Neurochem. Int. Vol. 20, No. 4, pp. 457-460, 1992 Printed in Great Britain. All rights reserved
0197-0186/92 $5.00 + 0.00 Copyright © 1992 Pergamon Press Ltd
CRITIQUE E N D O G E N O U S OPIOIDS A N D LTP: ANOTHER VIEW JOHN J. WAGNER and CHARLES CHAVKIN Department of Pharmacology, SJ-30, University of Washington, Seattle, WA 98195, U.S.A.
Clive Bramham has written a provocative review summarizing the data which suggests that endogenous opioid peptides regulate LTP at specific synapses in the hippocampus. We have also been studying the role of endogenous opioids in the hippocampus for several years, and would like to comment and expand on a few points brought up by Dr Bramham. As mentioned in the review, although the pharmacological effects of exogenously applied opioids in the hippocampus have been extensively studied, the actions of endogenously released opioids remain relatively undefined. What is clear is that further characterization of the physiologic roles of endogenous opioids in hippocampal function requires a better understanding of the physiologic conditions under which the peptides are released, their normal cellular sites of action, and their subsequent effects on the target cells, It is also clear that a simple extrapolation from the pharmacological effects of exogenously applied opioids to the physiological effects of endogenously released opioids will not be a trivial exercise. Dr Bramham presents many of the complexities of this issue. We do know that the diversity of opioid actions in the hippocampus suggests that the answer to the question, "Do endogenous opioids regulate LTP?." will not be a simple affirmative.
PHYSIOLOGICAL STIMULATION CONDITIONS REQUIRED TO RELEASE ENDOGENOUS OPIOID PEPTIDES IN THE HIPPOCAMPUS
As described, opioid peptides are present in the granule cells, scattered nonpyramidal cells, and lateral perforant path terminals within the hippocampal formation. Our work supports the hypothesis that opioids could be involved in LTP processes. As reviewed by Dr Bramham, opioid peptides present in the mossy fibers (the axons of the granule cells) and 457
lateral perforant path (axons from the enkephalincontaining cells in the entorhinal cortex) (Gall et al., 1981 ; McGinty et al., 1983), can release opioid peptides following appropriate stimulation. Using a hippocampal slice radioligand binding assay to measure peptide release in situ, we found that stimulation conditions which are the most effective in releasing endogenous opioids consist of high frequency (1050 Hz) trains of pulses (Caudle et al., 1991 ; Wagner et al., 1990, 1991), conditions that could also be effective in eliciting LTP. Other work cited by Dr Bramham supports the general theme that the release of peptide neurotransmitters may be frequency-encoded. These results suggest that opioids may function to modulate the properties of the hippocampal circuit under conditions of intense activity.
PHYSIOLOGICAL SITES OF ENDOGENOUS OPIOID ACTION Receptor autoradiography has been used to define the potential sites of opioid action, but as described by Herkenham and co-workers and reviewed by Dr Bramham, the "mismatch" between peptide and receptor distributions suggests that either the peptide can diffuse some distance from its sites of release to its sites of action or that only a subset of the available receptors normally see peptide. The specific sites of action for endogenous opioids in the hippoeampal formation remains to be rigorously characterized. This requires a measure of the direct effects of endogenously released peptide. Previous work using exogenously applied opioids can serve as a guide and has established potential targets in the hippocampus : (l) opioids inhibit the excitability of local circuit interneurons and reduce G A B A release (Madison and Nicoll, 1988), and (2) opioids inhibit the release of various other transmitters such as norepinephrine,
458
Critique
acetylcholine, and serotonin from afferent terminals (see llles, 1989 for review). The electrophysiological effects of opioid inhibition of GABA release has been documented by many laboratories (see Chavkin, 1988, for one review). The electrophysiological consequences of opioid inhibition of other transmitter's release has been more difficult to show. Using a high-frequency stimulation paradigm, we demonstrated that endogenous opioids released from the perforant path can modulate inhibitory postsynaptic potentials recorded in CA3 pyramidal cells (Caudle et al., 1991). Although indirect, this measure of endogenous opioid action indicated that the released opioid peptides were likely to be acting by inhibiting an excitatory adrenergic input to the interneurons involved in mediating the IPSP response in the CA3 cells. In the dentate gyrus, we have found that U69,593 (a ~,, selective opioid agonist) decreased excitatory transmission at the perforant path granule ceils synapse by inhibiting the release of excitatory amino acids from presynaptic terminals (Wagner et al., 1992). How these actions would affect LTP induction or expression is not yet known, but since glutamate, norepinephrine, and acctylcholine have each been shown to facilitate LTP (Stanton and Sarvey, 1985: Burgard and Sarvey, 1990), endogenous opioid inhibition of their actions could potentially inhibit LTP induction or expression.
