- Email: [email protected]
The involvement of the kappa opiate receptor in the control of food intake in the rat
Neuropharmncology
Vol. 25, No. 6, pp. 653-654,
OC28-3908/86 $3.00+ 0.00 PergamonJournalsLtd
1986
Printedin Great Britain
THE INVOLVEMENT OF THE KAPPA OPIATE RECEPTOR IN THE CONTROL OF FOOD INTAKE IN THE RAT ANNE JACKSONand S. J. COOPER* Department of Psychology, University of Birmingham, Birmingham B15 2TT, England
There is now considerable pharmacological evidence indicating a role for the endogenous opioid peptides in the control of food intake (Sanger, 1981; Morley, Levine, Yim and Lowy, 1983). Opioid receptor antagonists, such as naloxone and naltrexone, have been shown consistently to reduce the consumption of food in many situations (Holtzman, 1974; Cooper, 1980; Lowy, Maickel and Yim, 1980; Cooper, Jackson, Morgan and Carter, 1985) and in a diversity of species (Morley, Levine, Plotka and Seal, 1983; Sanger, 1983; Trenchard and Silverstone, 1983; Herman and Holtzman, 1984). Recent studies with antagonists have revealed that their anorexigenic properties may be due to an effect on satiety processes. Thus, Kirkham (1985) has shown that naloxone brings forward satiety by affecting meal termination. This suggests that opioid antagonists may affect the consumption of food by blocking the maintenance of feeding which is under the control of the release of endogenous opioid peptides (Cooper, Jackson and Kirkham, 1985). In turn, this leads to the prediction that drugs which act as agonists at opioid receptors should have effects opposite to those of the antagonists, that is, they should increase food intake and maintain feeding behaviour. With regard to this, morphine, the mu receptor agonist, has been shown to increase the intake of food in some situations (e.g., Sanger and McCarthy, 1980) but not in all cases (Cooper, 1981; Jackson and Cooper, 1985). More recently, drugs which act as agonists at kappa receptors have been shown to’produce hyperphagia. For example, bremazocine increased the consumption of food by non-deprived mice over a 24 hr period (Hartig and Opitz, 1983), whereas ketocyclazocine, ethylketocyclazocine (EKC) and trans-( +)-3,4-dichloro-N-methyl- N-[2-(1 -pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50,488H), amongst others, enhanced spontaneous feeding in rats (Sanger and McCarthy, 1981; Morley, Levine, Grace and Kneip, 1982; Morley and Levine, 1983). In addition to this, dynorphins 1-17 and 1-13, which are potent kappa agonists (Goldstein, Tachibana, Lowney, Hunkapiller and Hood, 1979), induced hyperphagia in rodents when administered intracerebroventricu-
larly (Walker, Katz and Akil, 1980; Morley and Levine, 1983). It appears, therefore, that the hyperphagia which is induced by treatments with kappa receptor agonists provides confirmatory evidence for the hypothesis that actions of endogenous opioid peptides serve to maintain feeding responses. KAPPAAGONISTSAND PALATABLE FOOD CONSUMPTION The effect of treatment with kappa agonists on the consumption of palatable food by the rat was investigated. In the first series of studies, non-deprived rats were allowed access to a sweet wet-mash diet for a 30 min period and the effects of kappa agonists on the intake of food were noted. The results demonstrated that two selective kappa agonists (U-50,488H and tifluadom) increased the consumption of the palatable diet, whereas two others (EKC and bremazocine) produced only reductions in the consumption of food. However, it was also found that when rats were allowed to consume a small amount of the palatable diet prior to administration of drug (in order to produce some degree of prior satiety) all four compounds subsequently increased consumption. Using such “partially-satiated” rats, reliable increases in food intake were found with small doses of kappa agonists and therefore this model was used in further experiments. The reason for the reduction in the consumption of food seen after EKC and bremazocine in the initial experiments, may have been the occurrence of side-effects which interfered with feeding behaviour. This may be related to their less selective action at opiate receptors, compared with the more selective kappa actions of U-50,488H and tifluadom (Jackson and Cooper, 1985). The reliable hyperphagic effects of kappa agonists seen in partially-satiated rats is further evidence in support of a role for kappa receptors in the control of food intake. OBSERVATIONAL ANALYSIS OF HYPERPHAGIA INDUCED BY THE KAPPA AGONIST U-50,488H
Although there are now many studies demonstrating the phenomenon of hyperphagia induced by kappa agonists (Sanger and McCarthy, 198 1; Morley
*Address correspondence and reprint requests to S. J. Cooper. 653
654
ANNT:JACKSONand S. J. COOPER
