Hypothermic action of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol and 11-hydroxy-Δ8-tetrahydrocannabinol in mice

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<ul><li><p>Life SciQ~es Vol . 13, pp. 1771-1778, 1973 .</p><p>Pergamon PressPrinted in Great Britain</p><p>HYPOTHERMIC ACTION OF A9-TETRAHYDROCANNABINOL, 11-HYDROXY-A9-TETRAHYDROCANNABINOL AND 11-HYDROXY-AB-TETRAHYDROCANNABINOL IN MICE</p><p>Coryce 0 . Haavik and Harold F . Hardman</p><p>Department of Pharmacology, The Medical College of WisconsinMilwaukee, Wisconsin 53233</p><p>(Received 17 September 1973 ; in final form 2 November 1973)Summary</p><p>The hypothermic activity of 09-tetrahydrocannabinol (D9-THC), ametabolite, 11-hydroxy-A 9 -tetrahydrocannabinol (11-OH-D 9 -THC) and 11-hydroxy-De-tetrahydrocannabinol (11-OH-AB-THC) has been determined inmale mice maintained at an ambient temperature of 20 loC . The meanbody temperature of mice that received 2, 4, 16 or 32 mg/kg, i .v., ofa tetrahydrocannabinol was significantly lower than that of vehicletreated mice (p </p></li><li><p>1772</p><p>Tetrahydroca.nnabinol-Induced Hypothermia .</p><p>Vol. 13, No . 12</p><p>The ability to lower body temperature is one of many actions of tetrahydro-</p><p>cannabinols . These agents are among the most potent hypothermic agents known</p><p>(8) .</p><p>Quantitation of the hypothermic action of :: 9 -THC in mice has been re</p><p>ported recently by this laboratory (9) .</p><p>Since the hypothermic response can be</p><p>measured with precision, this assay nw has been used to compare the onset of</p><p>action and the intrinsic activity of 11-OH-A 9 -THC and 11-hydroxy-AB-tetrahydro-</p><p>cannabinol (11-OH-Ae-THC) with that of A9-THC .</p><p>Methods</p><p>Male Cox mice (19-22 g boy weight) were transferred from animal quarters</p><p>to an environmentally controlled room 21 hours prior to drug administration .</p><p>In the environmental room ambient temperature was maintained at 20 1C and</p><p>humidity controlled at 45-55$ .</p><p>Deep rectal temperature was monitored by means</p><p>of a thermistor probe and telethermometer (Yellow Springs Instrument Co .) im-</p><p>mediately before and for 2 hours after intravenous drug administration . During</p><p>this time the animals were restrained by the tail but otherwise were free to</p><p>move . The tetrahydrocannabinols (A9-THC, 11-OH-, 9 -THC and 11-OH-AB-THC)~` were</p><p>prepared as suspensions in alcohol, Tween 80 and saline (20 mg drug in 0 .1 ml</p><p>95$ ethanol, 0 .1 ml Tween 80 and 0 .43 ml 0 .9$ NaCl) . This stock solution was</p><p>diluted with vehicle as required so that the desired drug dose was contained</p><p>in 0 .1 ml for a 25 g mouse . Vehicle consisted of ethanol, Tween 80 and saline</p><p>in the same proportions as in the stock drug solution .</p><p>The mean difference in body temperat~se t S .E . from the individual control</p><p>values was calculated for each time at which temperature was measured . Sig-</p><p>nificance was determined by Student's t-test and set at p c0.05 .</p><p>Results</p><p>The .dose related nature of the hypothermic response to A9-THC is shown in</p><p>Fig . 1 . Administration of 11-OH-D 9-THC and 11-OH-De-THC also resulted in a</p><p>dose related hypothermia .</p><p>The mean maximal hypothermia produced by these three</p><p>~A9 -THC, 11-OH-G 9-THC and 11-OH-GB-THC were supplied by Dr . M . C . Braude,National Institute of Mental Health .</p></li><li><p>Vol. 13, No . 