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Metabotropic glutamate receptors and opiate analgesia
Commentary
Metabotropic Glutamate Receptors and Opiate Analgesia Therapeutic Implications Gordon Blackburn-Munro
Morphine acts at u-opioid receptors within the brain and spinal cord to induce analgesia. However, tolerance and dependence are potentially undesirable side effects encountered with repeated opiate administration. Opiate withdrawal, the physical correlate of dependence, is involved in the negative reinforcement of opiate addiction. Recently, blockers of ionotropic subtypes of glutamate receptors have been suggested to have therapeutical potential for opiate withdrawal. Fundytus and Coderre have also shown that antagonism of metabotropic glutamate receptors (mGluRs) and 8-opioid receptors can separately alleviate the behavioral symptoms of withdrawal. They propose that mGluRs and 8-opioid receptors share intermediates and products of the same second messenger pathways as u-opioid receptors, thereby enhancing the desensitization of this receptor. Thus, mGluRs appear to be involved in the development of opiate tolerance and dependence and may provide a key target for adjunct therapy with opiate analgesia. Key words: dependence, morphine, second messengers, tolerance, withdrawal
he therapeutic potential of the opium poppy and its principal active constituent, morphine, have transcended the ancient civilizations into modern times. The analgesic benefits of opiates (exogenously derived drugs with actions at opioid receptors) have been somewhat superseded in the 20th
T
From the Department of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh. Reprint requests: Gordon Blackburn-Munro, PhD, Department of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK. ©
1999 the American Pain Society
1058-9139/0801-0004$5.00/0
Pain Forum 8(1): 19-21, 1999
century by abuse of their euphoric properties, particularly with the street availability of heroin. In the United States, it is currently estimated that over 70,000 heroinrelated emergency cases are dealt with each year [3]. The adverse social effects of opiate abuse have provided a massive stimulus to further our understanding of the cellular mechanisms involved in opiate tolerance and dependence. This is particularly important, because many types of chronic pain such as neuropathic disorders are relatively resistant to the analgesic properties of opiates, even when given at high doses; tolerance and dependence can develop rapidly to opiate administration in these patient groups. Recently, studies with mice lacking the u-opioid receptor gene have unequivocally shown that opiates exert their effects within the central nervous system to mediate analgesia in addition to controlling emotional, cognitive, and neuroendocrine functions. Opiates also have suppressive effects on immune responses in both animals and humans, and morphine immunosuppression is completely abolished in u-oplold receptor knockout mice [2]. For patients recovering/postoperatively from major surgery, this may be .of particular relevance. Although u-opioid-induced analgesia may be required for effective pain relief, it could compromise the immune system at a time when most required. In such cases, adjunct therapy may be preferable. Consequently, a greater understanding of the mechanisms involved in opiate tolerance and dependence should hopefully allow their safer prescription and administration with fewer adverse side effects. Fundytus and Coderre mention that glutamate receptor antagonists, particularly those specific for the NMDA receptor subtype (ionotropic), can attenuate signs of withdrawal in animal models of opiate dependence, and indeed there is a large body of scientific evidence to support this [4]. Human studies have been hindered by the lack of officially approved drugs that can act at this receptor, although the few studies that have been com19
20
COMMENTARY/Blackburn-Munro