DO O P I O I D RECEPTORS DIRECTLY AFFECT THE PRINCIPAL NEURONS IN THE H I P P O C A M P A L FORMATION?
The model presented by Dr Bramham suggests that ~5-receptors are present on the granule cells. Available physiologic evidence indicates that this is not likely. Neither our work nor that of others has revealed any direct action of opioids on pyramidal or granule cells in the hippocampal formation. The evidence suggests that the modulatory effects of endogenous opioids at dentate granule cell synapse are likely to be caused by an inhibition of interneuron activity or presynaptic transmitter release. In support of this conclusion, it recent report by Xie and Lewis (1991) described the effects of both the opioid antagonist naloxone and the p-selective agonist PLO17 on LTP at the lateral perforant path (LPP)-dentate granule cells synapse. Their analysis of the data led them to propose that endogenous opioids released from perforant path terminals facilitated the induction of LTP by inhibiting GABA release from interneurons. In another study, Mott and Lewis (1991) demonstrated that a disinhibitory mechanism mediated by GA BAu receptors
was required for LTP induction under certain conditions in the rat dentate gyrus. A second problem with the model presented by Dr Bramham is that all of the direct effects of ~%receptor activation reported in the hippocampus are inhibitory. Thus, a pcrinissivc role for endogenous opioids in LTP induction in thc dentate gyrus via a direct effect of opioid action on dentate granule cells or I.,PP terminals is currently unsupported. As presented in the review, the dissociation between opioid effects on LTP of the EPSP slope compared with LTP of the granule cell population spike response is an interesting observation. Dr Bramham has proposed that different types of opioid receptors may be involved in mediating this ettEct. By placing ,5receptors in the synaptic region and l~-receptors on interneurons regulating the population response, the results of Bramham et al. (1991) and Xie and Lewis (1991) can be rationalized. However, this placement of opioid receptors is not totally consistent with the natoxone data shown in Fig. 2 of the review. Naloxone has a 10-50-fold higher affinity for #-than ¢%receptors (Goldstein and Naidu, 1989): therefore, the sitc of LTP induction which should be most sensitive to the presence of naloxone was unaffected (granule cell population response), whereas the site proposed to be influenced by ~%receptors was blocked by 100 nM naloxone. ADDITIONAL CONCERNS
Whenever studies concerning the potential actions of endogenous opioids are being collated and distilled, some important issues need to be considered. As mentioned in the review, significant differences exist in the anatomical distribution of opioid receptors among the animal species commonly studied. For example, comparing opioid binding sites in the rat and the guinea pig reveals quite different patterns of receptor distribution. The re-receptor system is a useful illustration: two subtypes of r,--receptors can be distinguished based on binding selectivity profiles (Zukin et al., 1988; Nock et al., 1990). The x~ or U69.593sensitive receptor is localized primarily in the molecular layer of the dentate gyrus in guinea pig hippocampus (Wagner et al., 1991). In contrast, in the rat, this receptor subtype is a relatively rare ( > 10%) component of the total x-binding sites (Zukin et al., 1988). This becomes important when the physiologic actions of the putative endogenous ligands for ~¢receptor are being studied, as it has been shown thai dynorphins have a much higher affinity for the ~¢, subtype of receptor than for the ~c: subtype (Nock et
Critique al., 1990). The lack of xl sites in the CA3 region
