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Opiate receptors on catecholaminergic neurones in brain
TINS - June 1979
137
Neuro ieu' Opiate receptors on catecholaminergic neurones in brain Jean-Charles Schwartz
The identification o f neuronal systems bearing opiate receptors in brain is helping to elucidate the acute as well as the chronic behavioural actions o f morphine-like drugs. Lesion studies indicate that opiate receptors are to be found on dopaminergic and noradrenergic cells, not only on their nerve-endings, but probably also on their cell bodies. Can all opiate receptors therefore be regarded as postsynaptic receptors for opioid peptide-containing neurones? What are the actions they mediate on catecholaminergic transmission? Do these features contribute to our understanding o f the mechanisms o f addiction? As shown in this article, recent data are bringing some light on these various questions. It is already a truism to state that the field Morphine may interrupt these messages of opiate research has been characterized through presynaptic inhibition of the by major advances in the last years, the release of substance P: opiate receptors landmarks of which have been the are localized on the nerve-terminals of characterization of the opiate receptors by these sensory afferents as has been shown binding studies followed by the identifica- by the decreased number in substantia tion of several opioid peptides as their gelatinosa following dorsal root section; endogenous ligands. From a variety of these receptors could well represent the data it now appears very likely that these target of the short ENK neurones which peptides, particularly the enkephalins have been seen at this level; furthermore, (ENKs), which are contained in discrete they could also mediate an inhibition of sets of neurones in the brain, exert a substance P release as has been shown in a neurotransmitter role, thus suggesting tissue slice preparation 5. that opiate receptors should be considered But, in addition to their analgesic as postsynaptic receptors for these pep- effects, opioids have multiple behavioural tidergic neurones. actions and appear to modify the activity Recently, the localization of ENK of a variety of neuronal systems in the neurones by immunohistochemistry, that CNS. It would be of interest to analyse of the opiate receptors by binding and such actions in the same way as has been autoradiographic studies, and the charac- and is being done for the pain-transmitting terization of the action of opioid agents at system in the spinal cord. Indeed, opiate the cellular level, have begun to clarify the receptors are distributed heterogenously way in which morphine-like compounds throughout the CNS with,high densities in exert their complex behavioural effects. A areas relating to functions affected by the good example is provided by the analysis administration of opioids: for instance, of the mechanisms of analgesia at the level the high density of receptors in the limbic of the spinal cord. system may be related to the characteristic changes in mood which humans experiAnalgesic and non-analgesic actions of ence upon administration of morphineopioids like drugs, or during abstinence. HowIn the spinal cord, nociceptive messages ever, it is clear that a better understanding are conveyed to the substantia gelatinosa of such complex action requires a precise by sensory afferents entering through the identification of the neuronal systems dorsal root and which are likely to use bearing the opiate receptors, and which substance P as an excitatory transmitter. are therefore likely to be directly
involved. Catecholaminergic systems in brain appeared as valuable candidates to start such an investigation in view of (i) their well-establishedanatomical disposition; (ii) the availability of a chemical tool to ablate them selectively, i.e. 6-hydroxydopamine; (iii) their probable involvement in the control of mood; (iv) the numerous, although not always consistent, reports showing that their activity is modified upon morphine administration.