positive reinforcing effects of drugs of abuse) can be either activated or inhibited by glutamate actions at mGluRs, depending on the degree of receptor activation [1]. Thus, the actions of glutamate at mGluRs are probably much more complex than previously anticipated. Nevertheless, it would seem reasonable to assume that there may be downstream interactions within the second messenger cascades activated by mGluRs and opioid receptors, which play an important role in tolerance and dependence to opiates. On this basis, Fundytus and Coderre have gone on to investigate the role of mGluRs in opiate tolerance and dependence (see Fig. 1), mentioning that there is a close correlation in the distribution pattern between the two receptor families in the brain. This argument for an involvement of mGluRs in opiate tolerance and dependence is indeed compelling. The involvement of u-opioid receptors with the adenylate cyclase-cyclic adenosine monophosphate (cAMP) pathway has been known for many years, with evidence accumulated from a variety of cellular and whole animal systems. In addition, u-opioid receptor
pleted suggest that such drugs may have a therapeutic potential in alleviating withdrawal symptoms in opiate addicts. Prolonged opiate administration appears to tonically inhibit noradrenergic neurones within the locus ceruleus of the brain stem. Hyperactivity within these neurones may result from sudden withdrawal from opiates. The Q:2-adrenergic agonist clonldine acts to reduce this hyperactivity to alleviate withdrawal symptoms in opiatedependent humans. At the cellular level, clonldine acts via a G-protein-Iinked receptor, and appears to interact with the same second messenger pathways as those activated by opiates, such as morphine, to move the balance away from opiate-mediated activation and hence withdrawal associated symptoms. Glutamate also acts at metabotropic glutamate receptor subtypes (mGluRs) which act via G-proteins to affect cell function. Within the central nervous system, this action is principally excitatory. Recent work by Fiorillo and Williams has shown that dopaminergic activity within the ventral tegmental area (an area implicated in the
A
B
•
relative magnitude of withdrawal symptoms
Fig. 1. Diagram illustrating the relationship between second messenger activation by mGluRs and opioid receptors and the
magnitude of associated opiate tolerance and dependence according to Fundytus and Coderre. (A) with repeated morphirie administration phosphotidyl inositol hydrolysis is homeostatically reset via increased activity at group I mGluRs, o-opioid receptors, and their related intracellular cascade pathways, resulting in increased production of DAG and IP3 . This ultimatelyactivates protein kinase C (1) which desensitizes the p-opioid receptor. cAMP production is also homeostatically reset via heterologous desensitization of group II and group III mGluRs. The increasein cAMP concentration may enhance activity of protein kinaseA (2), which would be expected to densitize the u-opioid receptor resulting in pharmacological tolerance to exogenous opiate administration (3). IP3-mediated release of Ca2+ from intracellularstores might also lead to increased activation of protein kinases withinthe cell. Protein kinaseactivation might also be expectedto phosphorylate the NMDAsubtype of glutamate receptor, whereas cAMP might activate a hyperpolarization-activated cation channel, both of which would be expected to contribute to neuronal depolarization (not shown). (8) Adjunct therapy prior to or during withdrawal could involve two strategies. Chronic antagonism of group I mGluRs and s-optold receptors (1) would ultimately prevent mGluR and o-opioid-mediated increases in protein kinase C activity (2), resulting in partialattenuation of u-opioid receptor desensitization. Similarly, chronic antagonism of group II and group III mGluRs(3) would preventincreased productionof cAMPand activationof proteinkinaseA (4), with associated desensitization of the u-opioid receptor (5). Antagonism of these intracellularly mediated effects would be expected to diminishthe relative magnitude of opiatewithdrawal symptoms. DAG;diacylglycerol, IP3 ; inositol-1 ,4,5-triphosphate.
