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Lack of antiemetic effects of Δ9-tetrahydrocannabinol in apomorphine-induced emesis in the dog
Life Sciences Vol . 23, pp . 49-54 Printed in the U .S .A .
Pergamon Press
LACK OF ANTIEMETIC EFFECTS OF n 9 -TETRAHYDROCANNABINOL IN APOMORPHINE-INDUCED EMESIS IN THE DOG H . E . Shannon,*
W . R . Martin,** and D . Silcox
National Institute on Drug Abuse Division of Research Addiction Research Center Lexington, Kentucky U . S . DEPARTMENT OF HEALTH, EDUCATION AND WELFARE Public Health Service Alcohol, Drug Abuse, and Mental Health Administration (Received in final form May 16, 1978) Summary Clinical studies have suggested that n 9 -tetrahydrocannabtnol (THC) may be a clinically useful antiemetic . However, the ability of THC to decrease experimentally induced emesis in animals has not been extensively studied . The present study compares the antiemetic effects of THC with chlorpromazine on apomorphine-induced emesis in the dog . THC, chlorpromazine, THC vehicle, or saline was administered i .v . 30 min prior to an i .v . infusion of apomorphine ; apomorphine was infused until emesis occurred . THC had no effect on the dose of apomorphine required to produce emesis, whereas chlorpromazine increased this dose approximately 75~ . Moreover, THC nearly doubled the time from the first to the last occurrence of emesis relative to control values, while chlorpromazine greatly reduced this value . In addition, THC had no effect on the stimulation of pulse rate produced by apomorphine ; chlorpromazine potentiated this effect, probably through indirect mechanisms . These findings demonstrate that THC is not an antagonist of the emetic agent apomorphine in the dog . e 9 -Tetrahydrocannabinol (THC) has been reported to have antiemetic properties in some patients with nausea and vomiting produced by cancer chemotherapeutic agents (1,2) . In these studies, the patients were receiving a variety of cancer chemotherapeutic agents, and the results were collected by questionnaires or interviews given a day or more after treatment, thus leaving the interpretation of these findings somewhat ambiguous . For this reason, we have evaluated the capacity of THC and chlorpromazine to antagonize apomorphine-induced emesis in the dog . Methods Six male and 4 female mongrel dogs, weighing between 9 and 18 kg, were *To whôm requests for o pr n should be sent . **Current address : Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky .
Lack of Antie~etic Effects of THC
Vol . 23, No . 1, 1978
trained to rest quietly in a slin . THC (0 .003 to 0.3 mg/kg), vehicle, chlorpromazine (0 .3 and 1 .0 mg/kg~ or saline was administered intravenously in a volume of 0 .1 ml/kg 30 min prior to an intravenous infusion of apomorphine (0 .05 mg/kg/min in a volume of 0 .5 m1/kg/min) . Apomorphine was infused until emesis occurred or to a maximum total dose of 5 .0 mg (10 mg following the 1 .0 mg/kg dose of chlorpromazine) . The dose of apomorphine required to produce emesis as well as the latency to the onset of the first occurrence of emesis and the time until the onset of the last occurrence of emesis were recorded . In addition, pulse rate was measured immediately prior to the administration of each drug as well as 30 min after the apomorphine infusion . The vehicle for THC was ethanol, propylene glycol and saline in a ratio of 35 :35 :30 (v/v/v) . The vehicle for chlorpromazine was saline . Each dog received each dose of each drug and their respective vehicles in a different random order with the exception that the 1 .0 mg/kg dose of chlorpromazine was administered first to every dog . At least two days elapsed between experimental sessions in each individual animal . The data were analyzed using analysis of variance for a complete randomized block design and paired t-tests (3) . Apomorphine hydrochloride and chlorpromazine hydrochloride were used in this study . The doses of these drugs are expressed as the salts . The THC was obtained from Arthur D . Little, Inc ., Cambridge, Mass ., Lot No . ADL1697278 with a specified purity of 98X . Results THC, administered over a 100-fold dose range (0 .003-0 .3 mg/kg) had no effect on the total dose of apomorphine required to produce emesis relative to the values for saline and vehicle pretreatments (Fig . 