Opiate receptors localized on nigrostriatal dopaminergic neurones The striatum is one of the brain regions containing the highest density of opiate receptors. In this region dopaminergic neurones originating from the substantia nigra project in a heterogenous fashion as demonstrated by the antero-posterior variation in dopamine (DA) content. The somewhat parallel variation in opiate receptors suggested that these receptors might be localized upon DA nerveterminals themselves. In confirmation of this hypothesis, when nigrostriatal DA neurones are made to degenerate by various types of selective lesions, a decrease by about 30% in the number of opiate receptors in the striatum is consistently observed. This decrease occurs somewhat more slowly than that of DA levels, but this might reflect the slower disappearance of membrane components as compared with intracellular components (such as Storage granules) during the degeneration process. It is unlikely that the effect is consequent to trans-synaptic degeneration because intrastriatal cholinergic neurones, upon which D A neurones are known to impinge, are not affected when the DA neurones degenerate. The receptors on DA neurones account for only about one-third of the total number of opiate receptors in the striatum, but one should also bear in mind that D A neurones represent only a small percentage of the total number of striatal neurones. That the major fraction of the remaining receptors is present on other kinds of neurones having their cell bodies within the striatum is confirmed by local injection of kainic acid, a neurotoxin which rather selectively ablates neurones having their soma near the injection site. Thus, after kainic acid injection, the decrease in striatal opiate receptors is by about 50%, and this effect is additive to that following degeneration of DA neurones. Elsevier/North-Holland Biomedical Press 1979
138
TINS' - June 1979
The localization of opiate receptors upon D A nerve-terminals suggests that they might function as presynaptic receptors, and that ENK neurones might form axo-axonic contacts through which they could modulate D A release or synthesis. In agreement with this view we have recently observed that DA terminals bear not only opiate receptors, but also a high-affinity ENK-degrading peptidase ('enkephalinase') which might also represent a characteristic post-synaptic component of putative enkephalinergic synapses 9. However, such an interpretation cannot be accepted Without caution because morphologists have, as yet, failed to detect axo-axonic contacts upon striatal DA neurones. In addition, lesion studies show that opiate receptors are not only present on terminals of D A neurones, but also on their soma and/or dendrites. Furthermore, when one compares the total number of opiate receptors on the two parts of the D A neurones, i.e. in the substantia nigra and in the striatum, one finds that the ratio is approximately the same (1:15) as that estimated for DA uptake capacity in the two areas. Because this transport system is regarded as a constituent of the whole membrane of the
catecholamine neurone, this raises the interesting possibility that opiate receptors might be uniformly distributed on the entire neuronal membrane, as also suggested by their autoradiographic detection on axons?. This would probably mean that a number of these receptors are 'silent' ones, and that their presence detected at a certain level cannot be directly interpreted as evidence for an ENK contact, nor, even, for an opiate action at this level.
only about 1400 cells, essentially all of which are noradrenergic, and it exhibits a high density of opiate receptors ?. Therefore, for NA as for DA neurones, opiate receptors might be present at the terminals as well as on the soma. Actions of opiates on catecholaminergie neurones
That synthetic opiates and opioid peptides affect the activity of catecholaminergic neurones, is indicated by the increased turnover of NA and DA which they elicit. However, such an effect needs to be interpreted. Does it reflect increased or decreased catecholaminergic transmission, since it can be observed under both situations (in the latter case through compensatory mechanisms)? Is the effect a direct or an indirect one, mediated by opiate receptors on the neuronal surface (as indicated from our lesion studies)? If direct, does it involve receptors located on terminals or on cell bodies? As regards NA neurones originating from the locus coeruleus, it is clear that the net result of opiate administration is an impaired noradrenergic transmission. Thus morphine and ENKs reduce the depolarization-induced release of NA
Opiate receptors on other classes of catecholaminergic neurones
Following lesions of the mesolimbic DA neurones, opiate receptors decrease in regions to which the DA neurones project, regions like the nucleus accumbens or the septum. This DA system is possibly involved in the aetiology of chronic psychosis, and these receptors could mediate the effects of opioid peptides and their antagonists recently observed in these diseases, although reports are still inconsistent in this respect. Using the same kind of approach, opiate receptors have been demonstrated on cortical and cerebellar noradrenergic (NA) nerve-terminals originating from the locus coeruleusL This nucleus contains
Noradrenergic neurone
NA release
Response
°°°
Normal situation
o 0 o ooo
~
Opiate ~ receptors
(~)
AcUtemorphine
' ,4~'~
Normal
Noradrenergic receptors
....
o o
,,.
Decreased
~
Normal
Morphine
Chronic morphine
~
0 o
0
~
Morphine
I~)
Abstinence
000 000 QOO
Fig. I. Model for the effects o f acute and chronic morphine treatment on noradrenergic transmission B.