changes our expectations of endogenous dynorphin actions. At the mossy fiber-CA3 synapse, it is clear that the apparent lack of x-receptor mediated modulation of LTP by dynorphins released from the mossy fibers is likely due to the absence of X l receptors in the stratum lucidum of both guinea pig and rat CA3 regions. The distribution of x-receptors described in the review by Bramham was based on autoradiographic results using nonselective radioligands which would bind both the x~ and the x2 subtypes of x-receptor (McLean et al., 1987). More recent studies indicate that the reported population of K-binding sites present in the stratum lucidum of rat and guinea pig are likely to be the x2 subtype of receptor (Wagner et al., 1991). Further characterization of the x2 system awaits the development of selective ligands for that binding site; however, the very low affinities of the known endogenous opioids for this site is problematic. In addition to work on K-subtypes, other evidence has been accumulating which indicates that subtypes of/~- and &receptors also exist (Pasternak and Wood, 1986 ; Sofuoglu et al., 1991 ; Jiang et al., 1991). Obviously, as new subtype selective compounds become available, it will be necessary to reevaluate the results from previous studies. As mentioned above, we have recently reported evidence indicating that the perforant path terminals in the molecular layer of the guinea pig dentate gyrus are a likely endogenous target for dynorphins released from dentate granule cells (Wagner et al., 1991, 1992). As a result, in contrast to the facilitating role of endogenous opioids in LTP processes put forth in Dr Bramham's review, our work demonstrating that x~ ligands act to inhibit excitatory transmission would suggest an inhibitory role for endogeneously released dynorphin on LTP induction and/or expression by acting at the perforant path-dentate granule cell synapse in the guinea pig dentate gyrus (Wagner et al., 1992). DO ENDOGENOUS OPIOID PEPTIDES FACILITATE LTP INDUCTION? Studies cited by Dr Bramham clearly indicate that at two sites : the LPP synapse on the dentate granule cells and the mossy fiber synapse on the CA3 pyramidal cell, endogenous opioids can facilitate LTP induction. The actions of exogenously applied opioids have implicated two likely cellular sites of action. Endogenous opioids acting on interneurons to inhibit GABA release could contribute to LTP induction via a disinhibitory mechanism. Whether endogenous
459
opioids acting to inhibit glutamate, acetylcholine, or norepinephrine release could also facilitate LTP would appear much less likely. In particular, the inhibitory effects of x-opioids on glutamate release from the perforant path suggests that under some conditions, endogenous opioids might block LTP induction or expression. Since opioids regulate the release of a broad range of transmitters in the hippocampus, the net effect of endogenous opioid release would depend on the physiological state of the animal or preparation; it is obvious that the state of the hippocampus in an anesthetized animal and deafferented slice is likely to be different both from each other and from the freely moving animal. Although we have taken some exception to the specific hypothetical model presented by Dr Bramham, we are not attempting to detract from the evidence described which indicates that endogenous opioids can act to facilitate LTP processes occurring at certain synapses in the hippocampus. Rather we have presented some of our results to illustrate the point that the diversity present in the endogenous opioid peptide-receptor system allows for numerous potential mechanisms to be involved in determining the role of endogenous opioid peptides in neuronal plasticity and hippocampal function. Acknowledgement--The work in the authors laboratory was
supported by a grant from the U.S. Public Health Service (DA 04123). REFERENCES
Bramham C., Milgram N. and Srebro B. (199I) Delta opioid receptor activation is required to induce LTP of synaptic transmission in the lateral perforant path in vivo. Brain Res. 567, 42-50. Burgard E. C. and Sarvey J. M. (1990) Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rate dentate gyrus. Neurosci. Letl. 116, 34~39. Candle R. M., Wagner J. J. and Chavkin C. ( 199l) Endogenous opioids released from perforant path modulate norepinephrine release and inhibitory postsynaptic potentials in guinea pig CA3 pyramidal Cells. J. Pharmac. exp. Ther. 258, 18-26.
