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Autoaddiction: a hypothesis on hunger and obesity
Annotations
14.
15.
16.
17.
18.
lence and characteristics of disproportionate ventricular septal thickening in patients with coronary artery disease, Circulation 57: 250, 1978. Tencate. J. F.. Hueenholtz. G. P.. Van Doro. G. W.. and Roelandt, J.: ‘Preyalence of diagnostic abnormalities in patients with genetically transmitted asymmetric septal hypertrophy, Am. J. Cardiol. 43: 731, 1979. Gibson, D. G., Traill, T. A., Hall, R. J. C., and Brown, D. J.: Echocardiographic features of secondary left ventricular hypertrophy, Br. Heart J. 41: 54, 1979. Feizi, O., and Emanuel, R.: Echocardiographic spectrum of hypertrophic cardiomyopathy, Br. Heart J. 37: 1286, 1975. Menapace, F. J., Hammer, W. J., Kessler, K. K., Ritzer, T., Bove, A. A., Warner, H. II., and Spann, J. F.: Echocardiographic measurements of left ventricular wall thickness in weight lifters. A problem with the definition of A.S.H., Am. J. Cardiol. 39: 276, 1977. Roeske, W. R., O’Rourke, R. A., Klein, A., Leopold, G., and Karliner, J. S.: Non-invasive evaluation of ventricu-
Autoaddiction::
a hypothesis
19. 20. 21. 22.
23.
lar hypertrophy in professional athletes, Circulation 53: 286, 1976. Feigenbaum, H.: Echocardiography, Philadelphia, 1976, Lea & Febiger. Roelandt, J.: Practical echocardiography, Oregon, 1977, Research Studies Press. Chang, S.: M-mode Echocardiographic techniques and pattern recognition, Philadelphia. 1976, Lea & Febiger. Sahn, D. J., DeMaria, A., Kisslo, J., and Weyman, A.: Recommendations regarding quantitation in M-mode echocardiography. Results of a survey of echocardiographic measurements, Circulation 58: 1072, 1978. Fowles, R. E., Martin, R. P., and Popp, R. L.: Erroneous diagnosis of asymmetric septal hypertrophy due to angled interventricular seotum. Am. J. Cardiol. 43: 348. _ 1979.
24.
on hunger
Allen, J. W., Kim, S. J., Edmiston, W. A., and Venkataraman, K.: Problems in ultrasonic estimates of septal thickness, Am. J. Cardiol. 42:‘89, 1978.
and
obesity
cells recruited by the influx secretion of enkephalin from the activity of the neuron.
During the past ten years a group of some seven peptides with putative neurotransmitter and hormonal functions have been found both in the brain and the gut. One of these, enkephalin, has aroused special interest because it occupies the same receptor sites as morphine. Experiments in the brain have shown that neuronal pathways, already firmly associated with the reduction of hunger drive, are most probably part of an enkephalinergic system.’ Our proposal links this work with the enkephalin-containing cells in the grit to constitute a system which responds to the appropriate amounts of food in the stomach by switching off eating. 1.t gives the sensation of satiety and the feeling of postprandial well-being and sleepiness. From a consideration of the opioid nature of the system, we arrive at a feasible Idysfunction by which a person can become addicted to his endogenous opiates, a condition which we have called “autoaddiction.“’
Addiction All the indications are that endogenous opiates are at least as addictive as morphine, and we can see no good. reason why the release of excess enkephalin should not be as addictive as circulating morphine. We assume that addiction involves cellular changes, as in the theory proposed by Collier’ in which opiates act by inhibiting the production of cyclic AMP and hence the activity of the neuron. Continued inhibition leads to an increase in the capacity of the neuron to make more cyclic AMP, and so it will need more opiate to suppress it (tolerance). The removal of the excess opiate unleashes the increased capacity to increase cyclic AMP and the resulting hyperactivity of the neuron is the cellular equivalent of the withdrawal syndrome.