Increased
139
TINS - June 1979
from cortical and cerebellar slices, sug- aptic receptors, develops. As could be gesting the involvement of a presynaptic expected from the primary inhibitory inhibitory mechanism similar to that actions of opiates on N A neurotransmediating their antinociceptive actions at mission, the responsiveness of cerebral the level of the spinal cord a,l°. Presynaptic target-cells to N A progressively increases inhibition of N A release from postgang- in rats chronically treated with morphine. lionic sympathetic neurones is also appar- This change, demonstrated on the cyclic ently responsible for the inhibition of the A M P generating system of cortical slices, electrically induced contraction of mouse appears to be due to an increased number vas deferens, one of the favourite tests o f of fl-adrenergic receptors and outlasts the opiate pharmacologists. Because opiates triggering treatment by several days s. also inhibit the release of a variety of other We have proposed that 'disuse neurotransmitters, it is tempting to hypersensitivity' underlies the processes postulate that presynaptic inhibition is a of tolerance to, and physical dependence major mode of action of these agents. However, when morphine is applied to neurones in the locus coeruleus, their spontaneous activity diminishes, suggesting that an impairment of N A transmission might also be mediated by opiate receptors on the soma or dendrites of N A neurones e. Although likely, this hypothesis needs to be confirmed, and the identity of affected neurones and the precise localization of opiate receptors at this level needs to be clearly established. The situation as regards D A neurones is, at present, far from clear. In rats, the administration of opioids elicits behavioural symptoms of decreased dopaminergic transmission, such as akinesia. Along the same lines, these agents have been reported to impair the depolarization-induced release of D A from striatal slices, an observation which They're giving me morphine to stop the craving for would be consistent with the presence of clonidine, which they gave me to stop the craving for opiate receptors on D A nerve-terminals. morphine, to stop the craving f o r . . . However, recently this effect could not be confirmed: this raises the possibility that on, opiates, an hypothesis already put opiate binding sites might be scattered all forward several years ago in general terms along the D A neurones, but might be by Harry CollieP. As illustrated in Fig. 1, considered as functional receptors only at the primary inhibitory effect of morphine certain levels such as on the cell bodies in on N A transmission could be progresthe substantia nigra. The actions of sively compensated for, during a chronic opiates at this level are difficult to analyse treatment, by the increased responsivebecause opiate receptors are present not ness of the target-cell to NA (tolerance). only on D A cells, but also on GABAergic Upon morphine withdrawal, NA release nerve-endings (C. Llorens, H. Pollard and being restored, the rebound response of J.-C. Schwartz, unpublished observa- hypersensitive target-cells would account tions), where they appear to mediate a for the withdrawal symptoms which are presynaptic inhibition of y-amino- generally opposite to those observed upon butyric acid ( G A B A ) release 4. In view initial administration. Morphine would, of the tonic inhibitory action of G A B A therefore, be 'craved' to prevent excess on D A neurones, this would possibly responses of the target-cells. account for the increased D A turnover Because morphine does not only inhibit elicited by opiates. the release of NA, 'disuse hypersensitivity' to a variety of neurotransmitters in the Involvement of noradrenergic systems in CNS might be responsible for the complex addiction symptoms of the abstinence syndrome. When catecholaminergic transmission Nevertheless, the disappearance of major in CNS is durably impaired by various withdrawal signs in addicted humans treatments, a compensatory mechanism, receiving clonidine, a drug which rather i.e. 'disuse hypersensitivity' of postsyn- selectively diminishes noradrenergic
transmission, suggests that N A systems may be involved primarilyL According to the model of Fig, 1, it is not necessary to postulate that the chain of events from opiate-receptor binding to inhibition of N A release is modified in animals chronically treated with morphine. Whereas [all]opiate binding is, in fact, not modified in the brain of such animals ts,~s, further work is probably needed to assess whether changes in the subsequent events of the chain also occur, or whether 'disuse hypersensitivity' is the sole mechanism involved in tolerance and addiction. Reading list 1. Arbilla, S. and Langer, S. Z. (1978) Nature (London) 271,559-560. 2. Collier, H. O. J. (1965)Nature (London) 205, 181-182. 3. Gold, M. S., Redmond Jr., D. G. and Kleber, H. D. (1978) Lancet ii, 599-601. 4. Iwatsubo, K. and Kondo, Y. (1978) In : J. M. van Ree and L. Terenius (eds), Characteristics and Function of Opioids, Elsevier/NorthHolland Biomedical Press, Amsterdam, New York and Oxford, pp. 357-358. 