Life Sciences Vol. 17, pp . 55-56 Printed in the U .S .A .
Pergamon Press
POSSIBLE ROLE OF BRAIN HISTAMINE IN I40RPHINE ADDICTION (Received in final form May 24, 1975) R. W. Henwoodl and I. M. Mazurkiewicz-Kwilecki2 ' 3 Department of Pharmacology, Faculty of Medicine, Ottawa University 275 Nicholas Street, Ottawa, Ontario, Canada . Several biogenic amines have been suggested to play a possible role in opiate addiction. While some reports indicated changes in brain norepinephrine and dopamine concentrations and/or synthesis (1,2,3), others have demonstrated the involvement of serotonin or acetylcholine (4,5,6,7) . In view of recent reports suggesting a possible role for histamine in brain function as another putative neurotransmitter (8), we have investigated whether this biogenic amine might also participate in morphine addiction and withdrawal . Materials and Methods In acute eaperimenta, male Sprague Dawley rata (200-225 g) were injected intraperitoneally (i .p .) with morphine, methadone, or naloxone and sacrificed one hour after the morphine or methadone and 20 minutes following naloxone injection . In chronic studies the rata (starting weights 150-160 g) were treated i .p . with increasing doses of morphine according to the method of Takemori (9) and killed 18 hours after their last injection. Histamine was determined by the double isotope technique of Taylor and Snyder (10) using 14 C-S-adenosylmethionine ae the methyl donor and adding tracer quantities of 3H-histamine to correct for the varying degree of histamine methylation in different samples . 14C- 3ürmethylhistamine and 14C-methylhistamine were separated from 3H-histamine and 14C-S-adenosylmethionine by eatracting into chloroform from a salt-saturated alkaline solution . Results and Discussion Endogenous histamine concentrations of the hypothalamus, brain stem, or cortex were not significantly changed after acute treatments with morphine (30mg/kg), methadone (5mg/kg), or with naloxone (0 .4mg/kg), however chronic treatment with increasing doses of morphine for 21 days resulted in a significant decrease in the endogenous brain histamine concentration in the hypothalamus (71 .5í4 .6Z of control) . Decreases in the brain stem (92 .3í8 .3i of control) and cortex (77.6í16 .7X of control) were also noted although they were not statistically significant . The naloxone induced withdrawal syndrome in rats treated with morphine for 21 days as judged by wet dog shakes, teeth chattering, weight lose, and temperature decline, resulted in a further decrease in the endogenous histamine concentrations in the hypothalamus (64.0í5 .5Z of control), brain stem (84.6í10 .3Z of control) and cortex (66 .7í5 .1Z of control), which were, however, not significantly greater than the decrease seen in the morphine-treated rate . Abrupt withdrawal of morphine after 21 days of chronic morphine treatment and replacement with saline injections for an additional 2 days, induced a further significant decrease in the histamine concentrations in the hypo thalamus (53 .5í2 .9Z of control), brain stem (67 .7í9 .7Z of control), and cortex (50.0í4 .5Z of control) .
20ntario
Mental Health Foundation Research Student . This project was supported by OMHF grant ~ 379-71 D .
3Requesta for reprints to be addressed to I .M . Mazurkiewicz-Rwilecki .
56
Hrain Histamine in Morphine Addiction
Vol. 17, No . 1
These changes were statistically significant not only when compared with control rata treated with saline for an identical period of time but also with rate chronically treated with morphine for 21 or 23 days . Replacement of morphine, after 21 days of chronic treatment, with methadone (15mg/kg), for an additional 2 days, resulted in histamine values not different from those seen in the hypothalamus, brain stem, or cortex of rata chronically treated with morphine alone for 21 or 23 days . The morphinemethadone treated rata however, had significantly higher histamine concentrations in the three brain regions studied, than those seen in animals abruptly withdrawn from morphine . The presently observed decrease in histamine concentration induced by This cochronic morphine administration was most intense ín the hypothalamus . incides with the highest concentration and a very rapid turnover of histamine in this brain region (11) . The decrease in histamine concentration occurred only after chronic treatment which could indicate a slowly developing process which might have been due to an induced imbalance between the rate of synthesis and metabolism or release of this biogenic amine . Morphine is known to release histamine from the rat peripheral tissues (12) and chronic histamine administration influences catecholamine concentrations in the brain and peripheral tissues of rat (13) . The already reported changes in the concentration or synthesis of other biogenic amines after morphine administration could have been triggered by, associated with, or secondary to, a decrease of brain histamine . It seems nw acceptable that not one biogenic amine but the interaction between several of them may play an important role in the complicated proOur present data ceasea linked with tolerance development and addiction . indicates that in addition to other biogenic amines, histamine may be involved in the mechanism of morphine addiction. Refereaces 1. Narcotic Drugs, Biochemical Pharmacology, Ed . D .H . Clouet, Plenum Prese New York (1971) . 2 . K. KUSCHINSRY, Experientia,
29, 1365-1366,
(1973) .
