Glutamate receptors have been divided into two broad categories: iontotropic and metabotropic. Iontotropic glutamate receptors contain cation-specific ion channels as a component of their protein complex, whereas metabotropic glutamate receptors are coupled to G-proteins and modulate intracel-lular second-messenger systems. Iontotropic receptors are divided into three main subtypes: N-methyl-d-aspartate (NMDA), d-2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), and kainate. Eight different clones for metabotropic glutamate (mGlu) receptors have been isolated (mGlul-8). Based on agonist interactions, sequence homology, and second-messenger coupling, the eight mGlu receptors have been grouped into three large families (34). Group I mGlu receptors include mGlul and mGlu5, group II mGlu receptors include mGlu2 and mGlu3, and group III mGlu receptors include mGlu4, 6, 7, and 8. mGlu receptors can differentially modulate synaptic function through both presynaptic and postsynaptic sites (35). Group I mGlu receptors are primarily located postsynaptically and typically regulate neuronal excitability. Group II and III mGlu receptors are primarily located presynaptically and affect the release of glutamate and other neurotransmitters (36-39).
A role for glutamate receptors in opiate withdrawal was demonstrated through the use of kynurenic acid. A naturally occurring metabolite of tryptophan, kynurenic acid is a nonselective excitatory amino acid antagonist that does not readily cross the blood-brain barrier. Intraventricular administration of kynurenic acid dose-dependently attenuated the behavioral signs of naltrexone-precipitated withdrawal in morphine-dependent rats (40). Intraventricular administration does not allow precise localization of the excitatory amino acid receptors involved in the attenuation of the morphine-withdrawal symptoms. However, glutamate receptors in the LC are implicated as morphine-withdrawal-induced activation of the LC was also blocked by intraventricular kynurenic acid administration (18,40,41). The role of glutamate in the opiate-withdrawal-induced activation of the LC was also supported by microdialysis experiments showing increases of glutamate and aspartate release in the LC during morphine withdrawal (42,43), butorphanol withdrawal (44), and U-69,593 (a selective K-opioid agonist) withdrawal (45).
As mentioned above, other brain areas beside the LC play a role in opiate withdrawal. Indeed, in the studies with kynurenic acid, the block of the morphine-withdrawal-induced activation of the LC was nearly complete, whereas the suppression of withdrawal symptoms was only partial (40). Although anesthesia could account for some of this difference, another possibility is the participation of glutamate receptors in other brain areas in the genesis of morphine-withdrawal symptoms. One such area may be the nucleus accumbens. The nucleus accumbens has been hypothesized to play an important role in the effects of drugs of abuse, including a prominent role in opioid addiction and withdrawal (46). In particular, the nucleus accumbens has been hypothesized to play an important role in the aversive stimulus properties of opiate withdrawal (47,48). While decreased dopamine and serotonin release have been hypothesized to play a role in the effects of the nucleus accumbens during opiate withdrawal (49,50), glutamate may also play a role as glutamate and aspartate release increase by 300% during morphine withdrawal (51).
Another brain region that displays increased release of glutamate during opiate withdrawal is the spinal cord. In animals that received repeated spinal infusions of morphine, naloxone administration evoked a 300% increase of glutamate release (52). In addition, mRNA for the glutamate transporter GLT-1 has been shown to significantly increase in the striatum during morphine withdrawal, an effect most likely explained by enhanced glutamate release (53). However, not all brain areas will have an increased release of glutamate during morphine withdrawal. For example, in the ventral tegmental area, there may be a decreased release of glutamate during morphine withdrawal (54).
The role of different subtypes of glutamate receptors in morphine withdrawal has been examined with the use of selective pharmacological tools (55,56). Coadministration of competitive (e.g., MK-801) and noncompetitive (e.g., LY274614) NMDA antagonists can attenuate the development of morphine tolerance (57-60). In addition, administration of NMDA antagonists blocked the behavioral signs of withdrawal in morphine-dependent rats (61-63). However, the same doses of MK801 that blocked morphine withdrawal also simultaneously produced phencyclidine (PCP)-like behavioral effects (i.e., head-weaving, falls, and increased locomotor activity). The competitive NMDA antagonist LY274614 blocked the behavioral signs of withdrawal in morphine-dependent rats but did not produce any PCP-like behavioral effects (although sedation occurred at the higher doses tested). It is important to note that not all withdrawal symptoms were blocked by the NMDA antagonists. For example, both MK-801 and LY274614 produced reductions in the occurrence of teeth chatter, erections, ptosis, chews, diarrhea, and weight loss, whereas neither affected lacrimation or salivation. Thus, although NMDA receptors may play a role in the occurrence of many withdrawal signs, they are unlikely to play a role in all.
