Cell Mol Neurobiol (2008) 28:629–641 DOI 10.1007/s10571-007-9164-y ORIGINAL PAPER
Agmatine and Imidazoline Receptors: Their Role in Opioid Analgesia, Tolerance and Dependence Ning Wu Æ Rui-Bin Su Æ Jin Li
Received: 29 March 2007 / Accepted: 15 June 2007 / Published online: 25 July 2007 Ó Springer Science+Business Media, LLC 2007
Abstract Agmatine is an endogenous amine that is synthesized following the decarboxylation of L-arginine by arginine decarboxylase. Agmatine exists in mammalian brain and has been proposed as a neurotransmitter and/or neurotransmodulator. Agmatine binds to several targets and is considered as an endogenous ligand for imidazoline receptors. This review, mainly based on our research work in the past decade, focused on the modulations by agmatine action on imidazoline receptors to opioid analgesia, tolerance and dependence, and its possible neurochemical mechanisms. We went on to propose that agmatine and imidazoline receptors constitute a novel system of modulating opioid functions.
Keywords Agmatine Imidazoline receptors Opioid Analgesia Tolerance and dependence
Introduction Opioids, such as morphine, are widely used in pain relief, but the tolerance and dependence produced by prolonged or repeated administration greatly limit their clinical use. On the other hand, opioids, as a most important kind of abuse drug, have caused a series of severe problems in many aspects worldwide. The biological basis of tolerance and dependence induced by chronic exposure to opioids is considered as molecular, cellular, and neural network adaptations. These adaptations not only occur in the opioid system itself, but also in some non-opioid systems, such as dopamine system, glutamate system, c-amino butyric acid system, acetylcholine system, corticotrophin-releasing factor system. Recently, a growing body of research focuses on the adaptations of non-opioid systems during opioid tolerance and dependence. It has been
N. Wu R.-B. Su J. Li (&) Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, P.R. China e-mail:
[email protected];
[email protected]
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revealed that some agents, which are not able to interact with opioid receptors, play an important role in regulating the pharmacological actions of opioids. Especially, some of them show biphasic modulation on opioid functions, which enhance opioid analgesia (positive action) but inhibit tolerance to and dependence on opioids (negative actions). We attempt to define these agents which do not interact with opioid receptors, but do have biphasic modulation on opioid functions as ‘‘biphasic opioid function modulator’’ (Su et al. 2003a). Based on these recent advances, some novel pharmacotherapeutic strategies for the treatment of drug addiction have been developed and a few drugs acting on non-opioid receptors has been in the stage of clinical trials (Heidbreder and Hagan 2005). Agmatine is an endogenous amine that is synthesized following decarboxylation of Larginine by arginine decarboxylase (ADC) and degraded by agmatinase and diamine oxidase to putrescine and guanido butanoic acid (Figs. 1 and 2). In 1994, agmatine was identified in the mammalian brains (Li et al. 1994). It has been demonstrated that agmatine meets many criteria for a neurotransmitter and/or neurotransmodulator (Reis and Regunathan 2000). Agmatine is stored in the perikarya of a specific population of central neurons, and is found in small vesicles of axon terminals, and is presumably co-stored and released with traditional neurotransmitters/modulators, including Lglutamate and arginine vasopressin. Agmatine can be biologically inactivated by uptake into synaptosomes and degraded by agmatinase and diamine oxidase. Agmatine is considered as one of the endogenous ligands for imidazoline receptors. Besides imidazoline receptors, agmatine also binds to other target receptors such as a2 adrenergic, N-methyl-D-aspartate (NMDA) and serotonin receptors with lower affinity to produce physical functions. It was first reported by Kolesnikov et al. that agmatine enhanced morphine analgesia and inhibited morphine tolerance in mice (Kolesnikov et al. 1996). In the past decade, more and more accumulated studies reported by our laboratory and others have pointed out that agmatine remarkably modulate opioid analgesia, tolerance, and dependence, which is a good example for biphasic opioid
NH2
H N
NH2
HOOC NH Fig. 1 The structure of agmatine
L-Arginine Arginine decarboxylase
Agmatine Agmatinase
Putrescine Fig. 2 The synthesis and degradation of agmatine
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Guanido butanoic acid
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function modulator. The present review, mainly based on our researches in the past decade, focused on the modulations by agmatine action on imidazoline receptors to opioid functions and its possible mechanisms.