COMMENTARY/Blackburn-Munro
desensitization provides us with an explanation for the pharmacologic tolerance observed with repeated opiate administration. Such interactions are not without precedent. Other G-protein-coupled receptors including the l3-adrenergic receptor can undergo phosphorylation by protein kinases with associated desensitization. It should be noted that the assumed co-localization of mGluRs and u-opioid receptors-as important as it is for the proposed model-is probably not the case for all cells in the brain. Some cells will contain u-opioid receptors but not mGluRs and vice versa. More importantly, some cells may become tolerant and dependent to the inhibitory actions of opiates without a direct influence from mGluR activation. However, we are also told that co-activation of o-opioid receptors (which are also linked to phosphotidyl inositol hydrolysis and activation of protein kinase C) by opiates such as morphine may playa role in tolerance and dependence. The authors briefly mention that the increased levels of cAMP associated with opiate tolerance and dependence may activate a hyperpolarization-activated mixed cation current (termed Ih) , with resultant neuronal excitation. Such channels are primarily involved in the rhythmic firing of central neurones and have recently been molecularly identified [5]. Within the periphery, such channels may also be involved in the genesis and maintenance of primary afferent firing in response to tissue damage. This pattern of firing is proposed to underlie the hyperexcitability of neurones within the mammalian spinal cord. These neuronesare in turn part of the pain relaycircuitthat projects via the thalamus to the somatosensory cortex where the stimulus, if sufficiently damaging, is perceived as painful. As yet, specific drugs capable of blocking this Ih current are unavailable for use as pharmacologic tools, let alone for use clinically. Because it is likely that morphine and other opiates will continue to be used as analgesics of choice for the near future at least, the development of specific Ih blockers may serve two purposes. First, they could be used as analgesics in their own right. Second, as proposed by Fundytus and Coderre, they could help to reduce the development of opiate tolerance and dependence in addition to diminishing behavioral symptoms of opiate withdrawal. A combination approach of morphine and a specific Ih blocker could prove particularly attractive for mediating analgesia for the reasons outlined above. It is worth noting that the parameters chosen to show this involvement of mGluR, o-opioid receptor, and associated second messenger changes in the development and maintenance of morphine tolerance and dependence are primarily behavioral, induced upon withdrawal by administration of naloxone. Although the side effects of withdrawal in the human (shivering, motor tremor, nausea, vomiting) are reported to be extremely unpleasant, they do not necessarily of themselves as physical
21
observations constitute all the mechanisms involved in tolerance and dependence to opiates. That is, the attenuation of these observations in morphine-dependent rats with specific drug strategies is not necessarily proof in itself that drug tolerance and physical dependence are alleviated throughout all affected cell populations within the central nervous system. For example, many of these physical manifestations of withdrawal are thought to be mediated by removal of opioid-receptorinduced suppression of activity within the locus ceruleus, yet a numberof other brainareasare known to be involved in the maintenanceof opiatedependence. Althoughthis should not detractfrom the role undertaken by mGluRs and o-opioid receptors in opiate tolerance and dependence, it should underlinethat the cellularmechanismsinvolvedare complex and as yet far from resolved. Fundytus and Coderre finally mention that the development of more specific mGluR antagonists might provide suitable adjunct therapies with opiate administration. Indeed, other work by this group would appear to support this. Experimental evidence involving blocking of mGluR function with specific antibodies and inhibition of mGluR protein synthesis using antisense technology suggests that mGluRs appear to playa crucial role in the transmission of nociceptive information within the spinal cord. While their abuse continues, the clinical use of opiates will remain controversial. However, the model highlighted in the preceding Focus article suggests a number of factors includinq mGluRs may be involved in opiate tolerance and dependence. Pharmacologic exploitation of these key targets may well provide safer analgesic therapies to be used in combination with opiates for patients suffering from chronic pain. Acknowledgement The author thanks Drs R. E. Blackburn-Munro and P A. Heppenstall for helpful comments.
