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Butorphanol tartrate induces feeding in rats
Life Sciences, Vol. 32, pp. 781-785 Printed in the U.S.A.
Pergamon Press
BUTORPHANOL TARTRATE INDUCES FEEDING IN RATS A.S. Levine & J.E. Morley Neuroendocrine Research Laboratory, Minneapolis VA Medical Center, Minneapolis, Minnesota, 55417 and the Departments of Food Science and Nutrition and Medicine, University of Minnesota, St. Paul and Minneapolis, Minnesota. (Received in final form November 2, 1982) Summary Peripheral administration of butorphanol tartrate markedly enhanced feeding from 0800 to 1400 hours when compared with vehicle controls. Butorphanol tartrate feeding was not antagonized by doses of naloxone as high as i0 mg/kg. These data support the concept that the kappa or sigma opiate receptors are involved in feeding behavior. It is well recognized that the endogenous opiates play a role in the central regulation of appetite (1,2,3,4). Numerous studies have shown that the endogenous opioid peptides and morphine can initiate feeding under various conditions (5-12) whereas the opiate antagonist, naloxone can reduce food consumption (13-20). Recently, the endogenous opioid peptide, dynorphin, has been reported to enhance food intake (21-25). Much evidence has been accumulated indicating that a number of opiate receptors are present in the brain, each one having a high affinity for a specific endogenous opioid peptide (26,27). Both the cyclazocine related compounds (28) and the feeding enhancer, dynorphin (29-32), have been reported to be specific kappa receptor agonists. In the present study, we report on the effect of the morphinan congener, butorphanol tartrate (33), on ingestive behavior. Materials and Methods Food consumption was studied in one hundred individually housed male Sprague-Dawley rats (lO0-150g) kept under standard lighting conditions (12 hr/day artificial light - 0700-1900 hr). All rats were given free access to a standard diet (Purina laboratory chow) and water until the beginning of the experiments. Butorphanol tartrate (Bristol Laboratories, Syracuse, NY), morphine sulfate (Winthrop Laboratories, New York, NY) and/or naloxone (Endo Laboratories, Inc., Garden City, NY) were injected subcutaneously. Immediately after injection, each animal was replaced into its home cage and presented with a measured quantity of Purina chow. Animals had access to water ad llbltum during the experiments. The quantity of food consumed was measured at I, 2, 4 and 6 hours following the injection of the drugs or vehicle (experiments were begun at 0800 hours). All food intake is expressed as cumulative food intake and results were compared using analysis of variance and the protected least significance test.
0024-3205/83/070781-05503.00/0
782
Butorphanol Tartrate and Feeding
Vol. 32, No. 7, 1983
Results Butorphanol tartrate at the 3.5 and 35 pmol/kg dose significantly increased feeding in sated rats when compared with the vehicle controls four hours and six hours following their injection (Figure i). In contradistinction, morphine had no significant effect on food intake, although there was a tendency for increased food consumption following morphine injection. The opiate antagonist, naloxone did not alter the butorphanol tartrate effect on food intake even at the i0 mg/kg dose (Figure 2). The addition of 1 mg/kg naloxone to the morphine injection did, however, result in a significant increase (p < 0.05) in food intake when compared with the vehicle controls at the 4 hour (1.4 + 0.3 vs 0.5 + 0.2) and 6 hour (1.8 -+ 0.2 vs 0.7 -+ 0.2) time points.
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2
4 TIME
6
(hours)
FIG. i Effect of butorphanol tartrate (BT) and morphine (M) on food intake. The shaded area represents the standard error of the mean. Doses of butorphanol tartrate and morphine are expressed as ~moles/kg. t p < 0.05.
Vol. 32, No. 7, 1983
Butorphanol Tartrate and Feeding
783
4 v
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Z H (:3 0 0I i
2
2
~ ~ '
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A ~ A , . ~ o
M+NI M35
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6
TIME (hours) FIG. 2 Effect of naloxone (N) on food intake following administration of butorphanol tartrate (BT) and morphine (M). Doses of naloxone are expressed as mg/kg, fp < 0.05.