Chavkin C., Neumaier J. F. and Swearengen E. (1988) Opioid receptor mechanisms in the rat hippocampus. In : Opioids in the Hippocampus (McGinty J. and Friedman D., eds). NIDA Res. Monoyr. 82, 94-117. Gall C., Brecha N., Karten H. and Chang K-J. (1981) Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus. J. comp. Neurol. 198, 335 350. Goldstein A. and Naidu A. (I 989) Multiple opioid receptors : ligand selectivity profiles and binding site signature. Molec. Pharm. 36, 265 272. |lles P. (1989) Modulation of transmitter and hormone
460
Critique
release by multiple neuronal opioid receptors. ReL,. Physiol. Biochem. Pharmac. 112, 13~233. Jiang Q , Takemori A. E., Sultana M., Portoghese P. S., Bowen W. D., Mosberg H. I. and Porreca F. (1991) Differential antagonism ofopioid delta antinociception by [D-ala2,1euS,cys 6] enkephalin and naltrindole 5'-isotheriocynate: evidence for delta receptor subtypes~. J. Pharmac. exp. Ther. 257, 1069- 1075. Madison D. V. and Nicoll R. A. 0988) Enkephalin hyperpolarizes interneurones in the rat hippocampus. J. Physiol. 398, 123-130. McGinty J., Henriksen S., Goldstein A., Terenius L. and Bloom F. (1983) Dynorphin is contained within hippocampal mossy fibers: immunochemical alterations after kainic acid administration and colchicine induced neurotoxicity. Proc. natn. Acad. Sei., U.S.A. 80, 589-593. McLean S., Rothman R., Jacobson A., Rice K. and Herkenham M. (1987) Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster. J. comp. Neurol. 255, 497-510. Mott D. and Lewis (1991) Facilitation of the induction of long-term potentiation by GABAa receptors. Science 252, 1718--1720. Nock B., Giordano L., Cicero T. and O'Connor L. (1990) Affinity of drugs and peptides for U-69,593-sensitive and -insensitive kappa opiate binding sites : the U-69,593-insensitive site appears to be the beta endorphin-specific epsilon receptor. J. Pharmac. exp. Ther. 254, 412 419. Pasternak G. W. and Wood P. L. (1986) Multiple mu receptors. Life Sci. 38, 1889 1898.
Sofuoglu M., Portoghese P. S. and Takemori A. E. (1991) Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for delta receptor subtypes. J. Pharmae. exp. Ther. 257, 676- 680. Stanton P. K. and Sarvey J. M. (1985) Depletion of norepinephrine, but not serotonin, reduces long-term potentiation in the dentate of rat hippocampal slices. J. Neurosci. 5,2169 2176. Wagner J. J., Caudle R. M. and Chavkin C. (1990) Stimulation of endogeneous opioid release displaces mu receptor binding in rat hippocampus. Neuroscience 37, 45 53. Wagner J. J., Evans C. and Chavkin C. (1991) Focal stimulation of mossy fibers releases endogenous dynorphins that bind xropioid receptors in guinea pig hippocampus. J. Neurochem. 57, 333 343. Wagner J. J., Caudle R. M. and Chavkin C. (1992) Kappa opioids decrease excitatory transmission in the dentate gyrus of the guinea pig hippocampus. J. Neurosei. 12, 132 139. Xie C.-W. and Lewis D. V. (1991) Opioid-mediated facilitation of long-term potentiation at the lateral perforant path-dentate granule cell synapse. J. Pharmae. e vp. Ther. 256, 289 296. Zukin R., Eghbali M., Olive D., Unterwald E. and Tempel A. (1988) Characterization and visualization of rat and guinea pig i, opioid receptors: Evidence for ~-~ and ~'~ opioid receptors. Proc. natn Acad. Sci., U.S.A. 85, 4061 4065.