Satiety Experimental work has shown that satiety and cessation of feeding are elicited by samples of jfood from the stomach,” activating receptors in the wall of the duodenum.” We propose that enkephalin is a mediator. In the gut enkephalin is found in the highest concentration in the antrum of the stomach and the duodenum, both in neurons and in open-ended secretory cells.5 The enkephalin-containing cell is probably a receptorsecretory cell, sam,pling the contents of the duodenum at the open end of the cell and releasing enkephalin as a local hormone at the other.6 We propose that the released enkephalin inhibits nearby afferent enkephalinergic neurons to switch off feeding and the hunger drive in the brain. The strength of the reward depends on the number of secretory
000%8703/80/120933
+ 02$0020/O
0 1980 The
C. V. Mosby
of food into the duodenum. The each can do no more than inhibit
Autoaddiction
and obesity
If, for example, the receptor-secretory cells in the duodenum overproduce and release too much enkephalin (or if the released enkephalin is not degraded with sufficient rapidity), then the regular excess of enkephalin, over and above the amount required to reduce the activity of the receptor neuron, will have the same effect as circulating morphine. Repeated regularly after meals, the excess enkephalin, like uniform doses of morphine, will soon cease to satisfy. Tolerance/ dependence will develop. Some neurons cannot now be switched off by the released enkephalin and the satiety mechanism fails to an extent, depending on the number of
Co.
American
Heart
Journal
933
Annolations neurons involved. The consequence will be overeating. Many obese people are compulsive eaters and their cravings for food are often uncontrollable. Their condition has been described as carbohydrate addiction.” We think that the resemblances to narcotic addiction support our proposai of a common opioid mechanism. Considering the unpleasant mental symptoms during withdrawal from morphine addiction, it would be surprising if there were not some psychological symptoms associated with autoaddiction.
orphine in its short half-life, less than a minute; so as soon as the food leaves the duodenum there will be a rapid disappearance of enkephaiin from the entirons of the receptor neuron. This contrasts with the relatively slow removal of morphine from the circulation, This disappearance of enkephalin, about a couple of hours after a meal, will cause excessive activity in dependent neurons and will constitute a withdrawal syndrome before the next mea.1 is due. Eating snacks between meals will abate the consequent cravings for food, and of course eating between meals is a common feature in obesity.
addiction, the maximum enkephalin released by the secretory cells must not regularly exceed the amount required to reduce the activity of the receptor neurons. While the system can cope with episodic excess, chronic excess of enkepbalin would be pathological, and even a small regular excess would lead to some degree of autoaddiction. R. F. &-cc~Qy, F.R.C.S. General Hospital
Nortluvnpton
NNl 590 England James McCioy, D.F.C.. B.Sc. 82 Wood Vuie London NlO 3DN
1.
2. 3.
B It is a general observation that sugar has a special relationship to appetite and to satiety. We can, for example, eat a sweet when we are already replete with the savoury meat and vegetable course. Sugar must have been a rare item in the diet of preagricultural man, and the evolution of the satiety system must have taken place with a relatively sugar-free duodenum, In the intracellular digestive assay for the estimation.of calorific value, the direct diffusion of sugars into the cells might well swamp the process. Witb an average daily consumption of about, 130 g. of sugar, the sweet products of modern food technology may result in many people today being unable, naturally and unconsciously, to regulate their food intake. In conclusion, if we are not all to be in a perpetual state of
sf oral disopyra prospective
5.
6.
7,
8.
m digoxi stu
Recent publications suggest that in patients receiving digitalis the concomitant administration of quinidine may lead to increased serum digoxin levels and the development of digitalis intoxication.‘. z Disopyramide is a new antiarrhythmic drug with properties and indications similar to quinidine:, Therefore we studied prospectively the effect of disopyramide on serum digoxin levels. Ten patients were studied. Age, sex, and arrhythmia diagnosis are given in Table I. All fulfilled the following criteria: (1) stable cardiac function, (2) stable dosage and time of intake of digoxin, (3) normal values for serum creatinine, Na and K, and (4) no additional drugs possibly affecting digoxin
December,
4.