5. Jessel, T. M. and Iversen, L. L. (1977) Nature (London) 268. 549-551. 6. Korf, J., Bunney, B. S. and Aghajanian, G. K. (1974) Eur. J. Pharmacol. 25, 165-169. 7. Kuhar, M. J. (1978) In: M. A. Lipton, A. Di Mascio and K. 17. Kiliam (eds), Psychopharmacology: A Generation of Progress, Raven Press, New York, pp. 317-376. 8, LIorens, C,, Martres, M, P., Baudry, M, and Schwartz, J.-C. (1978) Nature (London) 274, 603--605. 9. Malfroy,B., Swerts, J. P., Guyon, A., Roques, B.P. and Schwartz, J.-C. (1978) Nature (London) 276, 523-526. 10. Montel, H., Starke, K. and Taube, H. D. (1975) Naunyn Schmiedebergs Archs Pharmakol. 288, 415-426. 11. Pollard, H., Llorens, C., Schwartz,J.-C., Gros, C. and Dray, F. (1978) Brain Res. 151, 392-398. 12. Simon,E. J. and Hiller, J. M. (1978)Annu. Rev. Pharmacol. Toxicol. 18, 371-394. 13. Snyder, S. H. and Simantov, R. (1977) J. Neurochem. 28. 13-20.
J.-C. SCHWARTZ J,-C. Schwartz is Professor o f Physiology and Head o f the Neurobiology Unit ( U. 109), Centre Paul Broca de I'I.N.S.E.R.M., 2ter rue d'Al~sia, 75014 Paris. France.
137
Neuro ieu' Opiate receptors on catecholaminergic neurones in brain Jean-Charles Schwartz
The identification o f neuronal systems bearing opiate receptors in brain is helping to elucidate the acute as well as the chronic behavioural actions o f morphine-like drugs. Lesion studies indicate that opiate receptors are to be found on dopaminergic and noradrenergic cells, not only on their nerve-endings, but probably also on their cell bodies. Can all opiate receptors therefore be regarded as postsynaptic receptors for opioid peptide-containing neurones? What are the actions they mediate on catecholaminergic transmission? Do these features contribute to our understanding o f the mechanisms o f addiction? As shown in this article, recent data are bringing some light on these various questions. It is already a truism to state that the field Morphine may interrupt these messages of opiate research has been characterized through presynaptic inhibition of the by major advances in the last years, the release of substance P: opiate receptors landmarks of which have been the are localized on the nerve-terminals of characterization of the opiate receptors by these sensory afferents as has been shown binding studies followed by the identifica- by the decreased number in substantia tion of several opioid peptides as their gelatinosa following dorsal root section; endogenous ligands. From a variety of these receptors could well represent the data it now appears very likely that these target of the short ENK neurones which peptides, particularly the enkephalins have been seen at this level; furthermore, (ENKs), which are contained in discrete they could also mediate an inhibition of sets of neurones in the brain, exert a substance P release as has been shown in a neurotransmitter role, thus suggesting tissue slice preparation 5. that opiate receptors should be considered But, in addition to their analgesic as postsynaptic receptors for these pep- effects, opioids have multiple behavioural tidergic neurones. actions and appear to modify the activity Recently, the localization of ENK of a variety of neuronal systems in the neurones by immunohistochemistry, that CNS. It would be of interest to analyse of the opiate receptors by binding and such actions in the same way as has been autoradiographic studies, and the charac- and is being done for the pain-transmitting terization of the action of opioid agents at system in the spinal cord. Indeed, opiate the cellular level, have begun to clarify the receptors are distributed heterogenously way in which morphine-like compounds throughout the CNS with,high densities in exert their complex behavioural effects. A areas relating to functions affected by the good example is provided by the analysis administration of opioids: for instance, of the mechanisms of analgesia at the level the high density of receptors in the limbic of the spinal cord. system may be related to the characteristic changes in mood which humans experiAnalgesic and non-analgesic actions of ence upon administration of morphineopioids like drugs, or during abstinence. HowIn the spinal cord, nociceptive messages ever, it is clear that a better understanding are conveyed to the substantia gelatinosa of such complex action requires a precise by sensory afferents entering through the identification of the neuronal systems dorsal root and which are likely to use bearing the opiate receptors, and which substance P as an excitatory transmitter. are therefore likely to be directly
involved. Catecholaminergic systems in brain appeared as valuable candidates to start such an investigation in view of (i) their well-establishedanatomical disposition; (ii) the availability of a chemical tool to ablate them selectively, i.e. 6-hydroxydopamine; (iii) their probable involvement in the control of mood; (iv) the numerous, although not always consistent, reports showing that their activity is modified upon morphine administration.