3. J .C . JOHNSON, M. RATHER, G .T . GOLD, D .H . CLOUET, Res. Comm . in Chem . Path . and Pharm., 9, 41-53, (1974) . 4. A. HERZ, J. BLASIG, R. PAPESCHI, Paychopharm.
(Berl), 39, 121-143 (1974?
5. S . KNAPP, A.J . MANDELL, Science, 177, 1209-1211,
(1972) .
6. F.H . SHEN, H .H . LOH, E .L . WAY, J . Pharm. Eapt . Ther ., _175, 427-434, (1970) . 7. E.F . DOMINO, A. WILSON, J. Pharm. Eapt . Ther ., 184, 18032,
(1973) .
8 . S .H . SNYDER, R.M . TAYLOR, p. 43-73 in Perspectives in Neuropharmacology Ed . S.H . Snyder, Oxford University Prese, Toronto (1972) . 9 . A.E . TAREMORI, J . Pharm. Expt . Ther ., 130,
370-374,
(1960) .
10 . K.M . TAYLOR, S .H . SNYDER, J . Neurochem ., 19, 1343-1358, 11 . R. DISMUKES, S .H . SNYDER, Brain Rea., 78, 101-109,
(1972) .
(1974) .
12 . A.M. ROTHSCHILD, P. 386-430 in Haadbook of Experimental Pharmacology Ed . 0. Eichler and A. Farah, Springer-Verlag, New York (1966) . 13 . I.M . MAZURKIEWICZ-RWILECRI and D .A .V . PETERS, Biochem. Pharm., _22, 3225-3235, (1973) .
Pergamon Press
POSSIBLE ROLE OF BRAIN HISTAMINE IN I40RPHINE ADDICTION (Received in final form May 24, 1975) R. W. Henwoodl and I. M. Mazurkiewicz-Kwilecki2 ' 3 Department of Pharmacology, Faculty of Medicine, Ottawa University 275 Nicholas Street, Ottawa, Ontario, Canada . Several biogenic amines have been suggested to play a possible role in opiate addiction. While some reports indicated changes in brain norepinephrine and dopamine concentrations and/or synthesis (1,2,3), others have demonstrated the involvement of serotonin or acetylcholine (4,5,6,7) . In view of recent reports suggesting a possible role for histamine in brain function as another putative neurotransmitter (8), we have investigated whether this biogenic amine might also participate in morphine addiction and withdrawal . Materials and Methods In acute eaperimenta, male Sprague Dawley rata (200-225 g) were injected intraperitoneally (i .p .) with morphine, methadone, or naloxone and sacrificed one hour after the morphine or methadone and 20 minutes following naloxone injection . In chronic studies the rata (starting weights 150-160 g) were treated i .p . with increasing doses of morphine according to the method of Takemori (9) and killed 18 hours after their last injection. Histamine was determined by the double isotope technique of Taylor and Snyder (10) using 14 C-S-adenosylmethionine ae the methyl donor and adding tracer quantities of 3H-histamine to correct for the varying degree of histamine methylation in different samples . 14C- 3ürmethylhistamine and 14C-methylhistamine were separated from 3H-histamine and 14C-S-adenosylmethionine by eatracting into chloroform from a salt-saturated alkaline solution . Results and Discussion Endogenous histamine concentrations of the hypothalamus, brain stem, or cortex were not significantly changed after acute treatments with morphine (30mg/kg), methadone (5mg/kg), or with naloxone (0 .4mg/kg), however chronic treatment with increasing doses of morphine for 21 days resulted in a significant decrease in the endogenous brain histamine concentration in the hypothalamus (71 .5í4 .6Z of control) . Decreases in the brain stem (92 .3í8 .3i of control) and cortex (77.6í16 .7X of control) were also noted although they were not statistically significant . The naloxone induced withdrawal syndrome in rats treated with morphine for 21 days as judged by wet dog shakes, teeth chattering, weight lose, and temperature decline, resulted in a further decrease in the endogenous histamine concentrations in the hypothalamus (64.0í5 .5Z of control), brain stem (84.6í10 .3Z of control) and cortex (66 .7í5 .1Z of control), which were, however, not significantly greater than the decrease seen in the morphine-treated rate . Abrupt withdrawal of morphine after 21 days of chronic morphine treatment and replacement with saline injections for an additional 2 days, induced a further significant decrease in the histamine concentrations in the hypo thalamus (53 .5í2 .9Z of control), brain stem (67 .7í9 .7Z of control), and cortex (50.0í4 .5Z of control) .
