819
in rats6, and in some human beings.7 8 WALL and his colleagues,9 however, have been unable to detect any increase of pain threshold after intravenous injection of naloxone 0-4—0-8 mg. BAUCHSBAUM et al.8 were more successful in increasing pain thresholds, perhaps partly because they used a bigger dose, 2 mg i.v. These workers made other important observations. If subjects were classified into two groups according to whether their normal pain threshold was greater or less than the mean threshold previously determined in a large control series, then those with a higher than average threshold (called, unfortunately, pain-insensitive) showed a reduced threshold after naloxone, whilst the other group showed a raised threshold. These results imply that a group of individuals having higher thresholds than the population mean owe that enviable distinction to an intrinsically active "analgesic-producing" neural pathway. As there was a bidirectional responsiveness to naloxone in different individuals, however, these findings also imply that endogenous compounds do not simply induce analgesia, but may be involved in a bidirectional modulation of pain sys-
reported
THE
LANCET
Enkephalins: the Search for a Functional Role THE mammalian brain contains peptides, the enkephalins and endorphins, which have pharmacological properties similar to those of morphine. Only two years ago the structure and origin of these peptides was the focus of attention.Now the
emphasis has switched to their physiological role. they, for example, released as neurotransmitters from neurons of a discrete "pain pathway"? Evidence for an anatomically discrete pathway has emerged from the demonstrations that electrical stimulation via implanted electrodes of the periventricular and periaqueductal grey matter of man can substantially alleviate otherwise intractable pain.22 These observations in man were inspired by experiments in animals.3-5 Of particular interest are the findings that tolerance arose, not only to the analgesic effects of electrical stimulation but also to opiate analgesic drugs (cross-tolerance).2Further, naloxone, a specific antagonist of opiate analgesics (used as a criterion in the isolation of enkephalins), blocked the electroanalgesia. These results are compatible with the concept of a neural pathway producing an increase of chronic pain threshold by releasing an endogenous compound susceptible to antagonism by naloxone. Though it increased chronic-pain thresholds, electrical stimulation had no effect on acute-pain thresholds in 4 of 6 patients2-a point to be discussed later. The question also arises of whether a neural "pain" system such as this is continuously active, determining normal, resting pain thresholds. Studies aimed at answering this have yielded conflicting results. The assumption has been that, if a pain system is normally active, then an analgesic antagonist such as naloxone should raise resting pain thresholds. Such a change of threshold has been Are
1. Lancet, 1976, ii, 665. 2. Hosobuchi, Y., Adams, J. E., Linchitz, R. Science, 1977, 197, 183. 3. Oliversa, J. L., Benson, J. M., Guilband, G., Liebeskind, J. C. Exp. Brain Res. 1974, 20, 32. 4. Melzack, R., Melinkoff, D. F. Exp. Neurol. 1974, 43, 369. 5. Mayer, D.J., Liebeskind,J. C.BrainRes. 1974, 68, 73. 6. Jacob, J. J , Tremblay, E. C., Colombel, M. C. Psychopharmacology, 1974,
37, 217. 7.
Lasagna, L.Proc.R.Soc.Med. 1965, 58, 978.
tems.
trying to resolve the effect of naloxone on pain thresholds, perhaps more consideration should be given to the type of pain involved. As pointed out above, naloxone can reverse central electroanalgesia for chronic pain, with no accompanying change of acute thresholds. This is consistent with the report by LEVINE et al. 10 in which naloxone produced hyperalgesia in postoperative dental patients-i.e., patients with chronic, persistent pain. This observation seems to be at least as important as the group’s main finding, that the analgesia resulting from administration of a placebo is also reversed by naloxone. The implication here is that placebo activates the central analgesia-related pathway. Two possible explanations for such an effect are that the relevant central pathways are activated by intrinsic neural (i.e., psychological) factors, and that the analgesia is related to stress. The stress explanation is attractive in view of the In
very close correlation shown in
rats between release of &bgr;-endorphin and release of adrenocorticotrophic hormone from the pituitary as a result of acute stress." However, any relation between endorphins and stress remains highly speculative: neither variations of -endorphin secretion by the pituitary" nor circulating plasma levels of &bgr;-endorphin12 bear any apparent relation to cerebral concentration of the peptide. Stress-induced release of p-endorphin 8. Buchsbaum, M. S., Davis, G. C., Bunney, W. E. Nature, 1977, 270, 620. 9. El-Sobky, A., Dostrovsky, J. O., Wall, P. D. ibid. 1976, 263, 783. 10. Levine, J. D., Gordon, N. C., Fields, H. L. Lancet, 1978, ii, 654. 11. Guillemin, R., Vargo, T., Rossier, J., Minick, S., Ling, N., Rivier, C., Vale, W., Bloom, F. Science, 1977, 197, 1367. 12. Jeffcoate, W. J., Rees, L. H., McLoughlin, L., Ratter, S. J., Hope, J., Lowry, P. J., Besser, G. M. Lancet, 1978, ii, 119.