et al., 1982; Jackson and Cooper, 1985) it is not yet known how these increases are brought about. In order to obtain more information about the behavioural mechanisms involved, an observational analysis of the effects of the selective kappa agonist, U-50,488H (Von Voigtlander, Lahti and Ludens, 1983), on the consumption of a palatable food was carried out in partially-satiated rats. Thus, rats which had been pre-fed were injected with either vehicle or U-50,488H (0.1-3.0 mg/kg), were allowed access to sweet wet-mash for 30min in familiar transparent plastic test boxes. During this time, their behaviour was recorded on videotape and intake was determined at the end of the session. Following this, the recorded behaviour (including eating, grooming and activity) was scored by an observer who was blind to the injection conditions, by means of a hand-held keyboard linked to a microcomputer which logged the precise time at which behavioural responses started and stopped. Thus, for each rat an accurate record of duration and frequency of behaviour was obtained. Analysis of these records then revealed dose-response data. The hyperphagic effect of U-50,488H was confirmed with significant dose-related increases at O-3-3.0 mg/kg, the peak effect occurring at 1 mg/kg. This was accompanied by increased duration and frequency of eating at these doses, but with no alteration of eating rate (intake/duration). No significant changes were found in the latency to initiate eating. However, there was a significant trend towards an increased latency to terminate consumption of food. Thus, with the larger doses of U-50,488H, rats tended to stop eating later than controls. It appears, therefore, that the hyperphagia induced by U-50,488H was due to an increase in the time devoted to eating, rather than to an increase in the rate of food consumption. The greater duration appears to have been the result of eating for longer, as opposed to eating sooner, that is, termination of the meal was delayed. Increased intake of food was also accompanied by a significant reduction in other activities at the largest dose (3 mg/kg). At the smallest dose (0.1 mg/kg) where intake remained unchanged, a significant increase in grooming was observed. This represents an indication of the behavioural mechanism by which kappa agonists act to increase the consumption of food. A delay in termination of meal is consistent with the hypothesis that opioid peptides might function to maintain feeding responses. Further research should be directed to establishing whether the hyperphagic effects of other drugs which act as kappa agonists, as well as dynorphin peptides, are also due to the prolongation in the duration of feeding activity. Acknow~ed~emenls-U-50,488H
was generously supplied by the Upjohn Company, Kalamazoo, Michigan, U.S.A. Anne Jackson is supported by the Medical Research Council.
REFERENCES
Cooper S. J. (1980) Naloxone: effects on food and water consumption in the non-deprived and deprived rat. Psychopharmacology 71: l--6.
Cooper S. J. (1981) Behaviourally-specific hyperdipsia in the non-deprived rat following acute morphine treatment. NeurophurmaeaIog.~ 20: 469472. Cooper S. J., Jackson A. and
Kirkham T. C. (1985) Endorphins and food intake: kappa opioid receptor
agonists and hyperpha~a~ Pharmac. Rio&em. Behav, 23: 889-90 1.
Cooper S. J., Jackson A., Morgan R. and Carter R. (1985) Evidence for opiate receptor involvement in the consumption of a high palatability diet in non-deprived rats. Neuropeptides 5: 345348.
Goldstein A., Tachibana S., Lowney L. I., Hunkapiller M. and Hood L. (1979) Dynorphin-( 1-l 3), an extraordinarily potent opioid peptide. Proc. natn. Acad. Sci. U.S.A. 76: 66666670.
Hartig U. and Opitz K. (I 983) The influence of the kappaagonist bremazocine on ingestive behaviour in mice and rats. Archs int. Pharmacodyn. Ther. 262: 4-12. Herman B. H. and Holtzman S. G. (1984) Repeated administration of naltrexone and dipreno~hine decreases food intake and body weight in squirrel monkeys. Lzfe Sci. 34:
. ._ I-12. Holtzman S. G. (1974) Behavioural effects of separate and combined administration of naloxone and d-amphetamine. J. Pharmac. exp. Ther. 189: 51-60. Jackson A. and Cooper S. J. (1985) Effects of kappa opiate agonists on palatable food consumption in non-deprived rats, with and without food preloads. Brain Res. Bull. llsl W-796
Kirkham T. C. (1985) Investigation of Opioid Mechanisms in the Control ofFeeding Behaviour. Ph.D. thesis, University of Leeds. Lowy M. T., Maickel R. P. and Yim G. K. W. (1980) Naloxone reduction of stress related feeding. Life Sci. 26: 2113-2118. Morley J. E. and Levine A. S. (1983) Involvement of dynorphin and the kappa opioid receptor in feeding. Peptides 4: 797-800.