Discussion It is well known that opiates can alter feeding behavior in rats, initially depressing food intake followed by an increase in food consumption (11,12,19). Recent studies have indicated that opiate agonists, such as ketocyclazocine and ethylketocyclazocine, which interact predominantly with kappa opiate receptors, increase ingestion of food following peripheral administration (34,35). We have recently reported (36) that the latter kappa opiate agonists and cyclazoclne appear to more potently induce feeding compared to morphine and have suggested that the early depression in feeding seen after administration of opiate agonists is due to their sedative effect exerted through the mu receptor, whereas the feeding effect is secondary to activation of the kappa receptor. In the present study we have shown that butorphanol tartrate markedly enhances food intake over a six hour period, whereas equlmolar doses of morphine sulfate did not statistically increase feeding compared with vehicle controls over the same time period. The profile
784
Butorphanol Tartrate and Feeding
Vol. 32, No. 7, 1983
of actions of butorphanol tartrate resemble those of pentazocine and other drugs whose actions are hypothesized to be exerted primarily on < and ~ opiate receptors (37,38). In addition, hutorphanol tartrate induced feeding was not suppressed by naloxone even at the i0 mg/kg dose and, in fact, naloxone in combination with morphine actually increased feeding when compared to vehicle controls. It should be noted that high dose naloxone (5 mg/kg) does suppress ketocyclazocine induced feeding for at least 6 hours (36). It has previously been noted that ketocyclazocine (36) and ethylketocyclazocine (34) enhanced feeding are resistant to the naloxone suppression of food intake which is in agreement with the observation that kappa agonists require high concentrations of naloxone to reverse their effects (26,27). These data are consistent with the view that the kappa receptor may play a role in the initiation of food intake although the failure of high dose naloxone to block butorphanol induced feeding suggests a possible role for the sigma receptors in feeding. Of interest was the enhancement of feeding observed with the concomitant administration of naloxone and morphine. This suggests that naloxone may have blocked the mu effects of morphine, thereby allowing escape from the sedative effects, and resulting in enhanced feeding due to activation of the kappa or sigma receptor. Acknowledgements We thank JoAnn Tallman for her expert secretarial aid and Martha Grace and Julie Kneip for their excellent technical assistance. We also thank Mohammad Khosti of Bristol Laboratories and Endo Laboratories for kindly supplying drugs for this study. This research was supported by the Veterans Administration. References i. 2. 3. 4. 5. 6. 7.
J.E. MORLEY, Life Sci. 27 355-368 (1980). D.J. SANGER, Appetite 2 193-208 (1981). D.L. MARGULES, Neurosci. Biobehav. Rev. 3 155-162,(1979). J.E. MORLEY and A.S. LEVINE, Am. J. Clin. Nutr. 35 757-761 (1982). J.D. BELLUZI and L. STEIN, Soc. Neurosei. Abstr. 8 405 (1978). S. GRANDISON and A. GUIDOTTI, Neuropharmacology i_~ 533-536 (1977). L.D. McKAY, N.J. KENNEY, N.K. EDENS, R.H. WILLIAMS and S.C. WOODS, Life Sci. 29 1429-1434 (1981). 8. J.E. MORLEY and A.S. LEVINE, Life Scl. 27 269-274 (1980). 9. J.E. MORLEY, A.S. LEVINE and C. PRASAD, Brain Res. 210 475-478 (1981). I0. W.R. MARTIN, A. WIKLER, C.G. EADES and F.T. PESCOR, Psychopharmacologia (Berl) 4 247-260 (1963). ii. J.A. THORNHILL, M. HIRST and C.W. GOWDEY, Arch. Int. Pharmacodyn. 223 120-131 (1976). 12. F.S. TEPPERMAN, M. HIRST and C. W. GOWDEY, Pharmacol. Biochem. Behav. 15 555-558 (1981). 13. S.G. HOLTZMAN, J. Pharmacol. Exp. Ther. 189 51-60 (1974). 14. D.R. BROWN and S.G. HOLTZMAN, Pharmacol. Biochem. Behav. ii 567-573 (1979). 15. B. BRANDS, J.A. THORN-HILL, M. HIRST and C.W. GOWDEY, Life Sci. 24 17731778 (1979). 16. J.E. MORLEY and A.S. LEVINE, Science 209 1259-1261 (1980). 17.1 M.T. LOWY, R.P. MAICKEL and G.K.W. YIM, Life Sci. 26 1213-1218 (1981). 18. J. STAPLETON, M.D. LIND, V.J. MERRIMAN and L.D. R E ~ , Life Sci. 24 2421-2426 (1979). 19. D.J. SANGER, P.S. McCARTHY and G. METCALF, Neuropharmacology 2__O045-47 (1981).
Vol. 32, No. 7, 1983
20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.