Role of Exogenous Agmatine in Opioid Analgesia, Tolerance and Dependence Analgesic Activity In some animal models of acute and chronic pain, we found agmatine produced notable analgesia. In mouse acetic acid writhing test and rat 4% saline writhing test, agmatine subcutaneous injection showed obvious analgesic activity with 10.1 and 14.1 mg/kg for ED50 values, respectively (Li et al. 1999a). However, agmatine failed to produce analgesia in severe nociceptive experimental models, such as hot radiation tail flicking test, the dosage ranging from 0.1 to 62.5 mg/kg. It suggests that agmatine has mild analgesia in acute pain. In chronic pain models, such as inflammatory pain and neuropathic pain, agmatine displays dose-dependent antinociceptive actions as well (Horvath et al. 1999; Fairbanks et al. 2000; Qin et al. 2005; Wang et al. 2005). The analgesia of agmatine could entirely block by idazoxan, an imidazoline/a2 adrenergic receptors-mixed antagonist, but not by yohimbine, a selective a2 adrenergic receptor antagonist. These indicate that imidazoline receptors mediate agmatine’s analgesia. Potentiation to Opioid Analgesia Though agmatine has no analgesia in severe nociceptive experimental models, it could enhance morphine analgesia in these models. It was observed that agmatine potentiated analgesia of morphine in mouse and rat tail flicking tests, as well as in monkey potassium penetrating test (Li et al. 1999a). Agmatine (12.5 mg/kg, sc) decreased ED50 value of morphine from 7.18 to 1.55 mg/kg in mouse tail flicking test. Agmatine was also able to produce the effect as mentioned above in spinal and superspinal administration, but the potencies varied. Intrathecal injection of agmatine decreased analgesic ED50 of morphine by over 94% (from 681 to 46 ng/mouse), while icv injection of agmatine decreased ED50 of morphine analgesia only by 75% (from 201 to 51 ng/mouse) (Lu et al. 2003a). These results indicate that the main site where agmatine enhances the analgesia of morphine is at spinal cord. Although agmatine enhances morphine analgesia, it dose not prolong the analgesic duration (Li et al. 1999a). The potentiation of agmatine to morphine analgesia was further observed in chronic neuropathic pain and inflammatory pain (Horvath et al. 1999; Qin et al. 2005; Wang et al. 2005). By using different antagonists, it was found that the potentiation of agmatine to opioid analgesia might be associated with imidazoline receptors (Li et al. 1999a). Subsequently, Roerig et al. also reported that agmatine acted at both a2 adrenergic receptors and imidazoline receptors in spinal cord and imidazoline receptors in brain to enhance morphine antinociception (Roerig et al. 2003). Attenuation to Opioid Tolerance In contrast to the potentiation of opioid analgesia, agmatine attenuates opioid tolerance. After an initial report by Kolesnikov et al. in 1996, our studies confirmed the attenuation of agmatine to opioid tolerance.