0197-0186/92 $5.00 + 0.00 Copyright © 1992 Pergamon Press Ltd
CRITIQUE E N D O G E N O U S OPIOIDS A N D LTP: ANOTHER VIEW JOHN J. WAGNER and CHARLES CHAVKIN Department of Pharmacology, SJ-30, University of Washington, Seattle, WA 98195, U.S.A.
Clive Bramham has written a provocative review summarizing the data which suggests that endogenous opioid peptides regulate LTP at specific synapses in the hippocampus. We have also been studying the role of endogenous opioids in the hippocampus for several years, and would like to comment and expand on a few points brought up by Dr Bramham. As mentioned in the review, although the pharmacological effects of exogenously applied opioids in the hippocampus have been extensively studied, the actions of endogenously released opioids remain relatively undefined. What is clear is that further characterization of the physiologic roles of endogenous opioids in hippocampal function requires a better understanding of the physiologic conditions under which the peptides are released, their normal cellular sites of action, and their subsequent effects on the target cells, It is also clear that a simple extrapolation from the pharmacological effects of exogenously applied opioids to the physiological effects of endogenously released opioids will not be a trivial exercise. Dr Bramham presents many of the complexities of this issue. We do know that the diversity of opioid actions in the hippocampus suggests that the answer to the question, "Do endogenous opioids regulate LTP?." will not be a simple affirmative.
PHYSIOLOGICAL STIMULATION CONDITIONS REQUIRED TO RELEASE ENDOGENOUS OPIOID PEPTIDES IN THE HIPPOCAMPUS
As described, opioid peptides are present in the granule cells, scattered nonpyramidal cells, and lateral perforant path terminals within the hippocampal formation. Our work supports the hypothesis that opioids could be involved in LTP processes. As reviewed by Dr Bramham, opioid peptides present in the mossy fibers (the axons of the granule cells) and 457
lateral perforant path (axons from the enkephalincontaining cells in the entorhinal cortex) (Gall et al., 1981 ; McGinty et al., 1983), can release opioid peptides following appropriate stimulation. Using a hippocampal slice radioligand binding assay to measure peptide release in situ, we found that stimulation conditions which are the most effective in releasing endogenous opioids consist of high frequency (1050 Hz) trains of pulses (Caudle et al., 1991 ; Wagner et al., 1990, 1991), conditions that could also be effective in eliciting LTP. Other work cited by Dr Bramham supports the general theme that the release of peptide neurotransmitters may be frequency-encoded. These results suggest that opioids may function to modulate the properties of the hippocampal circuit under conditions of intense activity.
PHYSIOLOGICAL SITES OF ENDOGENOUS OPIOID ACTION Receptor autoradiography has been used to define the potential sites of opioid action, but as described by Herkenham and co-workers and reviewed by Dr Bramham, the "mismatch" between peptide and receptor distributions suggests that either the peptide can diffuse some distance from its sites of release to its sites of action or that only a subset of the available receptors normally see peptide. The specific sites of action for endogenous opioids in the hippoeampal formation remains to be rigorously characterized. This requires a measure of the direct effects of endogenously released peptide. Previous work using exogenously applied opioids can serve as a guide and has established potential targets in the hippocampus : (l) opioids inhibit the excitability of local circuit interneurons and reduce G A B A release (Madison and Nicoll, 1988), and (2) opioids inhibit the release of various other transmitters such as norepinephrine,
458
Critique
acetylcholine, and serotonin from afferent terminals (see llles, 1989 for review). The electrophysiological effects of opioid inhibition of GABA release has been documented by many laboratories (see Chavkin, 1988, for one review). The electrophysiological consequences of opioid inhibition of other transmitter's release has been more difficult to show. Using a high-frequency stimulation paradigm, we demonstrated that endogenous opioids released from the perforant path can modulate inhibitory postsynaptic potentials recorded in CA3 pyramidal cells (Caudle et al., 1991). Although indirect, this measure of endogenous opioid action indicated that the released opioid peptides were likely to be acting by inhibiting an excitatory adrenergic input to the interneurons involved in mediating the IPSP response in the CA3 cells. In the dentate gyrus, we have found that U69,593 (a ~,, selective opioid agonist) decreased excitatory transmission at the perforant path granule ceils synapse by inhibiting the release of excitatory amino acids from presynaptic terminals (Wagner et al., 1992). How these actions would affect LTP induction or expression is not yet known, but since glutamate, norepinephrine, and acctylcholine have each been shown to facilitate LTP (Stanton and Sarvey, 1985: Burgard and Sarvey, 1990), endogenous opioid inhibition of their actions could potentially inhibit LTP induction or expression.