Stein, L., and Belluzzi, J. B.: Brain endorphins and the sense of well-being: a psychobiological hypothesis: in Advances in Biochemical Psychopharmacology, Costa, F., and Trabucchi, M., eds., New York, 1978, Raven Press, Vol. 18, p. 299. McCloy, J., and McCloy, R. F.: Enkephalins, hunger, and obesity, Lancet 2:156, 1979. Liebling, D. S., Eisner, J. D., Gibbs, J., and Smith. 6. P.: Intestinal satiety in rats, J. Comp. Phgsiol. Psychol. 89:995, 1975. Hunt, J. N., and Stubbs, D. F.: The volume and energy content of meals as determinants of gastric emptying, J. Physiol. 245:209, 1975. Polak, J. M., Sullivan, S. N., Buchan, A. IM. J,, et al.: Endorphins, in Gut Hormones, Bloom, S. R., ed., Edinburgh, 1978, Churchill Livingstone, p. 501. Fujita, T., and Kobayashi, S.: Paraneuronal cells in the G.E.P. endocrine system, in: Gut Hormones, Bloom. S. R., ed., Edinburgh, 1978, Churchill Livingstone, p. 414. Collier, H. 0. J.: Consequences of interaction between opioid and receptor, Biochemical Society Transactions 5:70, 1977. Craddock, D.: Obesity and its Management, London, 1978, Churchill Livingstone, p. 60.
1980, Vol. JOG, PIo. 6, part
1
levels.’ In all patients digoxin levels were determined on Tuesday and Friday at the same time interval after digoxin administration. Then oral disopyramide was given for two weeks in doses individually ranging from three to six tablets daily. Both digoxin and disopyramide levels were determined on Tuesday and Friday of the third week of the study at comparable time intervals to the first week. Statistical analyses were performed using the paired t test. As shown in Table I, prior to disopyramide administration serum digoxin levels varied from 0.8 to 1.5 (mean 1.1 t 0.2) ng./c.c. In the same patient the digoxin level varied by 0.1 to 0.4 (mean 0.17) ng./c.c. During disopyramide the serum
0002-8703/80/120934
+ 02$00.20/O
0 1980 The
C. V. Mosby
Co.
14.
15.
16.
17.
18.
lence and characteristics of disproportionate ventricular septal thickening in patients with coronary artery disease, Circulation 57: 250, 1978. Tencate. J. F.. Hueenholtz. G. P.. Van Doro. G. W.. and Roelandt, J.: ‘Preyalence of diagnostic abnormalities in patients with genetically transmitted asymmetric septal hypertrophy, Am. J. Cardiol. 43: 731, 1979. Gibson, D. G., Traill, T. A., Hall, R. J. C., and Brown, D. J.: Echocardiographic features of secondary left ventricular hypertrophy, Br. Heart J. 41: 54, 1979. Feizi, O., and Emanuel, R.: Echocardiographic spectrum of hypertrophic cardiomyopathy, Br. Heart J. 37: 1286, 1975. Menapace, F. J., Hammer, W. J., Kessler, K. K., Ritzer, T., Bove, A. A., Warner, H. II., and Spann, J. F.: Echocardiographic measurements of left ventricular wall thickness in weight lifters. A problem with the definition of A.S.H., Am. J. Cardiol. 39: 276, 1977. Roeske, W. R., O’Rourke, R. A., Klein, A., Leopold, G., and Karliner, J. S.: Non-invasive evaluation of ventricu-
Autoaddiction::
a hypothesis
19. 20. 21. 22.
23.
lar hypertrophy in professional athletes, Circulation 53: 286, 1976. Feigenbaum, H.: Echocardiography, Philadelphia, 1976, Lea & Febiger. Roelandt, J.: Practical echocardiography, Oregon, 1977, Research Studies Press. Chang, S.: M-mode Echocardiographic techniques and pattern recognition, Philadelphia. 1976, Lea & Febiger. Sahn, D. J., DeMaria, A., Kisslo, J., and Weyman, A.: Recommendations regarding quantitation in M-mode echocardiography. Results of a survey of echocardiographic measurements, Circulation 58: 1072, 1978. Fowles, R. E., Martin, R. P., and Popp, R. L.: Erroneous diagnosis of asymmetric septal hypertrophy due to angled interventricular seotum. Am. J. Cardiol. 43: 348. _ 1979.