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Electrical field stimulation induced twitch contractions of guinea pig ileum in vitro. Morphine concentration-dependently inhibited the contractions with 156 nM of IC50 value. Pretreatment of guinea pig ileum with morphine 270 nM for 8 h induced a tolerance indicated by a 38-fold increase in IC50 value (from 156 to 5864 nM) of morphine. Co-incubation of the preparation with agmatine and morphine prevented the development of tolerance to morphine indicated by a restore of guinea pig ileum sensitivity to the inhibitory effect of morphine (Li et al. 1998a). These results proved that agmatine prevented tolerance to opioids in vitro. In mice and rats, agmatine prevents the development of acute and chronic analgesic tolerance to morphine, and the main site is the brain rather than the spinal cord (Li et al. 1999a; Lu et al. 2003b). Besides preventing the development of tolerance, agmatine reverses tolerance to morphine after the tolerance has been established (Li et al. 1999b). Like potentiation to morphine analgesia, the attenuation of agmatine to tolerance in vivo and in vitro is mediated by action on imidazoline receptors (Li et al. 1998a, 1999b). It has been proved that opioid receptors desensitization caused by chronic exposure to opioids is one of important mechanisms of tolerance. Agmatine action on imidazoline receptors could inhibit the desensitization in NG108-15 cells, which might contribute to the attenuation of agmatine to opioid tolerance (Li et al. 1998b, 1999c). Attenuation to Opioid Dependence and Relapse Agmatine has been shown to attenuate opioid physical and psychological dependence. After pretreatment with morphine (270 nM) for 8 h, guinea pig ileum displayed a precipitated contractive response to naloxone, indicating the development of dependence in vitro. Agmatine co-incubation with morphine inhibited the naloxone-induced contraction in morphine-dependent guinea pig ileum. This effect of agmatine was completely abolished by idazoxan, suggesting agmatine action on imidazoline receptors inhibits the development of morphine dependence in vitro (Li et al. 1998a). Our result was confirmed by Aricioglu et al. (2003). In vivo, agmatine chronic pretreatment with morphine prevented the development of morphine-induced physical dependence in mice and rats (Li et al. 1999b). Additionally, acute injection of agmatine in a few hours for two or three times showed an inhibitory effect on abstinent syndrome precipitated by naloxone in morphine-dependent mice and rats (Li et al. 1999b; Aricioglu-Kartal and Uzbay 1997). These indicate that agmatine not only inhibits the development of opioid physical dependence, but also the expression of physical dependence or withdrawal. And these effects of agmatine might be related to activating imidazoline receptors. Similarly, the attenuations of agmatine to morphine physical dependence and withdrawal were observed in dogs and monkeys (our unpublished data). Agmatine inhibiting opioid physical dependence and withdrawal is related to the reduction of nitric oxide synthase activity and cAMP signal pathway supersensitization (Li et al. 1999c, d). Likewise, Aricioglu et al. subsequently reported that neuronal nitric oxide synthase partly mediated the effects of agmatine on morphine physical dependence (Aricioglu et al. 2004). Besides, opioid-induced physical dependence and withdrawal, agmatine attenuates psychological dependence and relapse as well. In the rat conditioned place preference (CPP) model, agmatine not only inhibited the acquisition and expression of morphineinduced CPP, but also abolished its reinstatement (Wei et al. 2005). In rat locomotion sensitization model, agmatine inhibited morphine-induced locomotion sensitization, and this effect was completely reversed by imidazoline receptors antagonist (our unpublished
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data). Drug self-administration is a favorable model to evaluate drug addiction. Morgan et al. reported that agmatine attenuated the escalation of fentanyl, but not cocaine, selfadministration if administered before the escalation begins (Morgan et al. 2002). More recently, our unpublished study found that agmatine, when given throughout selfadministration, significantly decreased dosage of morphine intake, while it did not affect sugar-induced natural reward. Furthermore, after self-administration establishment, agmatine treatment of two weeks reduced the reinstatement of self-administration. The same results were observed in the morphine-induced drug discrimination model. These demonstrate that agmatine has therapeutic effect on opioid relapse in animal models. Since relapse is a phenomenon pivotal for the understanding and treatment of drug addiction, our finding demonstrates that agmatine has a good prospect in therapeutic agents for opioid addiction.