820
from the pituitary may thus have a functional role totally divorced from analgesia. It has also been reported that naloxone will antagonise the analgesia induced by acupuncture,13 a finding which, if confirmed, has great potential implications in the neurophysiology of pain. There is no reason, of course, why these endogenous peptides should be concerned exclusively with pain. Indeed, a primary involvement in a more general emotional-state control system might include modification of pain sensitivity as merely one of many influences on sensory responsiveness and behaviour. The observation that minute doses of p-endorphin injected intraventricularly into rats to produce analgesia also induced catatonia 14 15 led to an early suspicion that the peptide could be involved in affective disorders. Increased amounts of endorphins have been detected in the cerebrospinal fluid of schizophrenic and manic patients, some showing decreased levels during remission. 16 If this correlation of endorphins and psychosis represents a cause-effect relationship, then blockade of endorphins by naloxone should alleviate the psychotic symptoms.17 Both positive and negative results have emerged with low doses (about 1 mg) of naloxone, 17-19 but encouraging results have lately been obtained by WATSON et al. 20 with 10 mg and by JANOWSKY et al. 21 with 20 mg. In particular, naloxone reduced auditory hallucinations in some schizophrenic subjects. The effect on the euphoric state is less clear. WATSON et al. observed swings of mood in their patients after naloxone, but most subjects soon became more relaxed and reported a sense of wellbeing.2O This was consistent with the results of several other laboratories. Different workers however, have shown a decrease in
euphoria patients.21-23
scores,
particularly
in
manic
The functional roles of endogenous "analgesic" peptides thus remain uncertain. Much of the existing confusion may be a result of premature attempts to study man since the vagaries of diagnosis, different antipsychotic drug treatments, emotional variations of pain thresholds, and many other experimental difficulties (not least the small numbers of subjects involved) make interpretation difficult. But even now we can be confident that
elucidation of the physiological roles of enkephalins ahd endorphins will ultimately yield information fundamental to many aspects of medicine.
FOR complete heart-block distal to the atrioventricular (A.V.) node the treatment of choice is a pacemaker,’ and the same is true of most cases of complete heartblock within the A.v. node, though here the risk of syncope and sudden death is lower.What of partial blocks? If the electrocardiogram suggests bilateral bundlebranch lesions, what is the likelihood of progression to complete heart-block, and is there ever a case for prophylactic insertion of a pacemaker? The concept of "hemiblocks", popularised by Rosenbaum and others,3 once seemed very helpful-especially in the light of reports that complete A.v. block tends to arise in patients with right-bundle-branch block and either right or left axis deviation4-but the relation between hemiblocks and the anatomical distribution of lesions in the left bundle-branch system has proved to be imprecise. Furthermore, prospective investigations suggest that hemiblocks seldom do progress to complete heart-block.6 One technique which has been employed in investigation of partial heart-block is intracardiac electrography, whereby recordings can be made from the bundle of His.7 Spurrell et al. used it to investigate patients with right-bundle-branch block and either left anterior or left posterior hemiblock, and they judged that prolonged intraventricular conduction indicated an increased risk of progression to complete heart-block. This conclusion gained support from the observation of Narula and others9 that symptomless patients with right-bundle-branch block, left-axis deviation, and prolonged intraventricular conduction were more likely to die than symptomatic patients with similar intraventricular conduction delay who had been fitted with pacemakers. This experience not, however, reproduced in a prospective study,1O the value of His-bundle recordings in these circumstances was an open question. Some of the doubts and uncertainties have now been resolved by a careful prospective study in Portland. McAnulty and colleagues" managed to locate 648 of 1211 patients with bilateral bundle-branch lesions, and was so
1. Furman, S. Am. Heart J. 1977, 93, 523. 2. Puech, P. in Cardiac Arrhythmias, the Modern Electrophysiological Approach (edited by D. M. Krikler and J. F. Goodwin); p. 81. London,
1975. 3. 13. Mayer, D. J., Price, D. D., Raffi, A. Brain Res. 1977, 121, 368. 14. Bloom, F., Segal, D., Ling, N., Guillemin, R. Science, 1976, 194, 630. 15. Jacquet, Y. E., Marks, N. ibid p. 632. 16. Terenius, L., Wahlstrom, A., Lindstrom, L., Widerlow, E. Neurosci. Lett.