DO O P I O I D RECEPTORS DIRECTLY AFFECT THE PRINCIPAL NEURONS IN THE H I P P O C A M P A L FORMATION?
The model presented by Dr Bramham suggests that ~5-receptors are present on the granule cells. Available physiologic evidence indicates that this is not likely. Neither our work nor that of others has revealed any direct action of opioids on pyramidal or granule cells in the hippocampal formation. The evidence suggests that the modulatory effects of endogenous opioids at dentate granule cell synapse are likely to be caused by an inhibition of interneuron activity or presynaptic transmitter release. In support of this conclusion, it recent report by Xie and Lewis (1991) described the effects of both the opioid antagonist naloxone and the p-selective agonist PLO17 on LTP at the lateral perforant path (LPP)-dentate granule cells synapse. Their analysis of the data led them to propose that endogenous opioids released from perforant path terminals facilitated the induction of LTP by inhibiting GABA release from interneurons. In another study, Mott and Lewis (1991) demonstrated that a disinhibitory mechanism mediated by GA BAu receptors
was required for LTP induction under certain conditions in the rat dentate gyrus. A second problem with the model presented by Dr Bramham is that all of the direct effects of ~%receptor activation reported in the hippocampus are inhibitory. Thus, a pcrinissivc role for endogenous opioids in LTP induction in thc dentate gyrus via a direct effect of opioid action on dentate granule cells or I.,PP terminals is currently unsupported. As presented in the review, the dissociation between opioid effects on LTP of the EPSP slope compared with LTP of the granule cell population spike response is an interesting observation. Dr Bramham has proposed that different types of opioid receptors may be involved in mediating this ettEct. By placing ,5receptors in the synaptic region and l~-receptors on interneurons regulating the population response, the results of Bramham et al. (1991) and Xie and Lewis (1991) can be rationalized. However, this placement of opioid receptors is not totally consistent with the natoxone data shown in Fig. 2 of the review. Naloxone has a 10-50-fold higher affinity for #-than ¢%receptors (Goldstein and Naidu, 1989): therefore, the sitc of LTP induction which should be most sensitive to the presence of naloxone was unaffected (granule cell population response), whereas the site proposed to be influenced by ~%receptors was blocked by 100 nM naloxone. ADDITIONAL CONCERNS
Whenever studies concerning the potential actions of endogenous opioids are being collated and distilled, some important issues need to be considered. As mentioned in the review, significant differences exist in the anatomical distribution of opioid receptors among the animal species commonly studied. For example, comparing opioid binding sites in the rat and the guinea pig reveals quite different patterns of receptor distribution. The re-receptor system is a useful illustration: two subtypes of r,--receptors can be distinguished based on binding selectivity profiles (Zukin et al., 1988; Nock et al., 1990). The x~ or U69.593sensitive receptor is localized primarily in the molecular layer of the dentate gyrus in guinea pig hippocampus (Wagner et al., 1991). In contrast, in the rat, this receptor subtype is a relatively rare ( > 10%) component of the total x-binding sites (Zukin et al., 1988). This becomes important when the physiologic actions of the putative endogenous ligands for ~¢receptor are being studied, as it has been shown thai dynorphins have a much higher affinity for the ~¢, subtype of receptor than for the ~c: subtype (Nock et
Critique al., 1990). The lack of xl sites in the CA3 region