Opiate receptors localized on nigrostriatal dopaminergic neurones The striatum is one of the brain regions containing the highest density of opiate receptors. In this region dopaminergic neurones originating from the substantia nigra project in a heterogenous fashion as demonstrated by the antero-posterior variation in dopamine (DA) content. The somewhat parallel variation in opiate receptors suggested that these receptors might be localized upon DA nerveterminals themselves. In confirmation of this hypothesis, when nigrostriatal DA neurones are made to degenerate by various types of selective lesions, a decrease by about 30% in the number of opiate receptors in the striatum is consistently observed. This decrease occurs somewhat more slowly than that of DA levels, but this might reflect the slower disappearance of membrane components as compared with intracellular components (such as Storage granules) during the degeneration process. It is unlikely that the effect is consequent to trans-synaptic degeneration because intrastriatal cholinergic neurones, upon which D A neurones are known to impinge, are not affected when the DA neurones degenerate. The receptors on DA neurones account for only about one-third of the total number of opiate receptors in the striatum, but one should also bear in mind that D A neurones represent only a small percentage of the total number of striatal neurones. That the major fraction of the remaining receptors is present on other kinds of neurones having their cell bodies within the striatum is confirmed by local injection of kainic acid, a neurotoxin which rather selectively ablates neurones having their soma near the injection site. Thus, after kainic acid injection, the decrease in striatal opiate receptors is by about 50%, and this effect is additive to that following degeneration of DA neurones. Elsevier/North-Holland Biomedical Press 1979
138
TINS' - June 1979
The localization of opiate receptors upon D A nerve-terminals suggests that they might function as presynaptic receptors, and that ENK neurones might form axo-axonic contacts through which they could modulate D A release or synthesis. In agreement with this view we have recently observed that DA terminals bear not only opiate receptors, but also a high-affinity ENK-degrading peptidase ('enkephalinase') which might also represent a characteristic post-synaptic component of putative enkephalinergic synapses 9. However, such an interpretation cannot be accepted Without caution because morphologists have, as yet, failed to detect axo-axonic contacts upon striatal DA neurones. In addition, lesion studies show that opiate receptors are not only present on terminals of D A neurones, but also on their soma and/or dendrites. Furthermore, when one compares the total number of opiate receptors on the two parts of the D A neurones, i.e. in the substantia nigra and in the striatum, one finds that the ratio is approximately the same (1:15) as that estimated for DA uptake capacity in the two areas. Because this transport system is regarded as a constituent of the whole membrane of the
catecholamine neurone, this raises the interesting possibility that opiate receptors might be uniformly distributed on the entire neuronal membrane, as also suggested by their autoradiographic detection on axons?. This would probably mean that a number of these receptors are 'silent' ones, and that their presence detected at a certain level cannot be directly interpreted as evidence for an ENK contact, nor, even, for an opiate action at this level.