Role of Endogenous Agmatine in Opioid Analgesia, Tolerance and Dependence While exogenous agmatine is definitely effective in modulating opioid analgesia, tolerance, and dependence, does endogenous agmatine have similar functions? It is important to note that most of the brain regions that are involved in drug addiction, such as ventral tegmental area, nucleus accumbens, amygdala, and locus coeruleus, contain agmatine immunoreactive neurons (Reis and Regunathan 2000). It has been shown that agmatine levels and its synthetase ADC activity decreased in morphine-dependent rat brain and other tissues (Aricioglu-Kartal and Regunathan 2002). This provides some evidence for the role of endogenous agmatine in opioid addiction. However, the ultimate proof will be to show that increasing endogenous agmatine levels has the same effects of exogenous agmatine on opioid functions, and vice versa. Effects of Increasing Endogenous Agmatine Levels on Opioid Pharmacological Actions Increasing biosynthesis of endogenous agmatine and blocking its degradation are the approaches to increasing endogenous agmatine levels. L-Arginine is the biosynthetic substrate of endogenous agmatine and the biosynthesis of agmatine by ADC is dependent upon the availability of L-arginine. We found that icv injection of L-arginine (10–40 lg/mouse) to increase endogenous agmatine levels in brain produced mild analgesia and enhanced morphine analgesia and prevented tolerance, which is similar to administration of exogenous agmatine (Su et al. 2003b, 2005). While increasing peripheral endogenous agmatine levels by sc injection of L-arginine had no such effect (Su et al. 2005). L-arginine is the collective substrate of agmatine, ornithine and nitric oxide, catalyzed by ADC, arginase and nitric oxide synthase, respectively (Reis and Regunathan 2000). Inhibition of one of the metabolic pathways of L-arginine might increase activity in the other metabolic pathways. a-Difluoromethyl-ornithine (DFMO) is an inhibitor of Lornithine decarboxylase (Selamnia et al. 1998) and a stimulator of ADC (Hernandez and Schwarcz de Tarlovsky 1999), so using DFMO would increase endogenous agmatine levels. Agmatine is degraded to putrescine and guanido butanoic acid by agmatinase and diamine oxidase (Reis and Regunathan 2000), and blocking agmatine degradation results in accumulation of endogenous agmatine. Although agmatinase is
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the major enzyme for agmatine degradation in the brain, no selective agmatinase inhibitors are presently available. We used diamine oxidase inhibitor aminoguanidine (AMG) to block one of the agmatine degradation pathways, which could increase endogenous agmatine levels (Holt and Baker 1995). In our report, both DFMO and AMG, increasing endogenous agmatine levels, was similar to exogenous agmatine in producing mild analgesia, enhancing morphine analgesia, and inhibiting tolerance (Lu et al. 2003a). Thus, it has been proved that increasing endogenous agmatine levels by different means has the same actions as exogenous agmatine on opioid functions. Effects of Decreasing Endogenous Agmatine Levels on Opioid Pharmacological Actions Blocking agmatine’s synthetase ADC can directly decrease endogenous agmatine levels. Although there is no selective inhibitor of mammalian ADC available, other means of decreasing ADC activity are feasible. We used specific ADC antibody to decrease endogenous agmatine levels in the brain. The study showed that ADC antibody (1:1000– 1:10 dilution, icv) significantly reduced morphine analgesia and exacerbated tolerance (Su et al. 2003b), which is contrary to exogenous agmatine. Recently, Regunathan reported that they have produced small interfering ribonucleic acid (siRNA) capable of reducing ADC mRNA levels and agmatine production in cultured neurons and glial cells (Regunathan 2006). But there is no report about the effect of the siRNA for ADC on opioid functions. Another approach is blocking the action of endogenous agmatine by agmatine antibodies. We have obtained an agmatine antibody with high potency and specificity, and further study is underway. Effects of Blocking Imidazoline Receptors on Opioid Pharmacological Actions As mentioned above, endogenous agmatine, as well as exogenous agmatine, clearly modulates opioid functions. Since agmatine is an endogenous ligand of imidazoline receptors, dose endogenous agmatine affect opioid functions through imidazoline receptors? If so, blocking imidazoline receptors by its antagonist would produce the contrary effects to exogenous agmatine. We found idazoxan (3–9 mg/kg), an antagonist of imidazoline receptors, reduced pain threshold and morphine analgesia, exacerbated morphine tolerance, and induced withdrawal syndromes in morphine-dependent mice (Su et al. 2000). However, Boronat et al. reported a contrary observation that idazoxan prevented morphine tolerance, which might be due to the higher dose of idazoxan they used which blocked a2 adrenergic receptors (Boronat et al. 1998). In addition, the effects of increasing endogenous agmatine levels on opioid analgesia and tolerance were antagonized by idazoxan (Lu et al. 2003a; Su et al. 2005). These suggest that endogenous agmatine, as well as exogenous agmatine, might activate imidazoline receptors to modulate opioid analgesia, tolerance and dependence.