changes our expectations of endogenous dynorphin actions. At the mossy fiber-CA3 synapse, it is clear that the apparent lack of x-receptor mediated modulation of LTP by dynorphins released from the mossy fibers is likely due to the absence of X l receptors in the stratum lucidum of both guinea pig and rat CA3 regions. The distribution of x-receptors described in the review by Bramham was based on autoradiographic results using nonselective radioligands which would bind both the x~ and the x2 subtypes of x-receptor (McLean et al., 1987). More recent studies indicate that the reported population of K-binding sites present in the stratum lucidum of rat and guinea pig are likely to be the x2 subtype of receptor (Wagner et al., 1991). Further characterization of the x2 system awaits the development of selective ligands for that binding site; however, the very low affinities of the known endogenous opioids for this site is problematic. In addition to work on K-subtypes, other evidence has been accumulating which indicates that subtypes of/~- and &receptors also exist (Pasternak and Wood, 1986 ; Sofuoglu et al., 1991 ; Jiang et al., 1991). Obviously, as new subtype selective compounds become available, it will be necessary to reevaluate the results from previous studies. As mentioned above, we have recently reported evidence indicating that the perforant path terminals in the molecular layer of the guinea pig dentate gyrus are a likely endogenous target for dynorphins released from dentate granule cells (Wagner et al., 1991, 1992). As a result, in contrast to the facilitating role of endogenous opioids in LTP processes put forth in Dr Bramham's review, our work demonstrating that x~ ligands act to inhibit excitatory transmission would suggest an inhibitory role for endogeneously released dynorphin on LTP induction and/or expression by acting at the perforant path-dentate granule cell synapse in the guinea pig dentate gyrus (Wagner et al., 1992). DO ENDOGENOUS OPIOID PEPTIDES FACILITATE LTP INDUCTION? Studies cited by Dr Bramham clearly indicate that at two sites : the LPP synapse on the dentate granule cells and the mossy fiber synapse on the CA3 pyramidal cell, endogenous opioids can facilitate LTP induction. The actions of exogenously applied opioids have implicated two likely cellular sites of action. Endogenous opioids acting on interneurons to inhibit GABA release could contribute to LTP induction via a disinhibitory mechanism. Whether endogenous
459
opioids acting to inhibit glutamate, acetylcholine, or norepinephrine release could also facilitate LTP would appear much less likely. In particular, the inhibitory effects of x-opioids on glutamate release from the perforant path suggests that under some conditions, endogenous opioids might block LTP induction or expression. Since opioids regulate the release of a broad range of transmitters in the hippocampus, the net effect of endogenous opioid release would depend on the physiological state of the animal or preparation; it is obvious that the state of the hippocampus in an anesthetized animal and deafferented slice is likely to be different both from each other and from the freely moving animal. Although we have taken some exception to the specific hypothetical model presented by Dr Bramham, we are not attempting to detract from the evidence described which indicates that endogenous opioids can act to facilitate LTP processes occurring at certain synapses in the hippocampus. Rather we have presented some of our results to illustrate the point that the diversity present in the endogenous opioid peptide-receptor system allows for numerous potential mechanisms to be involved in determining the role of endogenous opioid peptides in neuronal plasticity and hippocampal function. Acknowledgement--The work in the authors laboratory was
supported by a grant from the U.S. Public Health Service (DA 04123). REFERENCES
Bramham C., Milgram N. and Srebro B. (199I) Delta opioid receptor activation is required to induce LTP of synaptic transmission in the lateral perforant path in vivo. Brain Res. 567, 42-50. Burgard E. C. and Sarvey J. M. (1990) Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rate dentate gyrus. Neurosci. Letl. 116, 34~39. Candle R. M., Wagner J. J. and Chavkin C. ( 199l) Endogenous opioids released from perforant path modulate norepinephrine release and inhibitory postsynaptic potentials in guinea pig CA3 pyramidal Cells. J. Pharmac. exp. Ther. 258, 18-26.