only about 1400 cells, essentially all of which are noradrenergic, and it exhibits a high density of opiate receptors ?. Therefore, for NA as for DA neurones, opiate receptors might be present at the terminals as well as on the soma. Actions of opiates on catecholaminergie neurones
That synthetic opiates and opioid peptides affect the activity of catecholaminergic neurones, is indicated by the increased turnover of NA and DA which they elicit. However, such an effect needs to be interpreted. Does it reflect increased or decreased catecholaminergic transmission, since it can be observed under both situations (in the latter case through compensatory mechanisms)? Is the effect a direct or an indirect one, mediated by opiate receptors on the neuronal surface (as indicated from our lesion studies)? If direct, does it involve receptors located on terminals or on cell bodies? As regards NA neurones originating from the locus coeruleus, it is clear that the net result of opiate administration is an impaired noradrenergic transmission. Thus morphine and ENKs reduce the depolarization-induced release of NA
Opiate receptors on other classes of catecholaminergic neurones
Following lesions of the mesolimbic DA neurones, opiate receptors decrease in regions to which the DA neurones project, regions like the nucleus accumbens or the septum. This DA system is possibly involved in the aetiology of chronic psychosis, and these receptors could mediate the effects of opioid peptides and their antagonists recently observed in these diseases, although reports are still inconsistent in this respect. Using the same kind of approach, opiate receptors have been demonstrated on cortical and cerebellar noradrenergic (NA) nerve-terminals originating from the locus coeruleusL This nucleus contains
Noradrenergic neurone
NA release
Response
°°°
Normal situation
o 0 o ooo
~
Opiate ~ receptors
(~)
AcUtemorphine
' ,4~'~
Normal
Noradrenergic receptors
....
o o
,,.
Decreased
~
Normal
Morphine
Chronic morphine
~
0 o
0
~
Morphine
I~)
Abstinence
000 000 QOO
Fig. I. Model for the effects o f acute and chronic morphine treatment on noradrenergic transmission B.
Increased
139
TINS - June 1979
from cortical and cerebellar slices, sug- aptic receptors, develops. As could be gesting the involvement of a presynaptic expected from the primary inhibitory inhibitory mechanism similar to that actions of opiates on N A neurotransmediating their antinociceptive actions at mission, the responsiveness of cerebral the level of the spinal cord a,l°. Presynaptic target-cells to N A progressively increases inhibition of N A release from postgang- in rats chronically treated with morphine. lionic sympathetic neurones is also appar- This change, demonstrated on the cyclic ently responsible for the inhibition of the A M P generating system of cortical slices, electrically induced contraction of mouse appears to be due to an increased number vas deferens, one of the favourite tests o f of fl-adrenergic receptors and outlasts the opiate pharmacologists. Because opiates triggering treatment by several days s. also inhibit the release of a variety of other We have proposed that 'disuse neurotransmitters, it is tempting to hypersensitivity' underlies the processes postulate that presynaptic inhibition is a of tolerance to, and physical dependence major mode of action of these agents. However, when morphine is applied to neurones in the locus coeruleus, their spontaneous activity diminishes, suggesting that an impairment of N A transmission might also be mediated by opiate receptors on the soma or dendrites of N A neurones e. Although likely, this hypothesis needs to be confirmed, and the identity of affected neurones and the precise localization of opiate receptors at this level needs to be clearly established. The situation as regards D A neurones is, at present, far from clear. In rats, the administration of opioids elicits behavioural symptoms of decreased dopaminergic transmission, such as akinesia. Along the same lines, these agents have been reported to impair the depolarization-induced release of D A from striatal slices, an observation which They're giving me morphine to stop the craving