The effects of one NMDA antagonist on opiate-withdrawal symptoms has been examined in humans. Dextromethorphan is an over-the-counter antitussive agent that is (along with its metabolite dextrophan) a moderately potent NMDA antagonist (64,65). Administration of dextromethorphan has been shown to decrease opiate-withdrawal signs in rats and mice (66,67). In humans, dextromethor-phan showed some positive effects on opiate-withdrawal symptoms in one study (68) but not in another (69). Recently, higher doses of dextromethorphan than used in previous studies (68,69) have been shown to be well tolerated in methadone-maintained opiate-dependent subjects (70). Thus, it is possible that higher doses of dextromethorphan (i.e., 480 mg/d) may show efficacy in reducing opiate-withdrawal symptoms in man. In addition, more potent NMDA antagonists may have stronger effects on opiate withdrawal in humans; however, PCP-like side effects may preclude their routine use.
Electrophysiological recordings from LC neurons in morphine-dependent animals showed that neither MK801 nor LY274614 blocked the withdrawal-induced activation of these neurons (61). In addition, neither NMDA antagonist blocked the withdrawal-induced increase in norepinephrine turnover in the cortex, hippocampus, or hypothalamus. Thus, the LC-noradrenergic system appears to be fully activated in animals that are showing few overt signs of withdrawal because of pretreatment with an NMDA antagonist. It is important to note that these results do not necessarily indicate that the LC does not play a role in opiate withdrawal, as the NMDA antagonists may be blocking the effects of LC activation at a site distal to the LC.
N-Methyl-d-aspartate antagonists attenuate many signs of morphine withdrawal without blocking the withdrawal-induced increase of LC unit activity. Therefore, these studies indicate that the glutamate-induced activation of the LC during opiate withdrawal is not mediated primarily through NMDA receptors. Another study reported that direct injections of an NMDA antagonist into the LC produced a modest (approx 20%), but significant, reduction in withdrawal-induced activation of LC neurons (22). Results indicating that the excitatory amino acid projection to the LC from the PGi is mediated by non-NMDA receptors (17) are consistent with a relatively minor role of NMDA receptors in the morphine-withdrawal-induced activation of the LC.
Other brain regions that may be important for the effects of NMDA antagonists during morphine withdrawal have been suggested by studies of the induction of c-fos. The nuclear protein Fos is a product of the c-fos proto-oncogene that can regulate the transcription of cellular genes (71-74). The expression of c-fos mRNA and protein is rapidly stimulated in response to increases in neuronal activity. Thus, the presence of c-fos mRNA or protein can be used as a measure of neuronal activation (72-74). Opiate withdrawal leads to an induction of the c-fos proto-oncogene, Fos-like immunoreac-tivity, and Fos-related antigens (FRAs) in several regions of the rat and guinea pig brain (49, 75-77).
One study examined the effects of MK-801 and LY274614 on naltrexone-precipitated morphine withdrawal increased c-fos mRNA levels in the nucleus accumbens, frontal cortex, amygdala, and hippocampus (78). Pretreatment with MK-801 blocked the withdrawal-induced increased c-fos expression in the amygdala, but not in the nucleus accumbens, frontal cortex, or hippocampus, whereas pretreatment with LY274614 (or the a2-adrenergic agonist clonidine) blocked the withdrawal-induced increased c-fos expression in the amygdala and nucleus accumbens, but not in the frontal cortex or hippocampus. Because NMDA receptor sites are present in all four of these areas (79), these results indicate that the increased c-fos expression seen in the amygdala and nucleus accumbens during morphine withdrawal is mediated, at least in part, by activation of NMDA receptors. Conversely, the increased c-fos expression during morphine-withdrawal seen in the hippocampus and frontal cortex does not seem to be mediated primarily by activation of NMDA receptors. The nucleus accumbens and the amygdala have been suggested to play an important role in the aversive effects of opiate withdrawal (48) and MK-801 and clonidine have been shown to attenuate at least some aversive effects of opiate withdrawal (80,81). Thus, the effects of MK-801 and clonidine in the amygdala may play an important role in its ability to attenuate aversive effects of opiate withdrawal.