12</p><p>Tetrahydrocannabinol-hduced Hypothermia</p><p>1773</p><p>,u</p><p>FIG. 1</p><p>Mean body temperature decrease after i .v . administration of vehicle~ (~) orof A9-THC at doses of 2 ( d-~ ), 4 ( ~-~ ), 16 ( ~~ ) and 32 (f") mg/kgto mice . Each point represents the mean difference in body temperature t S .E .from the individual control values for at least 14 mice .</p><p>agents over the dosage range of 2 to 32 mg/kg is shown in Table 1 .</p><p>It can be</p><p>seen (table 1) that the hypothermic response to A9-THC increases continuously</p><p>over the dose range studied, while the maximum hypothermia following adminis-</p><p>tration of either 11-0H-A9-THC or 11-OH-AB-THC has been attained.</p><p>The onset of the hypothermic response to A9-THC occurs rapidly (Fig . 1) .</p><p>The decrease in mean body temperature during the first 5 minutes after adminis-</p><p>tration of vehicle or of a 2 mg/kg dose of A9-THC or 11-OH-A9-THC is shown is</p><p>Fig . 2 .</p><p>Within 2 minutes the mean body temperatures of both groups of drug</p><p>treated mice were significantly lower (p </p></li><li><p>1774</p><p>Tetrahydrocannabinol-Induced Hypothermia</p><p>Vol. 13, No. 12</p><p>TABLE 1</p><p>Mean Maximum Decrease S .E . ( C) in Rectal Temperature afterL V . Administration of A9-THC, 11-OH-D 9-THC or 11-OH-D9-THC to Mice</p><p>(Ambient Temperature = 20C)</p><p>Dose A9-THC 11-OH-A 9 -THC 11-OH-AB-THCmg/kg</p><p>X S .E .</p><p>N</p><p>X S .E .</p><p>N</p><p>X t S .E .</p><p>N</p><p>2</p><p>3 .47 t 0 .40 (16)</p><p>4 .28 0 .39 (8)</p><p>3 .00 t 0 .24 (8)</p><p>p </p></li><li><p>Vol . 13, No. 12</p><p>Tetrahydrocannabinol-Induced Hypothermia</p><p>1775</p><p>L 2S</p><p>~ VEHICLE~ eTHC</p><p>II-oHeTHC2mik9 `~</p><p>05 LO 1 .5 2A 2S 30 a5 4A 4,5 50</p><p>TIME (mimes)</p><p>FIG . 2</p><p>Mean body temperature decrease after i .v . administration of vehicle, A9-THC or11-OH-A9-THC . Each point represents the mean difference in body temperature tS .E . from the individual control values for at least 8 mice .</p><p>VEHKLE~</p><p>eTrlce n-oH eoTHC 2mih~ ."</p><p>FIG . 3</p><p>Mean body temperature decrease after i .v . administration of vehicle, e9 -THC or11-OH-AB-THC . Each point represents the mean difference in body temperature tS .E . from the individual control values for at least 8 mice .</p></li><li><p>1778</p><p>Tetrahydrocannabinol-Induced Hypothermia</p><p>Vol . 13, No. 12</p><p>intracerebrally .</p><p>Intravenous administration of 11-OH-A 9-THC to man produced</p><p>tachycardia and a feeling subjectively evaluated as a marihuana-like "high ."</p><p>The onset, magnitude and duration of tachycardia does not differ significantly</p><p>from that produced by intravenous administration of a comparable dose of A9-</p><p>THC . The psychological assay suggests that D9 -THC has greater efficacy and a</p><p>longer duration of action than does 11-OH-A 9 -THC (7) . Although the reports of</p><p>these investigators demonstrate that 11-0H-A 9-THC has activity on the cardio-</p><p>vascular and central nervous systems, the rapid onset of action of 09 -THC in</p><p>these systems suggests that prior conversion to an active metabolite may not</p><p>be required .</p><p>Gill and Jones (10) have measured the effect of D9-THC on be-</p><p>havior of mice pretreated with SKF 525A, an inhibitor of oxidative drug metab</p><p>olism .</p><p>Since this treatment significantly elevated brain 11-OH-D 9 -THC without</p><p>producing a comparable increase in behavioral effect, no conclusion could be</p><p>drawn regarding the relative pharmacological importance of D9-THC and 11-OH-</p><p>A9-THC as mediators of the behavioral response .