1) . Chlorpromazine, on the other hand, significantly ( < 0 .05) increased the dose of apomorphine required to produce emesis (Fig . 1~ . However, the doses of chlorpromazine used in this study appear to be supramaximal as 3 of the 10 dogs failed to vomit following the 0.3 mg/kg dose of chlorpromazine when the total maximal dose of apomorphine was 5 .0 mg . When pretreated with 1 .0 mg/kg of chlorpromazine, all 10 dogs vomited when the total maximal dose of apomorphine was 10 mg . Dose-related increases in the duration of emesis were observed following the administration of from 0 .003 to 0 .1 mg/kg of THC ; a further increase was not observed following the administration of 0 .3 mg/kg of THC (Fig . 2) . Partitioning the swn of squares between doses indicated a significant linear regression between dose of THC and duration of emesis (p < 0 .05) . Moreover, the Increase in duration following the administration of 0.1 mg/kg of THC was significantly increased as it fell outside the 95X confidence interval (20 to 350 sec) about the mean for the vehicle pretreatment . Chlorpromazine, on the other hand, significantly reduced (p < 0 .05) the duration of emesis (Fig . 2) relative to saline pretreatment . The effects of THC and chlorpromazine on another of apomorphine's effects, stimulation of pulse rate, were also evaluated . Apomorphine produced an Increase in the pulse rate of approximately 40 to 65 beats/min relative to pre-drug control values following saline and vehicle pretreatments, respectively . This difference between saline and vehicle pretreatments was not significant. THC, while producing a slight nonsignificant decrease in pulse rate, had no effect on the apomorphine-induced increase in pulse rate relative to vehicle and saline control values . On the other
Vol . 23, No . 1, 1978
Lack of Antiemetic Bffecta of THC
51
hand, the 1 .0 mg/kg dose of chlorpromazine significantly increased (p < 0 .05) the apomorphine-induced increase in pulse rate from a mean value of 4518 beats/min following saline to a mean value of 86112 beats/min . 0 .4 PRETREATMENT " -THC " -CPz ô 0 .3 0
E W 2
drc
0 .2
O O d
ô W Ol O C
O .I
0
Sal .
V~h .
0.003
OAI
OA3
DOSE OF DRUß (mq/kq)
O .I
0 .3
LO
FIG . 1 Lack of effect of à9-THC on the threshold dose of aportarphine required to produce emesis, and increase in the threshold dose of apomorphine required to produce emesis produced by chlorpromazine . Dogs were administered THC, chlorpromazine or their respective vehicles intravenously ; 30 min later apomorphine was infused intravenously (0 .05 mg/kg/min) until emesis occurred . The dose of apallorphine required to produce emesis after pretreatment with saline and the THC vehicle is represented by the open square (~ and open circle (o) at Sat and Veh, respectively . Each point represents the mean of one observation in each of 10 dogs ; the vertical lines represent t 1 S .E .M . The ordinate is the mean total dose of apomorphine infused in mg/kg ; the abscissa is the dose of drug in mg/kg . Discussion The present findings indicate that THC does not antagonize apomorphineinduced emesis in the dog . THC had no effect on the dose of apomorphine required to produce vomiting, whereas chlorpromazine, a known effective antiemetic, increased the emetic dose of apomorphine to approximately 175 of control values . Further, the length of time over which apomorphineinduced emesis occurred was nearly doubled following pretreatment with THC, whereas chlorpromazine pretreatment greatly reduced this value . In addition, THC had little effect on the stimulation of pulse rate produced by apomorphlne, whereas chlorpromazine potentiated this effect, probably through indirect mechanisms . Thus, we found no evidence to indicate that THC antagonized these actions of the emetic agent apomorphine in the dog .
Lack of Antiemetic Effects of THC
52
Vol. 23, No . 1, 1978
so0, PRETREATMENT " -THC ~-GP2 400
û W M
41 N 300 W W W
O 2 O
H 200 a
8
0
Sal.
V~h.