Coadministration of the AMPA antagonist LY293558 has been shown to attenuate analgesic tolerance and behavioral sensitization to morphine (82-84). Pretreatment with this same AMPA antagonist (or its racemate LY215490) will also block many morphine-withdrawal signs (85,86). Significant decreases in the occurrence of writhes, wet-dog shakes, stereotyped head movements, ptosis, lacrima-tion, salivation, diarrhea, and chews were observed following pretreatment with LY293558. No significant change in the occurrence of teeth chatter, irritability, erections, or the amount of weight loss was observed. Thus, the morphine-withdrawal symptoms attenuated by antagonism of AMPA receptors are similar, but not the same as those attenuated by NMDA receptors. Furthermore, AMPA antagonists do not produce PCP-like side effects and, thus, may be useful for treating opiate-withdrawal symptoms in humans.
The site of action of AMPA antagonists for the suppression of opiate-withdrawal signs has also been studied. Administration of LY293558 antagonized the morphine-withdrawal-induced activation of LC neurons in a dose-dependent manner. Thus, the morphine-withdrawal-induced activation of the LC appears to be mediated primarily by glutamate acting through AMPA receptors. These findings agree with an earlier study showing that intra-LC application of the nonselective AMPA/kainate antagonist CNQX can block most of the withdrawal-induced activation of LC neurons (22). Further support for the role of LC activation in the genesis of morphine-withdrawal signs was seen by a study showing that intra-LC infusions of CNQX significantly attenuated many signs of naloxone-precipitated morphine withdrawal (87).
The dose of LY293558 that was able to suppress most of the withdrawal-induced activation of LC neurons in anesthetized animals only suppressed the physical signs of opiate withdrawal by about 50%. Although anesthesia could account for some of this difference, another possibility is the participation of AMPA receptors in other brain areas in the genesis of morphine-withdrawal symptoms. Other potential brain sites include those with the highest density of AMPA receptors [(i.e., hippocampus, layers I-III of the cortex, dorsal lateral septum, striatum, and the molecular layer of cerebellum (88,89)]. Another area may be the central nucleus of the amygdala. The central nucleus of the amygdala has been hypothesized to play a role in aversive states (90) and morphine withdrawal (30). Indeed, local infusion of CNQX into the central nucleus of the amygdala also significantly attenuated many morphine-withdrawal symptoms, including irritability, ptosis, lacrimation, penile erections, wet-dog shakes, teeth chattering, and weight loss, but not diarrhea, rhinorrhea, abnormal posture, rearing, and grooming (87).
Although LY293558 is more selective for AMPA (iGluR1-4) receptors than CNQX (and is system-ically available), it has been shown to also have high affinity for one type of kainate receptor (iGluR5) in addition to AMPA receptors. Therefore, we examined the effects of a selective iGluR1-4 noncompetitive antagonist LY300168 [GYKI 53655 (91,92)] and a selective iGluR5 antagonist, LY382884 (93), on the morphine-withdrawal-induced activation of LC neurons and behavioral signs of morphine withdrawal (94). Administration of LY300168, but not LY382884, significantly attenuated the occurrence of morphine-withdrawal signs. LY300168 attenuated the occurrence of writhes, wet-dog shakes, ptosis, digging, salivation, irritability, diarrhea, chews, and weight gain, but not teeth chatter, jumps, or erections. LY382884 attenuated only lacrimation. The effect of LY382884 on lacrimation confirms that the compound is having biological activity under the present conditions and implicates iGluR5 receptors in morphine-withdrawal-induced lacrimation. Administration of LY300168 also completely attenuated the morphine-withdrawal-induced activation of LC neurons in a dose-dependent manner. However, administration of LY382884 did not affect the morphine-withdrawal-induced activation of LC neurons. LY382884 has previously been shown to have activity in vivo in rats following systemic administration at doses at and below those used in this study [i.e., 5- 100 mg/kg (95)]. Therefore, these results support the conclusion that the morphine-withdrawal-induced activation of LC neurons is mediated by glutamate acting at AMPA (iGluR 1-4) receptors and they indicate that iGluR5 receptors play little, if any, role.