Morley J. E., Levine A, S., Grace M. and Kneip J. (1982) An investigation of the role of kappa opiate receptor agonists in the initiation of feeding. Life Sci. 31: 2617-2626. Morley J. E., Levine A. S., Plotka E. D. and Seal U. S. (1983) The effect of naloxone on feeding and spontaneous locomotion in the wolf. Physiol. Behau. 30: 331-334. Morley J. E., Levine A. S., Yim G. K. W. and Lowy M. T. (I 983) Opioid modulation of appetite. Neurosci. Biobehar. Rev. 7: D-305.
Sanger D. J. (1981) Endorphinergic mechanisms in the control of food and water intake. Appetite 2: 193-208. Sanger D. J. (1983) Opiates and ingestive behaviour. In: Theory in Psyckapharmacology (Cooper S. J., Ed.), Vol. 2, pp. 75-113. Academic Press, London. Sanger D. J. and McCarthy P. S. (1980) Differential effects of morphine on food and water intake in food deprived and freely feeding rats. Psvchopharmacology 72: 103-106. Sanger D. J. and McCarthy P. S. (1981) Increased food and water intake produced in rats by opiate receptor agonists. Psychopharmacolog,y 74: 2 17.-220.
Trenchard E. and Silverstone T. (1983) Naloxone reduces the food intake of normal human volunteers. Appetite 4: 4% 50.
Von Voigtlander P. F., Lahti R. A. and Ludens J. H. (1983) U-50,488: a selective and structurally novel non-mu (kappa) opioid agonist. J. Pharmac. exp. Ther. 224,7-12. Walker J. M., Katz R. J. and Akil H. (1980) Behavioral effects of dyno~bin (l--13) in the mouse and rat: initial observations. Peptides 1: 341-345.
Vol. 25, No. 6, pp. 653-654,
OC28-3908/86 $3.00+ 0.00 PergamonJournalsLtd
1986
Printedin Great Britain
THE INVOLVEMENT OF THE KAPPA OPIATE RECEPTOR IN THE CONTROL OF FOOD INTAKE IN THE RAT ANNE JACKSONand S. J. COOPER* Department of Psychology, University of Birmingham, Birmingham B15 2TT, England
There is now considerable pharmacological evidence indicating a role for the endogenous opioid peptides in the control of food intake (Sanger, 1981; Morley, Levine, Yim and Lowy, 1983). Opioid receptor antagonists, such as naloxone and naltrexone, have been shown consistently to reduce the consumption of food in many situations (Holtzman, 1974; Cooper, 1980; Lowy, Maickel and Yim, 1980; Cooper, Jackson, Morgan and Carter, 1985) and in a diversity of species (Morley, Levine, Plotka and Seal, 1983; Sanger, 1983; Trenchard and Silverstone, 1983; Herman and Holtzman, 1984). Recent studies with antagonists have revealed that their anorexigenic properties may be due to an effect on satiety processes. Thus, Kirkham (1985) has shown that naloxone brings forward satiety by affecting meal termination. This suggests that opioid antagonists may affect the consumption of food by blocking the maintenance of feeding which is under the control of the release of endogenous opioid peptides (Cooper, Jackson and Kirkham, 1985). In turn, this leads to the prediction that drugs which act as agonists at opioid receptors should have effects opposite to those of the antagonists, that is, they should increase food intake and maintain feeding behaviour. With regard to this, morphine, the mu receptor agonist, has been shown to increase the intake of food in some situations (e.g., Sanger and McCarthy, 1980) but not in all cases (Cooper, 1981; Jackson and Cooper, 1985). More recently, drugs which act as agonists at kappa receptors have been shown to’produce hyperphagia. For example, bremazocine increased the consumption of food by non-deprived mice over a 24 hr period (Hartig and Opitz, 1983), whereas ketocyclazocine, ethylketocyclazocine (EKC) and trans-( +)-3,4-dichloro-N-methyl- N-[2-(1 -pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50,488H), amongst others, enhanced spontaneous feeding in rats (Sanger and McCarthy, 1981; Morley, Levine, Grace and Kneip, 1982; Morley and Levine, 1983). In addition to this, dynorphins 1-17 and 1-13, which are potent kappa agonists (Goldstein, Tachibana, Lowney, Hunkapiller and Hood, 1979), induced hyperphagia in rodents when administered intracerebroventricu-