c 100
0
0.03 0.003 O.OI DOSE OF DRUB (mp/kp)
O.I
0.3
1 .0
FIG . 2 Dose-response curves of the duration of apomorphine-induced emesis in dogs pretreated with e 9 -THC or chlorpromazine . The duration of emesis was defined as the time from the onset of the first to the onset of the last occurrence of emesis . Dogs were administered THC, chlorpromazine or their respective vehicles intravenously ; 30 min later apomorphine was infused i .v . (0 .05 mg/kg/min until emesis occurred . The duration of emesis after pretreatment with saline and the THC vehicle is represented by the open square (Q) and open circle (o) at Sal and Veh, respectively . Each point represents the mean of one observation in each of 10 dogs ; the vertical lines represent tl S .E .M . The ordinate 1s the mean duration of emesis expressed as seconds ; the abscissa is the dose of drug in mg/kg . Sallan et at . (1) reported that orally administered THC reduced nausea and vomiting during cancer chemotherapy only when the subjects reported feeling "high", while Regelson et aZ . (2) reported marginal antiemetic effects with somewhat lower doses . We tested THC over a 100-fold dose range including doses comparable to those which produce euphoria up to those which produce psychotomimetic effects in man (4), and all were ineffective in raising the emetic dose of apomorphine . Regelson It should also be noted that THC has emetic effects of its own . et aZ . (2) noted nausea in one patient during the THC treatment . Moreover, it is a known clinical observation that relatively high doses of THC produce nausea and vomiting in man (5) . We observed emesis in the dog following the
Vol . 23, No . 1, 1978
Lack of Antiemetic Effects of THC
53
administration of doses in excess of 0 .5 mg/kg of THC in pilot experiments, an observation also reported by other investigators (6) . Apomorphine acts directly at the chemoreceptor trigger zone to produce emesis in the dog (7) . The mechanism of action of cancer chemotherapeutic agents in producing emesis is unknown . If THC is an effective antiemetic in cancer chemotherapy, it is not a pharmacologic antagonist of these agents through an apomorphine-sensitive mechanism at the chemoreceptor trigger zone . References 1. 2. 3. 4. 5. 6. 7.
S . E . SALLAN, N . E . ZINBER6 and E . FREI, N . Eng1 .J . Med . 29 3 795-797 (1975) . W . REGELSON, J . R . BUTLER, J . SCHULZ, T . KIRK, L . PECK, M . L . GREEN and M . 0 . ZAUS, in The Pharmacol of Marihuana (M . C . BRAURE and S . SZARA, eds .), pp . 763, oven ress, ew or 6) . G . W . SNEDECOR and W . G . COCHRAN, Statistical Methods (6th Ed .), Iowa State University Press, Mies, Iowa 96 H . ISBELL and D . R . JASINSKI, Psychopharmacologia 14 115-123 (1969) . J . JAFFE, in fhe Pharmacolo ical Basis of Thera eut~cs (4th Ed .) (L . S . GOODMAN and A . , e s . , pp . an, ew York (1970) . an S . LOEWE, J . Pharmacol . Exp . Ther . 8 8 154-161 (1946) . S . C . WANG and H . L . BORISON, Gastroenterology 22 1-11 (1952) .
Pergamon Press
LACK OF ANTIEMETIC EFFECTS OF n 9 -TETRAHYDROCANNABINOL IN APOMORPHINE-INDUCED EMESIS IN THE DOG H . E . Shannon,*
W . R . Martin,** and D . Silcox
National Institute on Drug Abuse Division of Research Addiction Research Center Lexington, Kentucky U . S . DEPARTMENT OF HEALTH, EDUCATION AND WELFARE Public Health Service Alcohol, Drug Abuse, and Mental Health Administration (Received in final form May 16, 1978) Summary Clinical studies have suggested that n 9 -tetrahydrocannabtnol (THC) may be a clinically useful antiemetic . However, the ability of THC to decrease experimentally induced emesis in animals has not been extensively studied . The present study compares the antiemetic effects of THC with chlorpromazine on apomorphine-induced emesis in the dog . THC, chlorpromazine, THC vehicle, or saline was administered i .v . 30 min prior to an i .v . infusion of apomorphine ; apomorphine was infused until emesis occurred . THC had no effect on the dose of apomorphine required to produce emesis, whereas chlorpromazine increased this dose approximately 75~ . Moreover, THC nearly doubled the time from the first to the last occurrence of emesis relative to control values, while chlorpromazine greatly reduced this value . In addition, THC had no effect on the stimulation of pulse rate produced by apomorphine ; chlorpromazine potentiated this effect, probably through indirect mechanisms . These findings demonstrate that THC is not an antagonist of the emetic agent apomorphine in the dog . e 9 -Tetrahydrocannabinol (THC) has been reported to have antiemetic properties in some patients with nausea and vomiting produced by cancer chemotherapeutic agents (1,2) . In these studies, the patients were receiving a variety of cancer chemotherapeutic agents, and the results were collected by questionnaires or interviews given a day or more after treatment, thus leaving the interpretation of these findings somewhat ambiguous . For this reason, we have evaluated the capacity of THC and chlorpromazine to antagonize apomorphine-induced emesis in the dog . Methods Six male and 4 female mongrel dogs, weighing between 9 and 18 kg, were *To whôm requests for o pr n should be sent . **Current address : Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky .
Lack of Antie~etic Effects of THC
Vol . 23, No . 1, 1978
trained to rest quietly in a slin . THC (0 .003 to 0.3 mg/kg), vehicle, chlorpromazine (0 .3 and 1 .0 mg/kg~ or saline was administered intravenously in a volume of 0 .1 ml/kg 30 min prior to an intravenous infusion of apomorphine (0 .05 mg/kg/min in a volume of 0 .5 m1/kg/min) . Apomorphine was infused until emesis occurred or to a maximum total dose of 5 .0 mg (10 mg following the 1 .0 mg/kg dose of chlorpromazine) . The dose of apomorphine required to produce emesis as well as the latency to the onset of the first occurrence of emesis and the time until the onset of the last occurrence of emesis were recorded . In addition, pulse rate was measured immediately prior to the administration of each drug as well as 30 min after the apomorphine infusion . The vehicle for THC was ethanol, propylene glycol and saline in a ratio of 35 :35 :30 (v/v/v) . The vehicle for chlorpromazine was saline . Each dog received each dose of each drug and their respective vehicles in a different random order with the exception that the 1 .0 mg/kg dose of chlorpromazine was administered first to every dog . At least two days elapsed between experimental sessions in each individual animal . The data were analyzed using analysis of variance for a complete randomized block design and paired t-tests (3) . Apomorphine hydrochloride and chlorpromazine hydrochloride were used in this study . The doses of these drugs are expressed as the salts . The THC was obtained from Arthur D . Little, Inc ., Cambridge, Mass ., Lot No . ADL1697278 with a specified purity of 98X . Results THC, administered over a 100-fold dose range (0 .003-0 .3 mg/kg) had no effect on the total dose of apomorphine required to produce emesis relative to the values for saline and vehicle pretreatments (Fig . 1) . Chlorpromazine, on the other hand, significantly ( < 0 .05) increased the dose of apomorphine required to produce emesis (Fig . 1~ . However, the doses of chlorpromazine used in this study appear to be supramaximal as 3 of the 10 dogs failed to vomit following the 0.3 mg/kg dose of chlorpromazine when the total maximal dose of apomorphine was 5 .0 mg . When pretreated with 1 .0 mg/kg of chlorpromazine, all 10 dogs vomited when the total maximal dose of apomorphine was 10 mg . Dose-related increases in the duration of emesis were observed following the administration of from 0 .003 to 0 .1 mg/kg of THC ; a further increase was not observed following the administration of 0 .3 mg/kg of THC (Fig . 2) . Partitioning the swn of squares between doses indicated a significant linear regression between dose of THC and duration of emesis (p < 0 .05) . Moreover, the Increase in duration following the administration of 0.1 mg/kg of THC was significantly increased as it fell outside the 95X confidence interval (20 to 350 sec) about the mean for the vehicle pretreatment . Chlorpromazine, on the other hand, significantly reduced (p < 0 .05) the duration of emesis (Fig . 2) relative to saline pretreatment . The effects of THC and chlorpromazine on another of apomorphine's effects, stimulation of pulse rate, were also evaluated . Apomorphine produced an Increase in the pulse rate of approximately 40 to 65 beats/min relative to pre-drug control values following saline and vehicle pretreatments, respectively . This difference between saline and vehicle pretreatments was not significant. THC, while producing a slight nonsignificant decrease in pulse rate, had no effect on the apomorphine-induced increase in pulse rate relative to vehicle and saline control values . On the other
Vol . 23, No . 1, 1978
Lack of Antiemetic Bffecta of THC
51
hand, the 1 .0 mg/kg dose of chlorpromazine significantly increased (p < 0 .05) the apomorphine-induced increase in pulse rate from a mean value of 4518 beats/min following saline to a mean value of 86112 beats/min . 0 .4 PRETREATMENT " -THC " -CPz ô 0 .3 0
E W 2
drc
0 .2
O O d
ô W Ol O C
O .I
0
Sal .
V~h .