Butorphanol Tartrate and Feeding
785
J°E. MORLEY, A.S. LEVINE, S.S° MURRAY and J° KNEIP, Pharmacol. Biochem. Behav. 16 225-228 (1982). J.E. MORLEY and A.S. LEVINE, Life Sci. 29 1901-1903 (1981). J.M. WALKER, R.J. KATZ and H. AKIL, Peptides 1 341-345 (1980). R.J. KATZ, Neuropharmacology 1 9 801-803 (1980). J.E. MORLEY and A.S. LEVINE, Pharmacol. Biochem. Behav. 16 701-705 (1982). J.E. MORLEY and A.S. LEVINE, The Neural Basis of Feeding and Reward, Haer Institute, Brunswick (1982). K-J CHANG and P. CUATRECASAS, Fed. Proc. 40 2729-2732 (1981). R.S. ZUKIN and S.R. ZUKIN, Life Sci. 29 2681-2690 (1981). H.W. KOSTERLITZ and F.M. LESLIE, Br. J. Pharmacology 6 4 607-614 (1978). J.P. HUIDOBRO-TORO, K. YOSHIMURA, N.M. LEE, H.H. LOH and E.L. WAY, Eur. J. Pharmacol. 72 265-267 (1981). M. WUSTER and R. SCHULZ, Naunyn-ScP~niedeberg's Archives of Pharmacology 315 181-184 (1980). M. WUSTER, R. RUBINI and R. SCHULZ, Life Sci. 29 1219-1221 (1981). C. CHAVKIN, I.F. JAMES and A. GOLDSTEIN, Science 215 413-415 (1982). J.H. JOFFE and W.R. MARTIN, The Pharmacological Basis of Therapeutics~ MacMillan Publishing (1980). D.J. SANGER and P.S. McCARTHY, Psychopharmacology 7 4 217-220 (1981). M.T. LOWY and G.K.W. YIM, Psychopharmacology, in press (1982). J.E. MORLEY, A.S. LEVINE, M. GRACE and J. KNEIP, Life Sci. 3 1 2617-2626 (1982). H. NAGASHIMA, A. KARAMANIAN, R. MALOVANY, P. RODNAY, M. ANG, S. KOERNER and F.F. FOLDER, Clin. Pharmacol. Ther. 19 738-745 (1976). K.A. POPIO, D.H. JACKSON, A.M. ROSS, B.F. SCHREINER and P.N. YU, Clin. Pharmacol. Ther. 23 281-287 (1978).
Pergamon Press
BUTORPHANOL TARTRATE INDUCES FEEDING IN RATS A.S. Levine & J.E. Morley Neuroendocrine Research Laboratory, Minneapolis VA Medical Center, Minneapolis, Minnesota, 55417 and the Departments of Food Science and Nutrition and Medicine, University of Minnesota, St. Paul and Minneapolis, Minnesota. (Received in final form November 2, 1982) Summary Peripheral administration of butorphanol tartrate markedly enhanced feeding from 0800 to 1400 hours when compared with vehicle controls. Butorphanol tartrate feeding was not antagonized by doses of naloxone as high as i0 mg/kg. These data support the concept that the kappa or sigma opiate receptors are involved in feeding behavior. It is well recognized that the endogenous opiates play a role in the central regulation of appetite (1,2,3,4). Numerous studies have shown that the endogenous opioid peptides and morphine can initiate feeding under various conditions (5-12) whereas the opiate antagonist, naloxone can reduce food consumption (13-20). Recently, the endogenous opioid peptide, dynorphin, has been reported to enhance food intake (21-25). Much evidence has been accumulated indicating that a number of opiate receptors are present in the brain, each one having a high affinity for a specific endogenous opioid peptide (26,27). Both the cyclazocine related compounds (28) and the feeding enhancer, dynorphin (29-32), have been reported to be specific kappa receptor agonists. In the present study, we report on the effect of the morphinan congener, butorphanol tartrate (33), on ingestive behavior. Materials and Methods Food consumption was studied in one hundred individually housed male Sprague-Dawley rats (lO0-150g) kept under standard lighting conditions (12 hr/day artificial light - 0700-1900 hr). All rats were given free access to a standard diet (Purina laboratory chow) and water until the beginning of the experiments. Butorphanol tartrate (Bristol Laboratories, Syracuse, NY), morphine sulfate (Winthrop Laboratories, New York, NY) and/or naloxone (Endo Laboratories, Inc., Garden City, NY) were injected subcutaneously. Immediately after injection, each animal was replaced into its home cage and presented with a measured quantity of Purina chow. Animals had access to water ad llbltum during the experiments. The quantity of food consumed was measured at I, 2, 4 and 6 hours following the injection of the drugs or vehicle (experiments were begun at 0800 hours). All food intake is expressed as cumulative food intake and results were compared using analysis of variance and the protected least significance test.