Several studies have supported a role of metabotropic glutamate (mGlu) receptors in morphine dependence (96,97). Based on these results, a model in which the effects of mGlu receptors on intracellular second messengers influence opiate tolerance and dependence has been proposed (98). In addition, an mGlu receptor group II agonist decreased the severity of some morphine withdrawal signs (97). However, the interpretation of these experiments is clouded by the nonselective nature and lack of central penetration of some of the compounds employed (e.g., ACPD and DCG-IV). The selective, centrally penetrant mGlu receptor group II agonist LY354740 has also been studied in morphine dependence and withdrawal. Administration of LY354740 blocked morphine, but not fentanyl (a selective ^-opiate agonist), tolerance (99). LY354740 also has been shown to block opiate-withdrawal symptoms in the mouse (100) and rat (101). In the rat, pretreatment with LY354740 decreased the occurrence of writhes, digging, salivation, diarrhea, chews, wet-dog shakes, and ptosis, whereas teeth chatter, lacrimation, irritability, erections, and weight loss were not affected. Thus, LY354740 had similar effects on individual morphine-withdrawal symptoms as AMPA antagonists (86). The studies suggest that mGlu group II receptor agonists may be a novel treatment for opiate withdrawal in humans.
LY354740, but not its inactive isomer LY317207, significantly reduced morphine-withdrawal-induced acativation of LC neurons (101). This finding is consistent with reports that presynaptic mGlu receptors function as glutamate autoreceptors to inhibit activation of LC neurons (102). The release of glutamte in the LC during morphine withdrawal, as mentioned above is elevated (42,43) and LY354740 reduces veratridine-stimulated release of glutamate in vivo (103). Thus, it seems likely that LY354740 attenuates the morphine-withdrawal-induced activation of LC neurons, at least in part, by decreasing the release of glutamate. However, indirect effects of presynaptic mGlu receptors on the release of other neurotransmitter in the LC [e.g., GABA (104)] may also play a role in the effects of LY354740. Further studies are needed to explore the affects of LY354740 on the release of glutamate, GABA, and/or other neurotransmitter in the LC during morphine withdrawal.
In addition to the presynaptic actions of LY354740, the activation of postsynaptic mGlu2/3 receptors in the LC may also be involved in the suppression of morphine-withdrawal symptoms. LY354740 and other mGlu2/3 agonists can act via postsynaptic receptors to inhibit cAMP formation and adeny-late cyclase (AC) activity (105). In the LC, upregulation of cAMP and AC pathways plays an important role in the development and expression of morphine dependence (106-108). For example, chronic morphine administration increases levels of AC and cAMP-dependent protein kinases activity in the LC, and intra-LC administration of cAMP-dependent protein kinase inhibitors attenuates opiate withdrawal (109,110). Thus, LY354740 may attenuate the morphine-withdrawal-induced activation of LC neurons by reducing the production of cAMP in addition to inhibiting the release of glutamate.
The actions of LY354740 in other brain areas, in addition to the LC, may play a role in its suppression of morphine-withdrawal symptoms. Other potential sites of action of LY354740 include those with the highest densities of mGlu2/3 receptors, including the cerebral cortex, hippocampus, substan-tia nigra, habenula, and spinal cord (111). Importantly, mGlu2/3 receptors are located in some areas thought to be involved in opiate-withdrawal behaviors such as the amygdala, periaquaductal grey area, and spinal cord (30,111). One region that may especially be important for the actions of LY354740 during morphine withdrawal is the nucleus paragigantocellularis (PGi). The PGi contains mGlu2/3 receptors, sends a major glutamatergic afferent to the LC, and lesions of the PGi reduce morphine withdrawal symptoms (17,18,111). Thus, activation of mGlu2/3 receptors in the PGi may reduce subsequent release of glutamate in the LC and attenuate activation of LC neurons.
The relative contribution of mGlu2 versus mGlu3 receptors to the action of LY354740 is not clear. However, LY354740 has a higher affinity for mGlu2 than mGlu3 receptors (112) and mGlu2 and mGlu3 receptors have a differential distribution in the brain (113,114). Thus, activation of mGlu2 and mGlu3 receptors may have different effects on morphine withdrawal. Additional studies with compounds selective for mGlu2 or mGlu3 receptors will help shed light on the role of these receptor subtypes in opiate withdrawal.
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