1976, 3, 157. 17. Gunne, L-M., Lindstrom, L., Terenius, J. neural Transm. 1977, 40, 13. 18. Janowsky, D. S., Segal, D. S., Bloom, F., Abrams, A., Guillemin, R. Am. J. Psychiat. 1977, 134, 926. 19. Davis, G. C., Bunney, W. E., Defraites, E. G., Kleinman, J. E., van Kammen, D. P., Post, R. M., Wyatt, R. J. Science, 1977, 197, 74. 20. Watson, S. J., Berger, P. A., Akil, H., Mills, M. J., Barchas, J. D. ibid. 1978,
201, 73. 21.
Janowsky, D., Judd, L., Huey, L., Roitman, N., Parker, D., Segal,
Lancet, 1978, ii, 320. Byck, R. ibid. 1976, ii, 72. 23. Belluzzi, J. D., Stein, L. Nature, 1977, 266, 556. 22.
D.
Rosenbaum, M. B., Elizari, M. V., Lazzari, J. O. The Hemiblocks. Oldsmar, 1970.
4. 5. 6.
Rosenbaum, M. B. Mod. Concepts cardiovasc. Dis. 1970, 39, 141. Rossi, L. Br. Heart J. 1976, 38, 1304. Kulbertus, H. E., de-Laval Rutten, F., Dubois, M., Petit, J. M. Am. J. Cardiol. 1978, 41, 385. 7. Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, W. D., Stem, E., Damato, A. N. Circulation, 1969, 39, 13. 8. Spurrell, R. A. J., Smithen, C. S., Sowton, E. Br. Heart J. 1972, 34, 800. 9. Narula, O. S., Gann, D., Samet, P. in His Bundle Electrocardiography and Clinical Electrophysiology (edited by O.S. Narula); p. 437. Philadelphia,
1975. 10. Denes, P.,
Dhingra, R. C., Wu, D., Chuquimia, R., Amat-y-Leon, F., Wyndham, C., Rosen, K. M. Am. J. Cardiol. 1975, 35, 23. 11. McAnulty, J. H., Rahimtoola, S. H., Murphy, E. S., Kauffman, S., Ritzmann, L. W., Kanarek, P., DeMots, H. New Engl. J. Med. 1978, 299, 209.
in rats6, and in some human beings.7 8 WALL and his colleagues,9 however, have been unable to detect any increase of pain threshold after intravenous injection of naloxone 0-4—0-8 mg. BAUCHSBAUM et al.8 were more successful in increasing pain thresholds, perhaps partly because they used a bigger dose, 2 mg i.v. These workers made other important observations. If subjects were classified into two groups according to whether their normal pain threshold was greater or less than the mean threshold previously determined in a large control series, then those with a higher than average threshold (called, unfortunately, pain-insensitive) showed a reduced threshold after naloxone, whilst the other group showed a raised threshold. These results imply that a group of individuals having higher thresholds than the population mean owe that enviable distinction to an intrinsically active "analgesic-producing" neural pathway. As there was a bidirectional responsiveness to naloxone in different individuals, however, these findings also imply that endogenous compounds do not simply induce analgesia, but may be involved in a bidirectional modulation of pain sys-
reported
THE
LANCET
Enkephalins: the Search for a Functional Role THE mammalian brain contains peptides, the enkephalins and endorphins, which have pharmacological properties similar to those of morphine. Only two years ago the structure and origin of these peptides was the focus of attention.Now the
emphasis has switched to their physiological role. they, for example, released as neurotransmitters from neurons of a discrete "pain pathway"? Evidence for an anatomically discrete pathway has emerged from the demonstrations that electrical stimulation via implanted electrodes of the periventricular and periaqueductal grey matter of man can substantially alleviate otherwise intractable pain.22 These observations in man were inspired by experiments in animals.3-5 Of particular interest are the findings that tolerance arose, not only to the analgesic effects of electrical stimulation but also to opiate analgesic drugs (cross-tolerance).2Further, naloxone, a specific antagonist of opiate analgesics (used as a criterion in the isolation of enkephalins), blocked the electroanalgesia. These results are compatible with the concept of a neural pathway producing an increase of chronic pain threshold by releasing an endogenous compound susceptible to antagonism by naloxone. Though it increased chronic-pain thresholds, electrical stimulation had no effect on acute-pain thresholds in 4 of 6 patients2-a point to be discussed later. The question also arises of whether a neural "pain" system such as this is continuously active, determining normal, resting pain thresholds. Studies aimed at answering this have yielded conflicting results. The assumption has been that, if a pain system is normally active, then an analgesic antagonist such as naloxone should raise resting pain thresholds. Such a change of threshold has been Are
1. Lancet, 1976, ii, 665. 2. Hosobuchi, Y., Adams, J. E., Linchitz, R. Science, 1977, 197, 183. 3. Oliversa, J. L., Benson, J. M., Guilband, G., Liebeskind, J. C. Exp. Brain Res. 1974, 20, 32. 4. Melzack, R., Melinkoff, D. F. Exp. Neurol. 1974, 43, 369. 5. Mayer, D.J., Liebeskind,J. C.BrainRes. 1974, 68, 73. 6. Jacob, J. J , Tremblay, E. C., Colombel, M. C. Psychopharmacology, 1974,
37, 217. 7.