0024-3205/83/070781-05503.00/0
782
Butorphanol Tartrate and Feeding
Vol. 32, No. 7, 1983
Results Butorphanol tartrate at the 3.5 and 35 pmol/kg dose significantly increased feeding in sated rats when compared with the vehicle controls four hours and six hours following their injection (Figure i). In contradistinction, morphine had no significant effect on food intake, although there was a tendency for increased food consumption following morphine injection. The opiate antagonist, naloxone did not alter the butorphanol tartrate effect on food intake even at the i0 mg/kg dose (Figure 2). The addition of 1 mg/kg naloxone to the morphine injection did, however, result in a significant increase (p < 0.05) in food intake when compared with the vehicle controls at the 4 hour (1.4 + 0.3 vs 0.5 + 0.2) and 6 hour (1.8 -+ 0.2 vs 0.7 -+ 0.2) time points.
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Vehicle BT.35
u_ I
2
4 TIME
6
(hours)
FIG. i Effect of butorphanol tartrate (BT) and morphine (M) on food intake. The shaded area represents the standard error of the mean. Doses of butorphanol tartrate and morphine are expressed as ~moles/kg. t p < 0.05.
Vol. 32, No. 7, 1983
Butorphanol Tartrate and Feeding
783
4 v
IJJ
3
Z H (:3 0 0I i
2
2
~ ~ '
'BT35
A ~ A , . ~ o
M+NI M35
I
I
4
6
TIME (hours) FIG. 2 Effect of naloxone (N) on food intake following administration of butorphanol tartrate (BT) and morphine (M). Doses of naloxone are expressed as mg/kg, fp < 0.05.
Discussion It is well known that opiates can alter feeding behavior in rats, initially depressing food intake followed by an increase in food consumption (11,12,19). Recent studies have indicated that opiate agonists, such as ketocyclazocine and ethylketocyclazocine, which interact predominantly with kappa opiate receptors, increase ingestion of food following peripheral administration (34,35). We have recently reported (36) that the latter kappa opiate agonists and cyclazoclne appear to more potently induce feeding compared to morphine and have suggested that the early depression in feeding seen after administration of opiate agonists is due to their sedative effect exerted through the mu receptor, whereas the feeding effect is secondary to activation of the kappa receptor. In the present study we have shown that butorphanol tartrate markedly enhances food intake over a six hour period, whereas equlmolar doses of morphine sulfate did not statistically increase feeding compared with vehicle controls over the same time period. The profile
784
Butorphanol Tartrate and Feeding
Vol. 32, No. 7, 1983
of actions of butorphanol tartrate resemble those of pentazocine and other drugs whose actions are hypothesized to be exerted primarily on < and ~ opiate receptors (37,38). In addition, hutorphanol tartrate induced feeding was not suppressed by naloxone even at the i0 mg/kg dose and, in fact, naloxone in combination with morphine actually increased feeding when compared to vehicle controls. It should be noted that high dose naloxone (5 mg/kg) does suppress ketocyclazocine induced feeding for at least 6 hours (36). It has previously been noted that ketocyclazocine (36) and ethylketocyclazocine (34) enhanced feeding are resistant to the naloxone suppression of food intake which is in agreement with the observation that kappa agonists require high concentrations of naloxone to reverse their effects (26,27). These data are consistent with the view that the kappa receptor may play a role in the initiation of food intake although the failure of high dose naloxone to block butorphanol induced feeding suggests a possible role for the sigma receptors in feeding. Of interest was the enhancement of feeding observed with the concomitant administration of naloxone and morphine. This suggests that naloxone may have blocked the mu effects of morphine, thereby allowing escape from the sedative effects, and resulting in enhanced feeding due to activation of the kappa or sigma receptor. Acknowledgements We thank JoAnn Tallman for her expert secretarial aid and Martha Grace and Julie Kneip for their excellent technical assistance. We also thank Mohammad Khosti of Bristol Laboratories and Endo Laboratories for kindly supplying drugs for this study. This research was supported by the Veterans Administration. References i. 2. 3. 4. 5. 6. 7.
