scavenging properties [58]. There are also reports of melatonin attenuating antinociceptive tolerance to d receptor agonists in addition to enhancing the anti- and proconvulsant effects of morphine [59]. Although some of these effects have been attributed to the melatonin MT2 receptor subtype, contributions from the antioxidant nature of melatonin cannot be excluded and are likely. Finally, to our knowledge there are no reports of organoselenium compounds, such as ebselen, that behave as glutathione peroxidase mimics [60] in opioid tolerance. There is, however, a host of studies regarding ebselen and other organoselenium, organotellurium and organosulfur antioxidants displaying potent neuroprotective
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Figure 3. The catalytic decomposition of ONOO by metal–porphyrin complexes (M = Mn or Fe). Isomerase activity (a) can be envisioned as the reaction of ONOO with Fe(III) to afford Fe(IV) = O and NO2, followed by solvent-cage recombination of NO2 and the metal-oxo group generating Fe(III) and NO3 [49]. Reductase activity (b) can involve biological reductants to regenerate the active catalyst.
effects in addition to being effective in the detoxification of ONOO [61–63]. Strategy 3: ONOO -decomposition catalysts Many new catalytic antioxidant strategies have now been developed and offer great therapeutic potential for the management of pain and opioid tolerance. From the early work profiling iron and manganese porphyrin complexes as ONOO -decomposition catalysts [48,64–67] to the development of these systems into highly active and more druggable entities [68], it has been shown that destruction of the highly damaging ONOO is of paramount importance in restoring and in some cases potentiating the efficacy of opioid analgesics. The mechanistic chemistry and general biological impact of ONOO -decomposition catalysts has been thoroughly reviewed [48–51]. Thus, we highlight the prototypical systems that have been investigated within the framework of opioid tolerance. Various groups have shown
over the past 15 years that certain redox-active transition metal–porphyrin complexes react rapidly with ONOO and can function as ONOO reductases or isomerases (Figure 3). Either of these functions can provide a useful mechanism for the detoxification of the ONOO manifold. Manganese(III) and iron(III) porphyrin complexes such as FeTM-4-PyP5+ are active cataysts (Figure 4). It has recently been shown in mice that the coadministration of morphine with the NOS inhibitor L-NAME (1–10 mg 1kg 1d 1) or with the metalloporphyrin complexes MnTBAP3 (1–10 mg 1 kg 1d 1) or FeTM-4-PyP5+ (3–30 mg 1 kg 1d 1) over a 4-day period inhibited the development of tolerance in a dose-dependent manner. Control animals given morphine alone developed substantial antinociceptive tolerance to an acute injection of morphine on the 5th day. Remarkably, cutting off NO production with the NOS inhibitor (L-NAME; N-nitro-Larginine methyl ester) or scavenging O2 and catalytically decomposing ONOO with MnTBAP3 and FeTM-4-PyP5+
Figure 4. Catalytic antioxidants. The structures of metal porphyrins commonly used as SOD mimic (MnTBAP3 ) and peroxynitrite decomposition (FeTM-4-PyP5+) catalysts and the Mn(II)-polyazamacrocyclic complex SC-72325 developed as an SOD mimic at Monsanto-Searle [38].
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Figure 5. Conclusions and future implications.
both accomplish the goal of blocking morphine tolerance. In these studies, FeTM-4-PyP5+ was shown to effectively prevent the nitration and inactivation of the GT GLT-1 and GS. The coadministration of FeTM-4-PyP5+ with morphine not only attenuated the post-translational nitration of MnSOD (tyrosine-34) but also restored the activity of the enzyme. FeTM-4-PyP5+ was also shown to block the increased formation of TNF-a, IL-1b and IL-6 in the spinal cords of these animals. In addition, it was also shown that FeTM-4-PyP5+ blocked oxidative DNA damage and PARP activation and, therefore, attenuated neuronal and/or glial cell apoptosis [9]. Manganese(III)–porphyrin and iron(III)– porphyrin complexes behave in vivo as both SOD mimics and ONOO -decomposition catalysts. However, certain manganese(II) polyazamacrocyclic complexes such as SC-72325 (Figure 5) have been reported to react exclusively with O2 [69]. Although there is much to be sorted out with regard to the real in vivo selectivity of this class of molecules toward nitroxidative stress, it is clear that complexes such as SC-72325 have good in vitro SOD activities and have been shown to effectively prevent morphine analgesic tolerance [38]. Thus, we can conclude that inhibition of NOS, effective compartmental scavenging of O2 and decomposition of ONOO all lead to the prevention of morphine tolerance. Concluding remarks The formation and toxicity of ONOO in the spinal cord under neuroinflammatory conditions contributes to the nitration and inactivation of NMDA receptors and the GTs and GS. Nitration and inactivation of MnSOD by ONOO promotes an amplification of ONOO levels through a sustained unchecked O2 production and its subsequent reaction with NO, which itself is upregulated 200
under prolonged neuroexcitatory conditions. ONOO is also a proapoptotic species, and neuronal apoptosis is a component of nociceptive tolerance. Several studies have now been published that demonstrate that ONOO scavengers or decomposition catalysts can prevent or even reverse opioid analgesic tolerance. Taken together, these results not only point to ONOO as a crucial mediator of opioid antinociceptive tolerance but also validate the strategy of targeting ONOO as an adjunctive approach for reviving failing opioid therapies. Although not discussed here, ONOO -mediated nitroxidative stress has also been implicated in hyperalgesia associated with the development of acute and chronic inflammation and in response to NMDA receptor activation [70–73]. Hence, ONOO -decomposition catalysts are powerful inhibitors of inflammatory pain but the antihyperalgesic actions of these agents does not involve an interaction with the endogenous opiate system because the effects are naloxone insensitive [70,73]. Importantly, ONOO -decomposition catalysts synergize not only with the analgesic effects of opiates but also with those of nonselective COX inhibitors such as ibuprofen and those of selective COX-2 inhibitors such as NS-398 [73]. An imbalance between oxidant/antioxidant activity has also been observed in other models of inflammatory nociception. For example, increased levels of hydrogen peroxide (the dismutated product of O2 ) [74] and decreased levels of SOD activity in the spinal trigeminal nucleus coincided with facial hyperalgesia induced by a formalin injection into the lip [75]. Superoxide is also increased in dorsal horn neurons during neuropathic pain induced by spinal nerve ligation [76] and neurogenicinduced hyperalgesia induced by capsaicin [77]. Using nonselective antioxidants such as phenyl N-tert-butylnitrone (PBN) and 4-hydroxy-2,2,6,6-tetramethylpiperidine
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