Lasagna, L.Proc.R.Soc.Med. 1965, 58, 978.
tems.
trying to resolve the effect of naloxone on pain thresholds, perhaps more consideration should be given to the type of pain involved. As pointed out above, naloxone can reverse central electroanalgesia for chronic pain, with no accompanying change of acute thresholds. This is consistent with the report by LEVINE et al. 10 in which naloxone produced hyperalgesia in postoperative dental patients-i.e., patients with chronic, persistent pain. This observation seems to be at least as important as the group’s main finding, that the analgesia resulting from administration of a placebo is also reversed by naloxone. The implication here is that placebo activates the central analgesia-related pathway. Two possible explanations for such an effect are that the relevant central pathways are activated by intrinsic neural (i.e., psychological) factors, and that the analgesia is related to stress. The stress explanation is attractive in view of the In
very close correlation shown in
rats between release of &bgr;-endorphin and release of adrenocorticotrophic hormone from the pituitary as a result of acute stress." However, any relation between endorphins and stress remains highly speculative: neither variations of -endorphin secretion by the pituitary" nor circulating plasma levels of &bgr;-endorphin12 bear any apparent relation to cerebral concentration of the peptide. Stress-induced release of p-endorphin 8. Buchsbaum, M. S., Davis, G. C., Bunney, W. E. Nature, 1977, 270, 620. 9. El-Sobky, A., Dostrovsky, J. O., Wall, P. D. ibid. 1976, 263, 783. 10. Levine, J. D., Gordon, N. C., Fields, H. L. Lancet, 1978, ii, 654. 11. Guillemin, R., Vargo, T., Rossier, J., Minick, S., Ling, N., Rivier, C., Vale, W., Bloom, F. Science, 1977, 197, 1367. 12. Jeffcoate, W. J., Rees, L. H., McLoughlin, L., Ratter, S. J., Hope, J., Lowry, P. J., Besser, G. M. Lancet, 1978, ii, 119.
820
from the pituitary may thus have a functional role totally divorced from analgesia. It has also been reported that naloxone will antagonise the analgesia induced by acupuncture,13 a finding which, if confirmed, has great potential implications in the neurophysiology of pain. There is no reason, of course, why these endogenous peptides should be concerned exclusively with pain. Indeed, a primary involvement in a more general emotional-state control system might include modification of pain sensitivity as merely one of many influences on sensory responsiveness and behaviour. The observation that minute doses of p-endorphin injected intraventricularly into rats to produce analgesia also induced catatonia 14 15 led to an early suspicion that the peptide could be involved in affective disorders. Increased amounts of endorphins have been detected in the cerebrospinal fluid of schizophrenic and manic patients, some showing decreased levels during remission. 16 If this correlation of endorphins and psychosis represents a cause-effect relationship, then blockade of endorphins by naloxone should alleviate the psychotic symptoms.17 Both positive and negative results have emerged with low doses (about 1 mg) of naloxone, 17-19 but encouraging results have lately been obtained by WATSON et al. 20 with 10 mg and by JANOWSKY et al. 21 with 20 mg. In particular, naloxone reduced auditory hallucinations in some schizophrenic subjects. The effect on the euphoric state is less clear. WATSON et al. observed swings of mood in their patients after naloxone, but most subjects soon became more relaxed and reported a sense of wellbeing.2O This was consistent with the results of several other laboratories. Different workers however, have shown a decrease in
euphoria patients.21-23
scores,
particularly
in
manic
The functional roles of endogenous "analgesic" peptides thus remain uncertain. Much of the existing confusion may be a result of premature attempts to study man since the vagaries of diagnosis, different antipsychotic drug treatments, emotional variations of pain thresholds, and many other experimental difficulties (not least the small numbers of subjects involved) make interpretation difficult. But even now we can be confident that
elucidation of the physiological roles of enkephalins ahd endorphins will ultimately yield information fundamental to many aspects of medicine.