References 1. Fiorillo CD, Williams JT: Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394:78-
82,1998 2. Gaveriaux-Buff C, Matthes HWD, Peluso J, Kieffer B: Abolition of morphine-immunosuppression in mice lacking the p-opioid receptor gene. Proc Natl Acad Sci USA 95:
6326-6330,1998 3. Herman B, Iversen L: Introduction: strategies for treatment of opiate abuse. Sem Neurosci 9:69, 1997
4. Inturrisi CE: Preclinical evidence for a role of glutaminergic systems in opioid tolerance and dependence. Sem Neurosci 9:110-119,1997 5. Santoro B, Liu DT, Vao H, Bartsch 0, Kandel ER, Siegelbaum SA, Tibbs GR: Identification of a gene encoding a hyperpolarisation-activated pacemaker channel of brain. Cell 93:717-729, 1998
Metabotropic Glutamate Receptors and Opiate Analgesia Therapeutic Implications Gordon Blackburn-Munro
Morphine acts at u-opioid receptors within the brain and spinal cord to induce analgesia. However, tolerance and dependence are potentially undesirable side effects encountered with repeated opiate administration. Opiate withdrawal, the physical correlate of dependence, is involved in the negative reinforcement of opiate addiction. Recently, blockers of ionotropic subtypes of glutamate receptors have been suggested to have therapeutical potential for opiate withdrawal. Fundytus and Coderre have also shown that antagonism of metabotropic glutamate receptors (mGluRs) and 8-opioid receptors can separately alleviate the behavioral symptoms of withdrawal. They propose that mGluRs and 8-opioid receptors share intermediates and products of the same second messenger pathways as u-opioid receptors, thereby enhancing the desensitization of this receptor. Thus, mGluRs appear to be involved in the development of opiate tolerance and dependence and may provide a key target for adjunct therapy with opiate analgesia. Key words: dependence, morphine, second messengers, tolerance, withdrawal
he therapeutic potential of the opium poppy and its principal active constituent, morphine, have transcended the ancient civilizations into modern times. The analgesic benefits of opiates (exogenously derived drugs with actions at opioid receptors) have been somewhat superseded in the 20th
T
From the Department of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh. Reprint requests: Gordon Blackburn-Munro, PhD, Department of Preclinical Veterinary Sciences, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK. ©
1999 the American Pain Society
1058-9139/0801-0004$5.00/0
Pain Forum 8(1): 19-21, 1999
century by abuse of their euphoric properties, particularly with the street availability of heroin. In the United States, it is currently estimated that over 70,000 heroinrelated emergency cases are dealt with each year [3]. The adverse social effects of opiate abuse have provided a massive stimulus to further our understanding of the cellular mechanisms involved in opiate tolerance and dependence. This is particularly important, because many types of chronic pain such as neuropathic disorders are relatively resistant to the analgesic properties of opiates, even when given at high doses; tolerance and dependence can develop rapidly to opiate administration in these patient groups. Recently, studies with mice lacking the u-opioid receptor gene have unequivocally shown that opiates exert their effects within the central nervous system to mediate analgesia in addition to controlling emotional, cognitive, and neuroendocrine functions. Opiates also have suppressive effects on immune responses in both animals and humans, and morphine immunosuppression is completely abolished in u-oplold receptor knockout mice [2]. For patients recovering/postoperatively from major surgery, this may be .of particular relevance. Although u-opioid-induced analgesia may be required for effective pain relief, it could compromise the immune system at a time when most required. In such cases, adjunct therapy may be preferable. Consequently, a greater understanding of the mechanisms involved in opiate tolerance and dependence should hopefully allow their safer prescription and administration with fewer adverse side effects. Fundytus and Coderre mention that glutamate receptor antagonists, particularly those specific for the NMDA receptor subtype (ionotropic), can attenuate signs of withdrawal in animal models of opiate dependence, and indeed there is a large body of scientific evidence to support this [4]. Human studies have been hindered by the lack of officially approved drugs that can act at this receptor, although the few studies that have been com19