24.
on hunger
Allen, J. W., Kim, S. J., Edmiston, W. A., and Venkataraman, K.: Problems in ultrasonic estimates of septal thickness, Am. J. Cardiol. 42:‘89, 1978.
and
obesity
cells recruited by the influx secretion of enkephalin from the activity of the neuron.
During the past ten years a group of some seven peptides with putative neurotransmitter and hormonal functions have been found both in the brain and the gut. One of these, enkephalin, has aroused special interest because it occupies the same receptor sites as morphine. Experiments in the brain have shown that neuronal pathways, already firmly associated with the reduction of hunger drive, are most probably part of an enkephalinergic system.’ Our proposal links this work with the enkephalin-containing cells in the grit to constitute a system which responds to the appropriate amounts of food in the stomach by switching off eating. 1.t gives the sensation of satiety and the feeling of postprandial well-being and sleepiness. From a consideration of the opioid nature of the system, we arrive at a feasible Idysfunction by which a person can become addicted to his endogenous opiates, a condition which we have called “autoaddiction.“’
Addiction All the indications are that endogenous opiates are at least as addictive as morphine, and we can see no good. reason why the release of excess enkephalin should not be as addictive as circulating morphine. We assume that addiction involves cellular changes, as in the theory proposed by Collier’ in which opiates act by inhibiting the production of cyclic AMP and hence the activity of the neuron. Continued inhibition leads to an increase in the capacity of the neuron to make more cyclic AMP, and so it will need more opiate to suppress it (tolerance). The removal of the excess opiate unleashes the increased capacity to increase cyclic AMP and the resulting hyperactivity of the neuron is the cellular equivalent of the withdrawal syndrome.
Satiety Experimental work has shown that satiety and cessation of feeding are elicited by samples of jfood from the stomach,” activating receptors in the wall of the duodenum.” We propose that enkephalin is a mediator. In the gut enkephalin is found in the highest concentration in the antrum of the stomach and the duodenum, both in neurons and in open-ended secretory cells.5 The enkephalin-containing cell is probably a receptorsecretory cell, sam,pling the contents of the duodenum at the open end of the cell and releasing enkephalin as a local hormone at the other.6 We propose that the released enkephalin inhibits nearby afferent enkephalinergic neurons to switch off feeding and the hunger drive in the brain. The strength of the reward depends on the number of secretory
000%8703/80/120933
+ 02$0020/O
0 1980 The
C. V. Mosby
of food into the duodenum. The each can do no more than inhibit
Autoaddiction
and obesity
If, for example, the receptor-secretory cells in the duodenum overproduce and release too much enkephalin (or if the released enkephalin is not degraded with sufficient rapidity), then the regular excess of enkephalin, over and above the amount required to reduce the activity of the receptor neuron, will have the same effect as circulating morphine. Repeated regularly after meals, the excess enkephalin, like uniform doses of morphine, will soon cease to satisfy. Tolerance/ dependence will develop. Some neurons cannot now be switched off by the released enkephalin and the satiety mechanism fails to an extent, depending on the number of
Co.
American
Heart
Journal
933
Annolations neurons involved. The consequence will be overeating. Many obese people are compulsive eaters and their cravings for food are often uncontrollable. Their condition has been described as carbohydrate addiction.” We think that the resemblances to narcotic addiction support our proposai of a common opioid mechanism. Considering the unpleasant mental symptoms during withdrawal from morphine addiction, it would be surprising if there were not some psychological symptoms associated with autoaddiction.
orphine in its short half-life, less than a minute; so as soon as the food leaves the duodenum there will be a rapid disappearance of enkephaiin from the entirons of the receptor neuron. This contrasts with the relatively slow removal of morphine from the circulation, This disappearance of enkephalin, about a couple of hours after a meal, will cause excessive activity in dependent neurons and will constitute a withdrawal syndrome before the next mea.1 is due. Eating snacks between meals will abate the consequent cravings for food, and of course eating between meals is a common feature in obesity.
addiction, the maximum enkephalin released by the secretory cells must not regularly exceed the amount required to reduce the activity of the receptor neurons. While the system can cope with episodic excess, chronic excess of enkepbalin would be pathological, and even a small regular excess would lead to some degree of autoaddiction. R. F. &-cc~Qy, F.R.C.S. General Hospital
Nortluvnpton
NNl 590 England James McCioy, D.F.C.. B.Sc. 82 Wood Vuie London NlO 3DN
1.