Imidazoline Receptors as the Molecular Target of Agmatine Modulating Opioid Functions Imidazoline receptors, also known as imidazoline binding sites or imidazoline recognizing sites, exist in three subtypes, I1, I2 and an atypical I3 (non-I1/I2) subtypes. I1 imidazoline receptor is characterized by a high affinity to a group of agents including
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clonidine, rilmenidine, and moxonidine, which is located in plasma membranes (Ernsberger et al. 1995; Eglen et al. 1998). I2 imidazoline receptor shows high affinity to other imidazolines or guanidine, which is located in mitochondrial outer membranes and presents a novel recognition site on monoamine oxidase (Ernsberger et al. 1995; Eglen et al. 1998). There is some evidence that I3 (non-I1/I2) subtype is mainly distributed in pancreatic island b cells and regulates insulin secretion. I1 subtype is regionally distributed in some brain structures, such as rostral ventrolateral medulla oblongata, bed nucleus of stria terminalis, nucleus of the solitary tract, central gray, nucleus paraventricularis thalami, hippocampus, amygdala nucleus and striatum, while I2 subtype is widely distributed in brain (Ruggiero et al. 1998). According to our studies on exogenous and endogenous agmatine as mentioned above, it was hypothesized that agmatine and imidazoline receptors might be a novel system for modulating opioid functions. The known pharmacological actions of imidazoline receptors, such as blood pressure depression, are mainly mediated by I1 subtype. Although some reports showed that several I2 imidazoline receptor agonists, such as 2-BFI etc., enhanced morphine analgesia and attenuated tolerance, agmatine has lower affinity to I2 imidazoline receptor than these I2 subtype agonists. Meanwhile, the results derived from animal models of a2 adrenergic receptors knockout mice were contradictory to the hypothesis that ‘‘I2 imidazoline receptor mediates the modulation by agmatine to opioid analgesia and tolerance.’’ Thus, we think I1 subtype of imidazoline receptors, rather than I2 subtype, mainly mediates agmatine modulating opioid functions. Though our findings using imidazoline receptor antagonists suggest the modulation by agmatine to opioid functions might be related to activation of imidazoline receptors, there is no direct evidence for it. In fact, it has been difficult to directly demonstrate the relationship between imidazoline receptors, especially I1 subtype, and opioid analgesia, tolerance and dependence. The reason is that agents binding to I1 imidazoline receptor also bind to a2 adrenergic receptors, and selective antagonists for I1 imidazoline receptor are still not commercially available. Furthermore, there are no suitable cell types or animal models that express I1 imidazoline receptor and opioid receptors in the absence of a2 adrenergic receptors. Fortunately, the cloning of I1 imidazoline receptor makes it possible to directly demonstrate the role of I1 imidazoline receptor in agmatine modulating opioid functions. The Identity between Cloned IRAS and Native I1 Imidazoline Receptor In 2000, a gene encoding an I1 imidazoline receptor candidate protein, named imidazoline receptor antisera-selected protein (IRAS), was cloned from human hippocampus (Piletz et al. 2000). Several lines of evidences support the identity of native I1 imidazoline receptor and cloned IRAS in tissue distributions, ligand binding properties and cellular functions. Firstly, IRAS mRNA was shown to be appropriately localized in brain neurons as expected for I1 imidazoline receptor-binding sites (Ivanov et al. 1998), and a positive correlation was established between the mRNA for IRAS and membranous I1-binding sites (Bmax) over a range of native rat tissues (Piletz et al. 1999). Secondly, transfection of IRAS cDNA into CHO cells resulted in high affinity I1like binding sites without the appearance of a2 adrenergic receptors or the other major subtype of imidazoline binding sites (Piletz et al. 2000, 2003). Thirdly, it has been revealed that IRAS could promote cell survival, anti-apoptosis, and proliferation (Dontenwill et al. 2003a, b; Sano et al. 2002), which is similar to the intracellular