20ntario
Mental Health Foundation Research Student . This project was supported by OMHF grant ~ 379-71 D .
3Requesta for reprints to be addressed to I .M . Mazurkiewicz-Rwilecki .
56
Hrain Histamine in Morphine Addiction
Vol. 17, No . 1
These changes were statistically significant not only when compared with control rata treated with saline for an identical period of time but also with rate chronically treated with morphine for 21 or 23 days . Replacement of morphine, after 21 days of chronic treatment, with methadone (15mg/kg), for an additional 2 days, resulted in histamine values not different from those seen in the hypothalamus, brain stem, or cortex of rata chronically treated with morphine alone for 21 or 23 days . The morphinemethadone treated rata however, had significantly higher histamine concentrations in the three brain regions studied, than those seen in animals abruptly withdrawn from morphine . The presently observed decrease in histamine concentration induced by This cochronic morphine administration was most intense ín the hypothalamus . incides with the highest concentration and a very rapid turnover of histamine in this brain region (11) . The decrease in histamine concentration occurred only after chronic treatment which could indicate a slowly developing process which might have been due to an induced imbalance between the rate of synthesis and metabolism or release of this biogenic amine . Morphine is known to release histamine from the rat peripheral tissues (12) and chronic histamine administration influences catecholamine concentrations in the brain and peripheral tissues of rat (13) . The already reported changes in the concentration or synthesis of other biogenic amines after morphine administration could have been triggered by, associated with, or secondary to, a decrease of brain histamine . It seems nw acceptable that not one biogenic amine but the interaction between several of them may play an important role in the complicated proOur present data ceasea linked with tolerance development and addiction . indicates that in addition to other biogenic amines, histamine may be involved in the mechanism of morphine addiction. Refereaces 1. Narcotic Drugs, Biochemical Pharmacology, Ed . D .H . Clouet, Plenum Prese New York (1971) . 2 . K. KUSCHINSRY, Experientia,
29, 1365-1366,
(1973) .
3. J .C . JOHNSON, M. RATHER, G .T . GOLD, D .H . CLOUET, Res. Comm . in Chem . Path . and Pharm., 9, 41-53, (1974) . 4. A. HERZ, J. BLASIG, R. PAPESCHI, Paychopharm.
(Berl), 39, 121-143 (1974?
5. S . KNAPP, A.J . MANDELL, Science, 177, 1209-1211,
(1972) .
6. F.H . SHEN, H .H . LOH, E .L . WAY, J . Pharm. Eapt . Ther ., _175, 427-434, (1970) . 7. E.F . DOMINO, A. WILSON, J. Pharm. Eapt . Ther ., 184, 18032,
(1973) .
8 . S .H . SNYDER, R.M . TAYLOR, p. 43-73 in Perspectives in Neuropharmacology Ed . S.H . Snyder, Oxford University Prese, Toronto (1972) . 9 . A.E . TAREMORI, J . Pharm. Expt . Ther ., 130,
370-374,
(1960) .
10 . K.M . TAYLOR, S .H . SNYDER, J . Neurochem ., 19, 1343-1358, 11 . R. DISMUKES, S .H . SNYDER, Brain Rea., 78, 101-109,
(1972) .
(1974) .
12 . A.M. ROTHSCHILD, P. 386-430 in Haadbook of Experimental Pharmacology Ed . 0. Eichler and A. Farah, Springer-Verlag, New York (1966) . 13 . I.M . MAZURKIEWICZ-RWILECRI and D .A .V . PETERS, Biochem. Pharm., _22, 3225-3235, (1973) .