20
COMMENTARY/Blackburn-Munro
positive reinforcing effects of drugs of abuse) can be either activated or inhibited by glutamate actions at mGluRs, depending on the degree of receptor activation [1]. Thus, the actions of glutamate at mGluRs are probably much more complex than previously anticipated. Nevertheless, it would seem reasonable to assume that there may be downstream interactions within the second messenger cascades activated by mGluRs and opioid receptors, which play an important role in tolerance and dependence to opiates. On this basis, Fundytus and Coderre have gone on to investigate the role of mGluRs in opiate tolerance and dependence (see Fig. 1), mentioning that there is a close correlation in the distribution pattern between the two receptor families in the brain. This argument for an involvement of mGluRs in opiate tolerance and dependence is indeed compelling. The involvement of u-opioid receptors with the adenylate cyclase-cyclic adenosine monophosphate (cAMP) pathway has been known for many years, with evidence accumulated from a variety of cellular and whole animal systems. In addition, u-opioid receptor
pleted suggest that such drugs may have a therapeutic potential in alleviating withdrawal symptoms in opiate addicts. Prolonged opiate administration appears to tonically inhibit noradrenergic neurones within the locus ceruleus of the brain stem. Hyperactivity within these neurones may result from sudden withdrawal from opiates. The Q:2-adrenergic agonist clonldine acts to reduce this hyperactivity to alleviate withdrawal symptoms in opiatedependent humans. At the cellular level, clonldine acts via a G-protein-Iinked receptor, and appears to interact with the same second messenger pathways as those activated by opiates, such as morphine, to move the balance away from opiate-mediated activation and hence withdrawal associated symptoms. Glutamate also acts at metabotropic glutamate receptor subtypes (mGluRs) which act via G-proteins to affect cell function. Within the central nervous system, this action is principally excitatory. Recent work by Fiorillo and Williams has shown that dopaminergic activity within the ventral tegmental area (an area implicated in the
A
B
•
relative magnitude of withdrawal symptoms
Fig. 1. Diagram illustrating the relationship between second messenger activation by mGluRs and opioid receptors and the
magnitude of associated opiate tolerance and dependence according to Fundytus and Coderre. (A) with repeated morphirie administration phosphotidyl inositol hydrolysis is homeostatically reset via increased activity at group I mGluRs, o-opioid receptors, and their related intracellular cascade pathways, resulting in increased production of DAG and IP3 . This ultimatelyactivates protein kinase C (1) which desensitizes the p-opioid receptor. cAMP production is also homeostatically reset via heterologous desensitization of group II and group III mGluRs. The increasein cAMP concentration may enhance activity of protein kinaseA (2), which would be expected to densitize the u-opioid receptor resulting in pharmacological tolerance to exogenous opiate administration (3). IP3-mediated release of Ca2+ from intracellularstores might also lead to increased activation of protein kinases withinthe cell. Protein kinaseactivation might also be expectedto phosphorylate the NMDAsubtype of glutamate receptor, whereas cAMP might activate a hyperpolarization-activated cation channel, both of which would be expected to contribute to neuronal depolarization (not shown). (8) Adjunct therapy prior to or during withdrawal could involve two strategies. Chronic antagonism of group I mGluRs and s-optold receptors (1) would ultimately prevent mGluR and o-opioid-mediated increases in protein kinase C activity (2), resulting in partialattenuation of u-opioid receptor desensitization. Similarly, chronic antagonism of group II and group III mGluRs(3) would preventincreased productionof cAMPand activationof proteinkinaseA (4), with associated desensitization of the u-opioid receptor (5). Antagonism of these intracellularly mediated effects would be expected to diminishthe relative magnitude of opiatewithdrawal symptoms. DAG;diacylglycerol, IP3 ; inositol-1 ,4,5-triphosphate.