FOR complete heart-block distal to the atrioventricular (A.V.) node the treatment of choice is a pacemaker,’ and the same is true of most cases of complete heartblock within the A.v. node, though here the risk of syncope and sudden death is lower.What of partial blocks? If the electrocardiogram suggests bilateral bundlebranch lesions, what is the likelihood of progression to complete heart-block, and is there ever a case for prophylactic insertion of a pacemaker? The concept of "hemiblocks", popularised by Rosenbaum and others,3 once seemed very helpful-especially in the light of reports that complete A.v. block tends to arise in patients with right-bundle-branch block and either right or left axis deviation4-but the relation between hemiblocks and the anatomical distribution of lesions in the left bundle-branch system has proved to be imprecise. Furthermore, prospective investigations suggest that hemiblocks seldom do progress to complete heart-block.6 One technique which has been employed in investigation of partial heart-block is intracardiac electrography, whereby recordings can be made from the bundle of His.7 Spurrell et al. used it to investigate patients with right-bundle-branch block and either left anterior or left posterior hemiblock, and they judged that prolonged intraventricular conduction indicated an increased risk of progression to complete heart-block. This conclusion gained support from the observation of Narula and others9 that symptomless patients with right-bundle-branch block, left-axis deviation, and prolonged intraventricular conduction were more likely to die than symptomatic patients with similar intraventricular conduction delay who had been fitted with pacemakers. This experience not, however, reproduced in a prospective study,1O the value of His-bundle recordings in these circumstances was an open question. Some of the doubts and uncertainties have now been resolved by a careful prospective study in Portland. McAnulty and colleagues" managed to locate 648 of 1211 patients with bilateral bundle-branch lesions, and was so
1. Furman, S. Am. Heart J. 1977, 93, 523. 2. Puech, P. in Cardiac Arrhythmias, the Modern Electrophysiological Approach (edited by D. M. Krikler and J. F. Goodwin); p. 81. London,
1975. 3. 13. Mayer, D. J., Price, D. D., Raffi, A. Brain Res. 1977, 121, 368. 14. Bloom, F., Segal, D., Ling, N., Guillemin, R. Science, 1976, 194, 630. 15. Jacquet, Y. E., Marks, N. ibid p. 632. 16. Terenius, L., Wahlstrom, A., Lindstrom, L., Widerlow, E. Neurosci. Lett.
1976, 3, 157. 17. Gunne, L-M., Lindstrom, L., Terenius, J. neural Transm. 1977, 40, 13. 18. Janowsky, D. S., Segal, D. S., Bloom, F., Abrams, A., Guillemin, R. Am. J. Psychiat. 1977, 134, 926. 19. Davis, G. C., Bunney, W. E., Defraites, E. G., Kleinman, J. E., van Kammen, D. P., Post, R. M., Wyatt, R. J. Science, 1977, 197, 74. 20. Watson, S. J., Berger, P. A., Akil, H., Mills, M. J., Barchas, J. D. ibid. 1978,
201, 73. 21.
Janowsky, D., Judd, L., Huey, L., Roitman, N., Parker, D., Segal,
Lancet, 1978, ii, 320. Byck, R. ibid. 1976, ii, 72. 23. Belluzzi, J. D., Stein, L. Nature, 1977, 266, 556. 22.
D.
Rosenbaum, M. B., Elizari, M. V., Lazzari, J. O. The Hemiblocks. Oldsmar, 1970.
4. 5. 6.
Rosenbaum, M. B. Mod. Concepts cardiovasc. Dis. 1970, 39, 141. Rossi, L. Br. Heart J. 1976, 38, 1304. Kulbertus, H. E., de-Laval Rutten, F., Dubois, M., Petit, J. M. Am. J. Cardiol. 1978, 41, 385. 7. Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, W. D., Stem, E., Damato, A. N. Circulation, 1969, 39, 13. 8. Spurrell, R. A. J., Smithen, C. S., Sowton, E. Br. Heart J. 1972, 34, 800. 9. Narula, O. S., Gann, D., Samet, P. in His Bundle Electrocardiography and Clinical Electrophysiology (edited by O.S. Narula); p. 437. Philadelphia,
1975. 10. Denes, P.,
Dhingra, R. C., Wu, D., Chuquimia, R., Amat-y-Leon, F., Wyndham, C., Rosen, K. M. Am. J. Cardiol. 1975, 35, 23. 11. McAnulty, J. H., Rahimtoola, S. H., Murphy, E. S., Kauffman, S., Ritzmann, L. W., Kanarek, P., DeMots, H. New Engl. J. Med. 1978, 299, 209.