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functions of I1 imidazoline receptor (Dupuy et al. 2004). Most importantly, our recent study showed that the signal transduction pathway coupled to IRAS was similar to that coupled to I1 imidazoline receptor (Li et al. 2006), which is crucial to the identity of cloned IRAS and native I1 imidazoline receptor. The phospholipid metabolism-signaling pathway of I1 imidazoline receptor has been identified in rat PC12 cells and some other tissues expressing native I1 imidazoline receptor. Activation of I1 imidazoline receptor results in the activation of phosphatidylcholine-selective phospholipase C (PC-PLC) and the accumulation of diacylglycerol (DAG) (Liedtke and Ernsberger 1995; Separovic et al. 1996, 1997). DAG may activate protein kinase C (PKC) which phosphorylates and activates mitogen-activated protein kinases (MAPK) cascade pathway (Edward et al. 2001; Zhang et al. 2001). However, it is not clear whether I1 imidazoline receptor acts via the most common G-protein linked systems (Moldering et al. 1993; Ernsberger and Shen 1997; Takada et al. 1997; Piletz and Sletten 1993; Bricca et al. 1994). The paradox is probably due to the influence of other receptors that cannot be ruled out in the experimental model, especially a2 adrenergic receptors. Considering this influencing factor, we established CHO cells stably expressing IRAS (CHO-IRAS), which ruled out the interference of a2 adrenergic receptors (Zhao et al. 2004). In CHO-IRAS cells, we found IRAS did not couple to G protein by [35S]-GTPcS binding assay, which agrees with the prediction from sequence analysis of IRAS cDNA (Li et al. 2006). This suggests that I1 imidazoline receptor may not be a G-protein coupled receptor. Meanwhile, we found that IRAS activation by imidazolines causes PC-PLC activation and DAG accumulation, apparently leading to extracellular signal regulated kinase (ERK) phosphorylation (Li et al. 2006). The IRAS coupling to PC-PLC phospholipid metabolism pathway is similar to those reported for wild type I1 imidazoline receptor, which provides the pivotal evidence for the identity of cloned IRAS and wild type I1 imidazoline receptor. Thus, the cloned IRAS has characteristics of I1 imidazoline receptor. I1 Imidazoline Receptor Mediating the Modulation by Agmatine to Opioid Dependence Since agmatine binds to several targets which are closely associated with opioid tolerance and dependence, including imidazoline receptors, a2 adrenergic receptors, NMDA receptor and nitric oxide synthase, it is difficult to find out whether imidazoline receptors, especially I1 subtype, is the certain target of agmatine modulating opioid functions in vivo. Since it has been proved that cloned IRAS is functional I1 imidazoline receptor, it is reasonable to demonstrate the role of I1 imidazoline receptor in opioid dependence through IRAS. We first established a suitable cell model of CHO cells stable co-expressing l opioid receptor and IRAS (CHO-l/IRAS), in which no endogenous a2 adrenergic receptors, I2 imidazoline receptor, NMDA receptor and nitric oxide synthase exist (Wu et al. 2004). Up-regulation of activity of adenylyl cyclase following prolonged or repeated opioid treatment is considered as an important cellular mechanism underlying opioid dependence. Hence, naloxone-precipitated cAMP overshoot, also named cAMP supersensitization, after chronic opioid treatment of cells is an in vitro model of the abstinence state. Agmatine with low concentrations (0.01–2.5 lM) was observed to be able to reduce naloxone-induced cAMP overshoot in chronic morphine-pretreated CHO-l/IRAS cells. While in IRAS-negative CHO cells expressing l opioid receptor alone, the inhibition of agmatine was not observed. Since naloxone-precipitated cAMP