COMMENTARY/Blackburn-Munro
desensitization provides us with an explanation for the pharmacologic tolerance observed with repeated opiate administration. Such interactions are not without precedent. Other G-protein-coupled receptors including the l3-adrenergic receptor can undergo phosphorylation by protein kinases with associated desensitization. It should be noted that the assumed co-localization of mGluRs and u-opioid receptors-as important as it is for the proposed model-is probably not the case for all cells in the brain. Some cells will contain u-opioid receptors but not mGluRs and vice versa. More importantly, some cells may become tolerant and dependent to the inhibitory actions of opiates without a direct influence from mGluR activation. However, we are also told that co-activation of o-opioid receptors (which are also linked to phosphotidyl inositol hydrolysis and activation of protein kinase C) by opiates such as morphine may playa role in tolerance and dependence. The authors briefly mention that the increased levels of cAMP associated with opiate tolerance and dependence may activate a hyperpolarization-activated mixed cation current (termed Ih) , with resultant neuronal excitation. Such channels are primarily involved in the rhythmic firing of central neurones and have recently been molecularly identified [5]. Within the periphery, such channels may also be involved in the genesis and maintenance of primary afferent firing in response to tissue damage. This pattern of firing is proposed to underlie the hyperexcitability of neurones within the mammalian spinal cord. These neuronesare in turn part of the pain relaycircuitthat projects via the thalamus to the somatosensory cortex where the stimulus, if sufficiently damaging, is perceived as painful. As yet, specific drugs capable of blocking this Ih current are unavailable for use as pharmacologic tools, let alone for use clinically. Because it is likely that morphine and other opiates will continue to be used as analgesics of choice for the near future at least, the development of specific Ih blockers may serve two purposes. First, they could be used as analgesics in their own right. Second, as proposed by Fundytus and Coderre, they could help to reduce the development of opiate tolerance and dependence in addition to diminishing behavioral symptoms of opiate withdrawal. A combination approach of morphine and a specific Ih blocker could prove particularly attractive for mediating analgesia for the reasons outlined above. It is worth noting that the parameters chosen to show this involvement of mGluR, o-opioid receptor, and associated second messenger changes in the development and maintenance of morphine tolerance and dependence are primarily behavioral, induced upon withdrawal by administration of naloxone. Although the side effects of withdrawal in the human (shivering, motor tremor, nausea, vomiting) are reported to be extremely unpleasant, they do not necessarily of themselves as physical
21
observations constitute all the mechanisms involved in tolerance and dependence to opiates. That is, the attenuation of these observations in morphine-dependent rats with specific drug strategies is not necessarily proof in itself that drug tolerance and physical dependence are alleviated throughout all affected cell populations within the central nervous system. For example, many of these physical manifestations of withdrawal are thought to be mediated by removal of opioid-receptorinduced suppression of activity within the locus ceruleus, yet a numberof other brainareasare known to be involved in the maintenanceof opiatedependence. Althoughthis should not detractfrom the role undertaken by mGluRs and o-opioid receptors in opiate tolerance and dependence, it should underlinethat the cellularmechanismsinvolvedare complex and as yet far from resolved. Fundytus and Coderre finally mention that the development of more specific mGluR antagonists might provide suitable adjunct therapies with opiate administration. Indeed, other work by this group would appear to support this. Experimental evidence involving blocking of mGluR function with specific antibodies and inhibition of mGluR protein synthesis using antisense technology suggests that mGluRs appear to playa crucial role in the transmission of nociceptive information within the spinal cord. While their abuse continues, the clinical use of opiates will remain controversial. However, the model highlighted in the preceding Focus article suggests a number of factors includinq mGluRs may be involved in opiate tolerance and dependence. Pharmacologic exploitation of these key targets may well provide safer analgesic therapies to be used in combination with opiates for patients suffering from chronic pain. Acknowledgement The author thanks Drs R. E. Blackburn-Munro and P A. Heppenstall for helpful comments.
References 1. Fiorillo CD, Williams JT: Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394:78-
82,1998 2. Gaveriaux-Buff C, Matthes HWD, Peluso J, Kieffer B: Abolition of morphine-immunosuppression in mice lacking the p-opioid receptor gene. Proc Natl Acad Sci USA 95:
6326-6330,1998 3. Herman B, Iversen L: Introduction: strategies for treatment of opiate abuse. Sem Neurosci 9:69, 1997
4. Inturrisi CE: Preclinical evidence for a role of glutaminergic systems in opioid tolerance and dependence. Sem Neurosci 9:110-119,1997 5. Santoro B, Liu DT, Vao H, Bartsch 0, Kandel ER, Siegelbaum SA, Tibbs GR: Identification of a gene encoding a hyperpolarisation-activated pacemaker channel of brain. Cell 93:717-729, 1998