2. 3.
B It is a general observation that sugar has a special relationship to appetite and to satiety. We can, for example, eat a sweet when we are already replete with the savoury meat and vegetable course. Sugar must have been a rare item in the diet of preagricultural man, and the evolution of the satiety system must have taken place with a relatively sugar-free duodenum, In the intracellular digestive assay for the estimation.of calorific value, the direct diffusion of sugars into the cells might well swamp the process. Witb an average daily consumption of about, 130 g. of sugar, the sweet products of modern food technology may result in many people today being unable, naturally and unconsciously, to regulate their food intake. In conclusion, if we are not all to be in a perpetual state of
sf oral disopyra prospective
5.
6.
7,
8.
m digoxi stu
Recent publications suggest that in patients receiving digitalis the concomitant administration of quinidine may lead to increased serum digoxin levels and the development of digitalis intoxication.‘. z Disopyramide is a new antiarrhythmic drug with properties and indications similar to quinidine:, Therefore we studied prospectively the effect of disopyramide on serum digoxin levels. Ten patients were studied. Age, sex, and arrhythmia diagnosis are given in Table I. All fulfilled the following criteria: (1) stable cardiac function, (2) stable dosage and time of intake of digoxin, (3) normal values for serum creatinine, Na and K, and (4) no additional drugs possibly affecting digoxin
December,
4.
Stein, L., and Belluzzi, J. B.: Brain endorphins and the sense of well-being: a psychobiological hypothesis: in Advances in Biochemical Psychopharmacology, Costa, F., and Trabucchi, M., eds., New York, 1978, Raven Press, Vol. 18, p. 299. McCloy, J., and McCloy, R. F.: Enkephalins, hunger, and obesity, Lancet 2:156, 1979. Liebling, D. S., Eisner, J. D., Gibbs, J., and Smith. 6. P.: Intestinal satiety in rats, J. Comp. Phgsiol. Psychol. 89:995, 1975. Hunt, J. N., and Stubbs, D. F.: The volume and energy content of meals as determinants of gastric emptying, J. Physiol. 245:209, 1975. Polak, J. M., Sullivan, S. N., Buchan, A. IM. J,, et al.: Endorphins, in Gut Hormones, Bloom, S. R., ed., Edinburgh, 1978, Churchill Livingstone, p. 501. Fujita, T., and Kobayashi, S.: Paraneuronal cells in the G.E.P. endocrine system, in: Gut Hormones, Bloom. S. R., ed., Edinburgh, 1978, Churchill Livingstone, p. 414. Collier, H. 0. J.: Consequences of interaction between opioid and receptor, Biochemical Society Transactions 5:70, 1977. Craddock, D.: Obesity and its Management, London, 1978, Churchill Livingstone, p. 60.
1980, Vol. JOG, PIo. 6, part
1
levels.’ In all patients digoxin levels were determined on Tuesday and Friday at the same time interval after digoxin administration. Then oral disopyramide was given for two weeks in doses individually ranging from three to six tablets daily. Both digoxin and disopyramide levels were determined on Tuesday and Friday of the third week of the study at comparable time intervals to the first week. Statistical analyses were performed using the paired t test. As shown in Table I, prior to disopyramide administration serum digoxin levels varied from 0.8 to 1.5 (mean 1.1 t 0.2) ng./c.c. In the same patient the digoxin level varied by 0.1 to 0.4 (mean 0.17) ng./c.c. During disopyramide the serum
0002-8703/80/120934
+ 02$00.20/O
0 1980 The
C. V. Mosby
Co.