Chavkin C., Neumaier J. F. and Swearengen E. (1988) Opioid receptor mechanisms in the rat hippocampus. In : Opioids in the Hippocampus (McGinty J. and Friedman D., eds). NIDA Res. Monoyr. 82, 94-117. Gall C., Brecha N., Karten H. and Chang K-J. (1981) Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus. J. comp. Neurol. 198, 335 350. Goldstein A. and Naidu A. (I 989) Multiple opioid receptors : ligand selectivity profiles and binding site signature. Molec. Pharm. 36, 265 272. |lles P. (1989) Modulation of transmitter and hormone
460
Critique
release by multiple neuronal opioid receptors. ReL,. Physiol. Biochem. Pharmac. 112, 13~233. Jiang Q , Takemori A. E., Sultana M., Portoghese P. S., Bowen W. D., Mosberg H. I. and Porreca F. (1991) Differential antagonism ofopioid delta antinociception by [D-ala2,1euS,cys 6] enkephalin and naltrindole 5'-isotheriocynate: evidence for delta receptor subtypes~. J. Pharmac. exp. Ther. 257, 1069- 1075. Madison D. V. and Nicoll R. A. 0988) Enkephalin hyperpolarizes interneurones in the rat hippocampus. J. Physiol. 398, 123-130. McGinty J., Henriksen S., Goldstein A., Terenius L. and Bloom F. (1983) Dynorphin is contained within hippocampal mossy fibers: immunochemical alterations after kainic acid administration and colchicine induced neurotoxicity. Proc. natn. Acad. Sei., U.S.A. 80, 589-593. McLean S., Rothman R., Jacobson A., Rice K. and Herkenham M. (1987) Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster. J. comp. Neurol. 255, 497-510. Mott D. and Lewis (1991) Facilitation of the induction of long-term potentiation by GABAa receptors. Science 252, 1718--1720. Nock B., Giordano L., Cicero T. and O'Connor L. (1990) Affinity of drugs and peptides for U-69,593-sensitive and -insensitive kappa opiate binding sites : the U-69,593-insensitive site appears to be the beta endorphin-specific epsilon receptor. J. Pharmac. exp. Ther. 254, 412 419. Pasternak G. W. and Wood P. L. (1986) Multiple mu receptors. Life Sci. 38, 1889 1898.
Sofuoglu M., Portoghese P. S. and Takemori A. E. (1991) Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice: evidence for delta receptor subtypes. J. Pharmae. exp. Ther. 257, 676- 680. Stanton P. K. and Sarvey J. M. (1985) Depletion of norepinephrine, but not serotonin, reduces long-term potentiation in the dentate of rat hippocampal slices. J. Neurosci. 5,2169 2176. Wagner J. J., Caudle R. M. and Chavkin C. (1990) Stimulation of endogeneous opioid release displaces mu receptor binding in rat hippocampus. Neuroscience 37, 45 53. Wagner J. J., Evans C. and Chavkin C. (1991) Focal stimulation of mossy fibers releases endogenous dynorphins that bind xropioid receptors in guinea pig hippocampus. J. Neurochem. 57, 333 343. Wagner J. J., Caudle R. M. and Chavkin C. (1992) Kappa opioids decrease excitatory transmission in the dentate gyrus of the guinea pig hippocampus. J. Neurosei. 12, 132 139. Xie C.-W. and Lewis D. V. (1991) Opioid-mediated facilitation of long-term potentiation at the lateral perforant path-dentate granule cell synapse. J. Pharmae. e vp. Ther. 256, 289 296. Zukin R., Eghbali M., Olive D., Unterwald E. and Tempel A. (1988) Characterization and visualization of rat and guinea pig i, opioid receptors: Evidence for ~-~ and ~'~ opioid receptors. Proc. natn Acad. Sci., U.S.A. 85, 4061 4065.