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overshoot is an acceptable criterion reflecting opioid dependence and withdrawal in vitro, these suggests that I1 imidazoline receptor mediates the inhibition of agmatine to opioid dependence (Wu et al. 2005). Additionally, high concentration of agmatine (5–100 lM) reduced naloxone-precipitated cAMP overshoot in morphine-dependent cells by both activating I1 imidazoline receptor and blocking endogenous L-type calcium channels in CHO cells (Wu et al. 2005, Weng et al. 2003, Zheng et al. 2004). Calcium signal is another important signal pathway undergoing compensatory adaptations during opioid dependence. Owing to further confirm the role of I1 imidazoline receptor in inhibition of agmatine to opioid dependence, we observed the effects of agmatine action on IRAS on calcium signal up-regulation. It has been proved that IRAS is essential to agmatine when attenuating naloxone-precipitated elevation of intracellular calcium concentration in morphine-dependent cells (Wu et al. 2006). These studies provide the direct evidence for I1 imidazoline receptor as the target of agmatine modulating opioid functions. Furthermore, besides modulating the compensatory adaptations of cAMP and calcium second messenger pathways separately, agmatine activating I1 imidazoline receptor also modulated the integration points for the two signals in morphine dependence, such as ERK and cAMP-responsive element binding protein (CREB) phosphorylations and c-Fos expression. By regulating transcription factor CREB and immediate early gene product c-Fos, agmatine-IRAS system might result in the alternations of gene expression in response to opioid (Wu et al. 2006). These might be the molecular mechanisms of agmatine action on I1 imidazoline receptor modulating opioid dependence. According to the modulations by exogenous and endogenous agmatine on opioid analgesia, tolerance, and dependence mentioned above and the role of I1 imidazoline receptor in agmatine modulating opioid dependence, we suggest that agmatine and imidazoline receptors, especially I1 subtype, constitute a novel opioid functions modulating system. Possible Neurochemical Mechanisms of Agmatine and Imidazoline Receptor System Modulating Opioid Dependence Opioid addiction is a chronic, relapsing disease of the brain. Continuous administration of opioids induces adaptive changes of the intricate neural network in the central nervous system, which is responsible for tolerance, physical dependence, sensitization, craving, and relapse. Among them, the adaptations of dopamine and glutamate systems are crucial to opioid dependence, withdrawal, and relapse. Now that agmatine is a novel neurotransmitter or neurotransmodulator, dose agmatine action on imidazoline receptors modulate other neurotransmissions? And what are the possible neurochemical mechanisms of agmatine-imidazoline receptor system modulating opioid dependence? Agmatine-imidazoline Receptor System Modulating the Adaptations of Dopamine Transmission in Morphine Dependence Mesolimbic dopamine rewarding system plays a leading role in opioid addiction and relapse. Our previous study showed that agmatine action on imidazoline receptors reduced the increases of dopamine, noradrenaline release in striatal, thalamus and hippocampus slices in morphine-dependent rats, suggesting that agmatine-imidazoline receptor system might modulate the function of dopamine system in opioid dependence
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(Li et al. 1999e). Our recent study demonstrated agmatine and imidazoline receptor system reduces the increase in dopamine release in morphine-induced locomotion sensitization rats by in vivo microdialysis with high-performance liquid chromatography techniques. Locomotion sensitization is a commonly used animal model to study neural mechanisms underlying drug craving and relapse. The repeated, intermittent administration of opioids or psychostimulants produces persistent increases in locomotion and incentive motivation (Vanderschuren and Kalivas 2000), manifested by increased locomotor activity and other behavioral responses upon re-exposure to opioids or psychostimulants (Kornetsky 2004). There is an