Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol 2013;260(1):285-95. View abstract.
Some medications changed by the liver include acetaminophen, chlorzoxazone (Parafon Forte), ethanol, theophylline, and anesthetics such as enflurane (Ethrane), halothane (Fluothane), isoflurane (Forane), methoxyflurane (Penthrane).
Niederle, N., Schutte, J., and Schmidt, C. G. Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin therapy. Klin.Wochenschr. 4-15-1986;64(8):362-365. View abstract.
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Carter, G. T. and Ugalde, V. Medical marijuana: emerging applications for the management of neurologic disorders. Phys.Med.Rehabil.Clin.N.Am. 2004;15(4):943-54, ix. View abstract.
Moore, T. M., Stuart, G. L., Meehan, J. C., Rhatigan, D. L., Hellmuth, J. C., and Keen, S. M. Drug abuse and aggression between intimate partners: a meta-analytic review. Clin.Psychol.Rev. 2008;28(2):247-274. View abstract.
Frytak, S., Moertel, C. G., O’Fallon, J. R., Rubin, J., Creagan, E. T., O’Connell, M. J., Schutt, A. J., and Schwartau, N. W. Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo. Ann.Intern.Med. 1979;91(6):825-830. View abstract.
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CB1 receptor levels in cerebellum were compared in mice that received 7-day treatment with either vehicle or 10 mg/kg THC and were then sacrificed 24 hours after the last injection ( Fig. 5 ). Mouse cerebellum has previously been shown to have a high density of CB1 receptors sites (Herkenham et al., 1991) that are sensitive to downregulation (McKinney et al., 2008). The Bmax for CB1 receptors in vehicle-mice was 170 ± 30 pmol/mg. The Bmax value in mice that received daily THC was 75 ± 9 pmol/mg, significantly lower than Bmax values obtained from vehicle treated mice [F(2,6) = 29.77, P < 0.01.].
In summary, the present results confirm and extend earlier observations of cannabinoid tolerance by demonstrating that a relatively low dose of 10 mg/kg daily THC is adequate to produce antinociceptive tolerance that endures for at least 14 days. Using the same dosing regimen, we further show that roughly equivalent tolerance is produced to the diuretic effects of cannabinoids. Moreover, despite the curvilinear nature of the diuresis dose-effect curves, rightward shifts were obtained in both the ascending and descending limbs of the functions, suggesting the cannabinoid tolerance is receptor-mediated and surmountable; however, daily exposure to THC also decreased the effects of a κ-opioid agonist, demonstrating that THC-induced tolerance extends beyond the cannabinoid system, specifically to the κ-opioid receptor system. The attenuation of U50,488-mediated diuresis was different in appearance, as the dose-response curve was shifted downward, not rightward, like the cannabinoid dose-response curves, and yet the duration of the tolerance was similar to that expressed by THC and AM4054. Cannabinoid CB1 receptors are frequently cited as being among the most abundant G-protein– coupled receptors, widely distributed within the central nervous system; thus, it is not unreasonable to anticipate that acutely administered cannabinoid agonists interact with ligands of other receptor systems (Herkenham et al., 1991; Gifford et al., 1999; Sim-Selley et al., 2006). Our findings suggest that, in addition to acute effects, repeated exposure to cannabinoid agonists also may profoundly alter the effects of drugs that produce their effects through other neurotransmitter systems.