for would be consistent with the presence of clonidine, which they gave me to stop the craving for opiate receptors on D A nerve-terminals. morphine, to stop the craving f o r . . . However, recently this effect could not be confirmed: this raises the possibility that on, opiates, an hypothesis already put opiate binding sites might be scattered all forward several years ago in general terms along the D A neurones, but might be by Harry CollieP. As illustrated in Fig. 1, considered as functional receptors only at the primary inhibitory effect of morphine certain levels such as on the cell bodies in on N A transmission could be progresthe substantia nigra. The actions of sively compensated for, during a chronic opiates at this level are difficult to analyse treatment, by the increased responsivebecause opiate receptors are present not ness of the target-cell to NA (tolerance). only on D A cells, but also on GABAergic Upon morphine withdrawal, NA release nerve-endings (C. Llorens, H. Pollard and being restored, the rebound response of J.-C. Schwartz, unpublished observa- hypersensitive target-cells would account tions), where they appear to mediate a for the withdrawal symptoms which are presynaptic inhibition of y-amino- generally opposite to those observed upon butyric acid ( G A B A ) release 4. In view initial administration. Morphine would, of the tonic inhibitory action of G A B A therefore, be 'craved' to prevent excess on D A neurones, this would possibly responses of the target-cells. account for the increased D A turnover Because morphine does not only inhibit elicited by opiates. the release of NA, 'disuse hypersensitivity' to a variety of neurotransmitters in the Involvement of noradrenergic systems in CNS might be responsible for the complex addiction symptoms of the abstinence syndrome. When catecholaminergic transmission Nevertheless, the disappearance of major in CNS is durably impaired by various withdrawal signs in addicted humans treatments, a compensatory mechanism, receiving clonidine, a drug which rather i.e. 'disuse hypersensitivity' of postsyn- selectively diminishes noradrenergic
transmission, suggests that N A systems may be involved primarilyL According to the model of Fig, 1, it is not necessary to postulate that the chain of events from opiate-receptor binding to inhibition of N A release is modified in animals chronically treated with morphine. Whereas [all]opiate binding is, in fact, not modified in the brain of such animals ts,~s, further work is probably needed to assess whether changes in the subsequent events of the chain also occur, or whether 'disuse hypersensitivity' is the sole mechanism involved in tolerance and addiction. Reading list 1. Arbilla, S. and Langer, S. Z. (1978) Nature (London) 271,559-560. 2. Collier, H. O. J. (1965)Nature (London) 205, 181-182. 3. Gold, M. S., Redmond Jr., D. G. and Kleber, H. D. (1978) Lancet ii, 599-601. 4. Iwatsubo, K. and Kondo, Y. (1978) In : J. M. van Ree and L. Terenius (eds), Characteristics and Function of Opioids, Elsevier/NorthHolland Biomedical Press, Amsterdam, New York and Oxford, pp. 357-358. 5. Jessel, T. M. and Iversen, L. L. (1977) Nature (London) 268. 549-551. 6. Korf, J., Bunney, B. S. and Aghajanian, G. K. (1974) Eur. J. Pharmacol. 25, 165-169. 7. Kuhar, M. J. (1978) In: M. A. Lipton, A. Di Mascio and K. 17. Kiliam (eds), Psychopharmacology: A Generation of Progress, Raven Press, New York, pp. 317-376. 8, LIorens, C,, Martres, M, P., Baudry, M, and Schwartz, J.-C. (1978) Nature (London) 274, 603--605. 9. Malfroy,B., Swerts, J. P., Guyon, A., Roques, B.P. and Schwartz, J.-C. (1978) Nature (London) 276, 523-526. 10. Montel, H., Starke, K. and Taube, H. D. (1975) Naunyn Schmiedebergs Archs Pharmakol. 288, 415-426. 11. Pollard, H., Llorens, C., Schwartz,J.-C., Gros, C. and Dray, F. (1978) Brain Res. 151, 392-398. 12. Simon,E. J. and Hiller, J. M. (1978)Annu. Rev. Pharmacol. Toxicol. 18, 371-394. 13. Snyder, S. H. and Simantov, R. (1977) J. Neurochem. 28. 13-20.
J.-C. SCHWARTZ J,-C. Schwartz is Professor o f Physiology and Head o f the Neurobiology Unit ( U. 109), Centre Paul Broca de I'I.N.S.E.R.M., 2ter rue d'Al~sia, 75014 Paris. France.