larly (Walker, Katz and Akil, 1980; Morley and Levine, 1983). It appears, therefore, that the hyperphagia which is induced by treatments with kappa receptor agonists provides confirmatory evidence for the hypothesis that actions of endogenous opioid peptides serve to maintain feeding responses. KAPPAAGONISTSAND PALATABLE FOOD CONSUMPTION The effect of treatment with kappa agonists on the consumption of palatable food by the rat was investigated. In the first series of studies, non-deprived rats were allowed access to a sweet wet-mash diet for a 30 min period and the effects of kappa agonists on the intake of food were noted. The results demonstrated that two selective kappa agonists (U-50,488H and tifluadom) increased the consumption of the palatable diet, whereas two others (EKC and bremazocine) produced only reductions in the consumption of food. However, it was also found that when rats were allowed to consume a small amount of the palatable diet prior to administration of drug (in order to produce some degree of prior satiety) all four compounds subsequently increased consumption. Using such “partially-satiated” rats, reliable increases in food intake were found with small doses of kappa agonists and therefore this model was used in further experiments. The reason for the reduction in the consumption of food seen after EKC and bremazocine in the initial experiments, may have been the occurrence of side-effects which interfered with feeding behaviour. This may be related to their less selective action at opiate receptors, compared with the more selective kappa actions of U-50,488H and tifluadom (Jackson and Cooper, 1985). The reliable hyperphagic effects of kappa agonists seen in partially-satiated rats is further evidence in support of a role for kappa receptors in the control of food intake. OBSERVATIONAL ANALYSIS OF HYPERPHAGIA INDUCED BY THE KAPPA AGONIST U-50,488H
Although there are now many studies demonstrating the phenomenon of hyperphagia induced by kappa agonists (Sanger and McCarthy, 198 1; Morley
*Address correspondence and reprint requests to S. J. Cooper. 653
654
ANNT:JACKSONand S. J. COOPER
et al., 1982; Jackson and Cooper, 1985) it is not yet known how these increases are brought about. In order to obtain more information about the behavioural mechanisms involved, an observational analysis of the effects of the selective kappa agonist, U-50,488H (Von Voigtlander, Lahti and Ludens, 1983), on the consumption of a palatable food was carried out in partially-satiated rats. Thus, rats which had been pre-fed were injected with either vehicle or U-50,488H (0.1-3.0 mg/kg), were allowed access to sweet wet-mash for 30min in familiar transparent plastic test boxes. During this time, their behaviour was recorded on videotape and intake was determined at the end of the session. Following this, the recorded behaviour (including eating, grooming and activity) was scored by an observer who was blind to the injection conditions, by means of a hand-held keyboard linked to a microcomputer which logged the precise time at which behavioural responses started and stopped. Thus, for each rat an accurate record of duration and frequency of behaviour was obtained. Analysis of these records then revealed dose-response data. The hyperphagic effect of U-50,488H was confirmed with significant dose-related increases at O-3-3.0 mg/kg, the peak effect occurring at 1 mg/kg. This was accompanied by increased duration and frequency of eating at these doses, but with no alteration of eating rate (intake/duration). No significant changes were found in the latency to initiate eating. However, there was a significant trend towards an increased latency to terminate consumption of food. Thus, with the larger doses of U-50,488H, rats tended to stop eating later than controls. It appears, therefore, that the hyperphagia induced by U-50,488H was due to an increase in the time devoted to eating, rather than to an increase in the rate of food consumption. The greater duration appears to have been the result of eating for longer, as opposed to eating sooner, that is, termination of the meal was delayed. Increased intake of food was also accompanied by a significant reduction in other activities at the largest dose (3 mg/kg). At the smallest dose (0.1 mg/kg) where intake remained unchanged, a significant increase in grooming was observed. This represents an indication of the behavioural mechanism by which kappa agonists act to increase the consumption of food. A delay in termination of meal is consistent with the hypothesis that opioid peptides might function to maintain feeding responses. Further research should be directed to establishing whether the hyperphagic effects of other drugs which act as kappa agonists, as well as dynorphin peptides, are also due to the prolongation in the duration of feeding activity. Acknow~ed~emenls-U-50,488H
was generously supplied by the Upjohn Company, Kalamazoo, Michigan, U.S.A. Anne Jackson is supported by the Medical Research Council.