Interactions between cannabinoids and κ-opioids have been explored previously, based on their common signaling transduction mechanisms or their often similar behavioral effects (Hampson et al., 2000; Walentiny et al., 2010; Maguire et al., 2014). For example, the κ-opioid antagonist nor-binaltorphimine will block the antinociceptive effects of THC, whereas coadministration of cannabinoid and κ-opioid agonists has additive antinociceptive effects (Smith et al., 1994; Maguire and France, 2016). Early reports of a bidirectional antinociceptive cross-tolerance between THC and κ-opioid agonists led to subsequent studies demonstrating the involvement of the endogenous κ-opioid dynorphin in the antinociceptive effects of THC (Smith et al., 1994; Pugh et al., 1996). Dynorphin and κ-opioid receptor activation also has been implicated in reducing the reinforcing effects of cannabinoid agonists in mice, although blockade or removal of κ-opioid receptors does not alter other “tetrad” effects of THC (Ghozland et al., 2002; Mendizábal et al., 2006). It is conceivable that dynorphin also mediates the diuretic effects of cannabinoids, although preliminary studies from our laboratory found no effects of pretreatment with the opioid antagonist naltrexone on THC or AM4054-induced diuresis.
Urine output (in ml/kg, mean ± S.E.M.) after saline or furosemide before and 24 hours after 7-day treatment with 10 mg/kg THC (n = 6/group)
ND, not determined.
Δ 9 -THC was obtained from the National Institute on Drug Abuse (Rockville, MD); U50,488 [trans-(+/−)3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide methane sulfate] and furosemide were purchased from Sigma-Aldrich (St. Louis, MO). AM4054 [9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol] was synthesized at the Center for Drug Discovery, Northeastern University. U50,488 was dissolved in saline. Furosemide was dissolved in 1% 1N NaOH and sterile water. THC and AM4054 were initially dissolved in ethanol, to which an equal volume of emulphor-620 (Rhodia, Cranbury, NJ) was added and then further diluted with saline to achieve a 1:1:18 mixture; this 1:1:18 solution, without drug, is referred to as vehicle. Drug doses are expressed in terms of the weight of free base, and injections were delivered s.c. in volumes of 1 ml/100g body weight. All drug injections were given between 8 and 10 AM.
Cannabinoid diuresis over 6 hours. (A) Effects of THC before (closed symbols) and 24 hours or 14 days after 7 days of THC administration. (B) Effects of AM4054 before (closed symbols) and 24 hours, 7 days, or 14 days after 7-day THC administration. Each point represents the mean of 6–10 mice (except n = 3 after 10 mg/kg AM4054), and vertical bars indicate ±S.E.M. The shaded area in between dotted lines marks the 99% CI for urine volume after saline injection. Ordinates: urine output over 6 hours in ml/kg of body weight. Abscissae: drug dose in mg/kg.
ED50 values (in mg/kg) and 95% confidence interval for diuretic and hypothermic effects in female rats (n = 6)
Rats that received no treatment or that were subcutaneously injected with 1.0 ml/kg saline or vehicle voided a mean of 0.9±0.2 g urine over 2 hours. Hydrating the rats with 10.0–30.0 ml/kg, p.o. water immediately before the session significantly increased diuresis, resulting in 4–9 g of voided urine or 12.5–27.5 g urine per kg body weight ( Fig. 1A ). In nonhydrated rats, both the loop diuretic furosemide and the κ-opioid agonist U50,488 produced dose-related increases in diuresis and, at the highest doses, resulted in urine volumes similar to those obtained in rats that had received 30.0 ml/kg water ( Fig. 1B ).
ED50 values with 95% confidence intervals (CI; in mg/kg) and potency ratios for AM4054-induced diuresis after 30 minutes pretreatment with rimonabant
After initial exposure to handling procedures, rats were placed in customized restraint devices made of polyvinyl chloride tubing. Individual absorbent pads, placed in each restraint device, were weighed before and after the experiment; the difference in pad weight was recorded as the weight (in grams) of voided urine. Unless otherwise noted, sessions lasted 2 hours.
Effects of AM4054; Δ 9 -THC; AM2389; WIN 55,212; and rimonabant on diuresis (top) and hypothermia (bottom) (n=6 per drug); points above V represent the effects of vehicle, averaged from all groups. Bottom ordinate represents peak hypothermic effects obtained within 6 hours after drug injections and are expressed as a change from baseline values (mean, 38.55°C; range, 37.60-39.01°C); other details as in Fig 2 .