J.E. MORLEY, Life Sci. 27 355-368 (1980). D.J. SANGER, Appetite 2 193-208 (1981). D.L. MARGULES, Neurosci. Biobehav. Rev. 3 155-162,(1979). J.E. MORLEY and A.S. LEVINE, Am. J. Clin. Nutr. 35 757-761 (1982). J.D. BELLUZI and L. STEIN, Soc. Neurosei. Abstr. 8 405 (1978). S. GRANDISON and A. GUIDOTTI, Neuropharmacology i_~ 533-536 (1977). L.D. McKAY, N.J. KENNEY, N.K. EDENS, R.H. WILLIAMS and S.C. WOODS, Life Sci. 29 1429-1434 (1981). 8. J.E. MORLEY and A.S. LEVINE, Life Scl. 27 269-274 (1980). 9. J.E. MORLEY, A.S. LEVINE and C. PRASAD, Brain Res. 210 475-478 (1981). I0. W.R. MARTIN, A. WIKLER, C.G. EADES and F.T. PESCOR, Psychopharmacologia (Berl) 4 247-260 (1963). ii. J.A. THORNHILL, M. HIRST and C.W. GOWDEY, Arch. Int. Pharmacodyn. 223 120-131 (1976). 12. F.S. TEPPERMAN, M. HIRST and C. W. GOWDEY, Pharmacol. Biochem. Behav. 15 555-558 (1981). 13. S.G. HOLTZMAN, J. Pharmacol. Exp. Ther. 189 51-60 (1974). 14. D.R. BROWN and S.G. HOLTZMAN, Pharmacol. Biochem. Behav. ii 567-573 (1979). 15. B. BRANDS, J.A. THORN-HILL, M. HIRST and C.W. GOWDEY, Life Sci. 24 17731778 (1979). 16. J.E. MORLEY and A.S. LEVINE, Science 209 1259-1261 (1980). 17.1 M.T. LOWY, R.P. MAICKEL and G.K.W. YIM, Life Sci. 26 1213-1218 (1981). 18. J. STAPLETON, M.D. LIND, V.J. MERRIMAN and L.D. R E ~ , Life Sci. 24 2421-2426 (1979). 19. D.J. SANGER, P.S. McCARTHY and G. METCALF, Neuropharmacology 2__O045-47 (1981).
Vol. 32, No. 7, 1983
20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.
Butorphanol Tartrate and Feeding
785
J°E. MORLEY, A.S. LEVINE, S.S° MURRAY and J° KNEIP, Pharmacol. Biochem. Behav. 16 225-228 (1982). J.E. MORLEY and A.S. LEVINE, Life Sci. 29 1901-1903 (1981). J.M. WALKER, R.J. KATZ and H. AKIL, Peptides 1 341-345 (1980). R.J. KATZ, Neuropharmacology 1 9 801-803 (1980). J.E. MORLEY and A.S. LEVINE, Pharmacol. Biochem. Behav. 16 701-705 (1982). J.E. MORLEY and A.S. LEVINE, The Neural Basis of Feeding and Reward, Haer Institute, Brunswick (1982). K-J CHANG and P. CUATRECASAS, Fed. Proc. 40 2729-2732 (1981). R.S. ZUKIN and S.R. ZUKIN, Life Sci. 29 2681-2690 (1981). H.W. KOSTERLITZ and F.M. LESLIE, Br. J. Pharmacology 6 4 607-614 (1978). J.P. HUIDOBRO-TORO, K. YOSHIMURA, N.M. LEE, H.H. LOH and E.L. WAY, Eur. J. Pharmacol. 72 265-267 (1981). M. WUSTER and R. SCHULZ, Naunyn-ScP~niedeberg's Archives of Pharmacology 315 181-184 (1980). M. WUSTER, R. RUBINI and R. SCHULZ, Life Sci. 29 1219-1221 (1981). C. CHAVKIN, I.F. JAMES and A. GOLDSTEIN, Science 215 413-415 (1982). J.H. JOFFE and W.R. MARTIN, The Pharmacological Basis of Therapeutics~ MacMillan Publishing (1980). D.J. SANGER and P.S. McCARTHY, Psychopharmacology 7 4 217-220 (1981). M.T. LOWY and G.K.W. YIM, Psychopharmacology, in press (1982). J.E. MORLEY, A.S. LEVINE, M. GRACE and J. KNEIP, Life Sci. 3 1 2617-2626 (1982). H. NAGASHIMA, A. KARAMANIAN, R. MALOVANY, P. RODNAY, M. ANG, S. KOERNER and F.F. FOLDER, Clin. Pharmacol. Ther. 19 738-745 (1976). K.A. POPIO, D.H. JACKSON, A.M. ROSS, B.F. SCHREINER and P.N. YU, Clin. Pharmacol. Ther. 23 281-287 (1978).