increasing evidence that the mesolimbic dopamine system plays an essential role in the mediation of locomotion sensitization to morphine (Vanderschuren and Kalivas 2000). Agmatine reduced an increase in striatal dopamine levels response to morphine challenge in locomotion sensitization rats after withdrawal, which was parallel to the inhibition of agmatine activation of imidazoline receptors to morphine-induced locomotion sensitization in behavior (our unpublished data). Furthermore, the mechanism of agmatine action on imidazoline receptors inhibiting the increase in striatal dopamine levels might be due to the enhancement of negative feedback modulation by dynorphin to dopamine release, rather than due to decrease in dopamine synthesis or increase in metabolism (our unpublished data). Agmatine-Imidazoline Receptor System Modulating the Adaptations of Glutamate Transmission in Morphine Dependence Besides dopamine transmission, glutamate transmission also plays a crucial role in regulating the physiological and behavioral actions of drug addiction. Opioid dependence is an experience-dependent process, in which learning and memory plays an important role. The glutamate system of the brain is responsible for the long-term plasticity associated with learning and memory. It is, therefore, not surprising that glutamate transmission also underlies addiction-related behavior. Indeed, the dysfunctions of glutamate transmission occur in the whole processes of opioid dependence, withdrawal, and relapse. Our unpublished study showed that agmatine, either administrated with morphine during the development of dependence or with naloxone during the withdrawal, reduced naloxone precipitation-induced increases in glutamate levels in hippocampus and nucleus accumbens of morphine dependent rats. And this effect was parallel to the inhibition of agmatine activating imidazoline receptors to morphine dependence and withdrawal. Furthermore, agmatine inhibiting the increases in glutamate levels of withdrawal might be associated with both decreasing the release and increasing the re-uptake of glutamate in hippocampus, and increasing the re-uptake of glutamate in nucleus accumbens, respectively. Besides the modulation to glutamate levels, we also observed the modulation by agmatine to NMDA receptors expression in morphine-dependent rats. It has been showed that agmatine modulated NMDA receptors expression in different manners in hippocampus and nucleus accumbens (Wang et al. 2006). In hippocampus, agmatine mainly changed the constitution of NMDA receptors with different NR2 subunits rather than the density of NMDA receptors in morphine dependence, which affects NMDA receptors function. While in nucleus accumbens, agmatine reduced an increase in NMDA receptors density. These suggest that the agmatine-imidazoline receptor system modulates glutamate system functions in various manners in morphine dependence. Thus, agmatine action on imidazoline receptors modulates dysfunctions of dopamine and glutamate neurotransmissions in opioid dependence, which might be the
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neurochemical mechanisms of agmatine and imidazoline receptor system inhibiting opioid dependence and relapse.
Conclusion Agmatine, as an endogenous ligand for imidazoline receptors, has the ability to enhance analgesia of morphine while reducing morphine tolerance, dependence and relapse. These effects mainly target on imidazoline receptors, especially I1 subtype. We think agmatine and imidazoline receptor is a novel system of modulating opioid functions. Without any adverse effects on behavior, locomotion, or cardiovascular functions, agmatine itself will be a valuable therapeutic agent for pain, opioid dependence and relapse. And imidazoline receptors might be a novel target for treatment of opioid addiction. Acknowledgement This work was supported by National Basic Research Program of China (2003CB515400). We thank Prof. Xian-Sheng Lu for correcting the writing of the manuscript.
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