REFERENCES
Cooper S. J. (1980) Naloxone: effects on food and water consumption in the non-deprived and deprived rat. Psychopharmacology 71: l--6.
Cooper S. J. (1981) Behaviourally-specific hyperdipsia in the non-deprived rat following acute morphine treatment. NeurophurmaeaIog.~ 20: 469472. Cooper S. J., Jackson A. and
Kirkham T. C. (1985) Endorphins and food intake: kappa opioid receptor
agonists and hyperpha~a~ Pharmac. Rio&em. Behav, 23: 889-90 1.
Cooper S. J., Jackson A., Morgan R. and Carter R. (1985) Evidence for opiate receptor involvement in the consumption of a high palatability diet in non-deprived rats. Neuropeptides 5: 345348.
Goldstein A., Tachibana S., Lowney L. I., Hunkapiller M. and Hood L. (1979) Dynorphin-( 1-l 3), an extraordinarily potent opioid peptide. Proc. natn. Acad. Sci. U.S.A. 76: 66666670.
Hartig U. and Opitz K. (I 983) The influence of the kappaagonist bremazocine on ingestive behaviour in mice and rats. Archs int. Pharmacodyn. Ther. 262: 4-12. Herman B. H. and Holtzman S. G. (1984) Repeated administration of naltrexone and dipreno~hine decreases food intake and body weight in squirrel monkeys. Lzfe Sci. 34:
. ._ I-12. Holtzman S. G. (1974) Behavioural effects of separate and combined administration of naloxone and d-amphetamine. J. Pharmac. exp. Ther. 189: 51-60. Jackson A. and Cooper S. J. (1985) Effects of kappa opiate agonists on palatable food consumption in non-deprived rats, with and without food preloads. Brain Res. Bull. llsl W-796
Kirkham T. C. (1985) Investigation of Opioid Mechanisms in the Control ofFeeding Behaviour. Ph.D. thesis, University of Leeds. Lowy M. T., Maickel R. P. and Yim G. K. W. (1980) Naloxone reduction of stress related feeding. Life Sci. 26: 2113-2118. Morley J. E. and Levine A. S. (1983) Involvement of dynorphin and the kappa opioid receptor in feeding. Peptides 4: 797-800.
Morley J. E., Levine A, S., Grace M. and Kneip J. (1982) An investigation of the role of kappa opiate receptor agonists in the initiation of feeding. Life Sci. 31: 2617-2626. Morley J. E., Levine A. S., Plotka E. D. and Seal U. S. (1983) The effect of naloxone on feeding and spontaneous locomotion in the wolf. Physiol. Behau. 30: 331-334. Morley J. E., Levine A. S., Yim G. K. W. and Lowy M. T. (I 983) Opioid modulation of appetite. Neurosci. Biobehar. Rev. 7: D-305.
Sanger D. J. (1981) Endorphinergic mechanisms in the control of food and water intake. Appetite 2: 193-208. Sanger D. J. (1983) Opiates and ingestive behaviour. In: Theory in Psyckapharmacology (Cooper S. J., Ed.), Vol. 2, pp. 75-113. Academic Press, London. Sanger D. J. and McCarthy P. S. (1980) Differential effects of morphine on food and water intake in food deprived and freely feeding rats. Psvchopharmacology 72: 103-106. Sanger D. J. and McCarthy P. S. (1981) Increased food and water intake produced in rats by opiate receptor agonists. Psychopharmacolog,y 74: 2 17.-220.
Trenchard E. and Silverstone T. (1983) Naloxone reduces the food intake of normal human volunteers. Appetite 4: 4% 50.
Von Voigtlander P. F., Lahti R. A. and Ludens J. H. (1983) U-50,488: a selective and structurally novel non-mu (kappa) opioid agonist. J. Pharmac. exp. Ther. 224,7-12. Walker J. M., Katz R. J. and Akil H. (1980) Behavioral effects of dyno~bin (l--13) in the mouse and rat: initial observations. Peptides 1: 341-345.