</p><p>Investigations from many laboratories have established that the tetrahy-</p><p>drocannabinols are potent hypothermic agents (8) . Since the dose related</p><p>nature of the hypothermic response can be demonstrated and quantitated without</p><p>difficulty (9), this system is of value for comparing the activity of A9-THC</p><p>with that of its metabolite, 11-OH-A 9-THC . In addition, the activities of</p><p>11-OH-D 9-THC and another hydroxy tetrahydrocannabinol, 11-OH-Ae-THC have been</p><p>compared .</p><p>A significant hypothermic response has been shown to develop within two</p><p>minutes after intravenous administration of 2 mg/kg of A9 -THC, 11-OH-D 9 -THC or</p><p>11-OH-AB-THC .</p><p>Since these data do not show a lag in the onset of hypothermia</p><p>produced by D9-THC as compared to its major metabolite, 11-OH-A 9-THC, it ap-</p><p>pears likely that both G9 -THC and 11-OH-A 9-THC have activity per ae in this</p><p>system .</p><p>This possibility is supported by the fact that no significant differ-</p><p>ence has been found in the hypothermia produced by A9-THC and by 11-OH-D 9 -THC</p></li><li><p>Vol. 13, No. 12</p><p>Tetrahydrocannabi~l-Induced Hypothermia</p><p>1777</p><p>during the firet 5 minutes after injection .</p><p>A comparison of the dose-response relationship of these drugs (Table 1)</p><p>shows that 11-OH-A9-THC alone cannot account for the hypothermia seen follow-</p><p>ing D9 -THC .</p><p>The maximum hypothermic response which A9 -THC can produce at an</p><p>ambient temperature of 20C has not been measured in the experiments reported</p><p>here, and may not be attainable at doses below the LD50 (48 mg/kg) .</p><p>In con-</p><p>tract, the lack of a significant difference between the hypothermic response</p><p>to doses of 4, 16 and 32 mg/kg of 11-OH-09-THC or 11-OH-DB-THC indicates that</p><p>the maximum response to these agents has been attained . Since this maximum issignificantly leas than the highest value measured after A9-THC, the intrinsic</p><p>activity of 11-OH-A9 -THC is lower than that of the parent compound, D9-THC.</p><p>The intrinsic activity of 11-OH-AB-THC also is less than that of A9-THC, and</p><p>in addition, appears to be less than that of 11-OH-d9-THC.</p><p>The data show that although the three tetrahydrocannabinola tested cannot</p><p>be distinguished on the basis of onset of action, they differ significantly in</p><p>intrinsic activity. The conclusion appears justified that in this system</p><p>pharmacological activity resides in each of the tetrahydrocannabinols studied .</p><p>Ackaowled~nents</p><p>We thank Fred Colline, Canillia Laboy, Jeannine Moore and Timothy Siglock</p><p>for their valuable technical assistance .</p><p>References</p><p>1. L. S. Harris, Pharmaool. Rev. 23 285-294 (1971) .</p><p>2 . R. Mechoulam, Soienoe 168 1159-1166 (1970) .</p><p>3. M . E . Wall, Aras . A. Y. Aced. Sci. 19 1 23-37 (1971) .</p><p>4 . L. Lemberger, S . D. Silberstein, J. Axelrod, and I . J. Kopin, Soienae170 1320-1322 (1970) .</p><p>5 . H . D . Chriatensen, M. E . Wall, R. I . Freudenthal, J. T . Gidley, R.Rosenfeld, G. Bcegli, D. R. Brine, L . Testino, and C. G . Pitt, Soienoe172 165-167 (1971) .</p></li><li><p>1778</p><p>Tetrahydrocannabinol-Induced Hylothermia</p><p>Vol. 13, No. 12</p><p>6 . L . Lemberger, R . E . Crabtree, and H . M. Rowe, Science 177 62-63 (1972) .</p><p>7 . M . Perez-Reyes, M. C . Tiamions, M. A. Lipton, K. H . Davis, and M . E . Wall,Science 177 633-635 (1972) .</p><p>8 . C . 0 . Haavik and H . F . Hardman, The Pharmacology of Thermonegulatian, p.410-416, Karger, Basel (1973) .</p><p>9 . C . 0 . Haavik and H . F . Hardman, ~. PharmaooZ . Eacp . Ther . (in press) .</p><p>10 . E . W . Gill and G . Jones, Biochem . Pharmacol . 21 2237-2248 (1972) .</p></li></ul>

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