0.003
OAI
OA3
DOSE OF DRUß (mq/kq)
O .I
0 .3
LO
FIG . 1 Lack of effect of à9-THC on the threshold dose of aportarphine required to produce emesis, and increase in the threshold dose of apomorphine required to produce emesis produced by chlorpromazine . Dogs were administered THC, chlorpromazine or their respective vehicles intravenously ; 30 min later apomorphine was infused intravenously (0 .05 mg/kg/min) until emesis occurred . The dose of apallorphine required to produce emesis after pretreatment with saline and the THC vehicle is represented by the open square (~ and open circle (o) at Sat and Veh, respectively . Each point represents the mean of one observation in each of 10 dogs ; the vertical lines represent t 1 S .E .M . The ordinate is the mean total dose of apomorphine infused in mg/kg ; the abscissa is the dose of drug in mg/kg . Discussion The present findings indicate that THC does not antagonize apomorphineinduced emesis in the dog . THC had no effect on the dose of apomorphine required to produce vomiting, whereas chlorpromazine, a known effective antiemetic, increased the emetic dose of apomorphine to approximately 175 of control values . Further, the length of time over which apomorphineinduced emesis occurred was nearly doubled following pretreatment with THC, whereas chlorpromazine pretreatment greatly reduced this value . In addition, THC had little effect on the stimulation of pulse rate produced by apomorphlne, whereas chlorpromazine potentiated this effect, probably through indirect mechanisms . Thus, we found no evidence to indicate that THC antagonized these actions of the emetic agent apomorphine in the dog .
Lack of Antiemetic Effects of THC
52
Vol. 23, No . 1, 1978
so0, PRETREATMENT " -THC ~-GP2 400
û W M
41 N 300 W W W
O 2 O
H 200 a
8
0
Sal.
V~h.
c 100
0
0.03 0.003 O.OI DOSE OF DRUB (mp/kp)
O.I
0.3
1 .0
FIG . 2 Dose-response curves of the duration of apomorphine-induced emesis in dogs pretreated with e 9 -THC or chlorpromazine . The duration of emesis was defined as the time from the onset of the first to the onset of the last occurrence of emesis . Dogs were administered THC, chlorpromazine or their respective vehicles intravenously ; 30 min later apomorphine was infused i .v . (0 .05 mg/kg/min until emesis occurred . The duration of emesis after pretreatment with saline and the THC vehicle is represented by the open square (Q) and open circle (o) at Sal and Veh, respectively . Each point represents the mean of one observation in each of 10 dogs ; the vertical lines represent tl S .E .M . The ordinate 1s the mean duration of emesis expressed as seconds ; the abscissa is the dose of drug in mg/kg . Sallan et at . (1) reported that orally administered THC reduced nausea and vomiting during cancer chemotherapy only when the subjects reported feeling "high", while Regelson et aZ . (2) reported marginal antiemetic effects with somewhat lower doses . We tested THC over a 100-fold dose range including doses comparable to those which produce euphoria up to those which produce psychotomimetic effects in man (4), and all were ineffective in raising the emetic dose of apomorphine . Regelson It should also be noted that THC has emetic effects of its own . et aZ . (2) noted nausea in one patient during the THC treatment . Moreover, it is a known clinical observation that relatively high doses of THC produce nausea and vomiting in man (5) . We observed emesis in the dog following the
Vol . 23, No . 1, 1978
Lack of Antiemetic Effects of THC
53
administration of doses in excess of 0 .5 mg/kg of THC in pilot experiments, an observation also reported by other investigators (6) . Apomorphine acts directly at the chemoreceptor trigger zone to produce emesis in the dog (7) . The mechanism of action of cancer chemotherapeutic agents in producing emesis is unknown . If THC is an effective antiemetic in cancer chemotherapy, it is not a pharmacologic antagonist of these agents through an apomorphine-sensitive mechanism at the chemoreceptor trigger zone . References 1. 2. 3. 4. 5. 6. 7.
S . E . SALLAN, N . E . ZINBER6 and E . FREI, N . Eng1 .J . Med . 29 3 795-797 (1975) . W . REGELSON, J . R . BUTLER, J . SCHULZ, T . KIRK, L . PECK, M . L . GREEN and M . 0 . ZAUS, in The Pharmacol of Marihuana (M . C . BRAURE and S . SZARA, eds .), pp . 763, oven ress, ew or 6) . G . W . SNEDECOR and W . G . COCHRAN, Statistical Methods (6th Ed .), Iowa State University Press, Mies, Iowa 96 H . ISBELL and D . R . JASINSKI, Psychopharmacologia 14 115-123 (1969) . J . JAFFE, in fhe Pharmacolo ical Basis of Thera eut~cs (4th Ed .) (L . S . GOODMAN and A . , e s . , pp . an, ew York (1970) . an S . LOEWE, J . Pharmacol . Exp . Ther . 8 8 154-161 (1946) . S . C . WANG and H . L . BORISON, Gastroenterology 22 1-11 (1952) .