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The co-administration of cannabinol with delta1-tetrahydrocannabinol accelerates the rate of clearance of delta1-tetrahydrocannabinol from rat blood. This increased rate of clearance appears to follow that of cannabinol. The implications of these findings are discussed.
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Rats were trained to respond according to a low rate differential reinforcement (DRL) 72 sec schedule of operant behaviour. The animals were then tested with delta 1-tetrahydrocannabinol (delta 1-THC), cannabinol, and cannabidiol alone and in combination. Tests with single doses of delta 1-THC (dose-range: 0.3-5.6 mg/kg) and cannabinol (dose-range: 1-56 mg/kg) but not cannabidiol (dose-range 3-100 mg/kg), yielded a dose-related biphasic effect on the response rate. Small doses of delta 1-THC and cannabinol increased the rate of responding, large doses of these agents decreased it. Cannabidiol alone only decreased the rate of responding (occurring at large doses). The rate of reinforcement generally was decreased when response rates increased and vice versa. Cannabidiol (10 and 30 kg/kg), together with delta 1-THC (1 and 3 mg/kg), decreased the response output and increased the rate of reinforcement. Similar results were observed with combinations of cannabinol (10 and 30 mg/kg) and cannabidiol (10 and 30 mg/kg). Combinations of delta 1-THC (0.3 and 1 mg/kg) and cannabinol (1 and 3 mg/kg) also reduced the response rate and there were no significant changes in the rate of reinforcement. Hence the actions of delta 1-THC and cannabinol on behaviour in rats maintained by low rate differential reinforcement were similar (approximate difference in potency 1:10), whereas no stimulation of response rate was demonstrated with cannabidiol. Vehicle and day of testing (Tuesday or Friday) variables were found not to affect the results.
Cannabinoids can paradoxically regulate interleukin-2 (IL-2) expression either positively or negatively. This study investigated the mechanism responsible for cannabinol-mediated IL-2 modulation. In primary murine splenocytes and EL4.IL-2 T cells, the contrasting effects of cannabinol on IL-2 secretion depended on the magnitude but not the mode of T-cell activation. Suboptimal activation of T cells in the presence of cannabinol produced an enhancement of IL-2 secretion, which was paralleled by an increase in nuclear phospho-extracellular-regulated kinase (ERK) 1/2. In contrast, T cells activated with stimuli that were optimized to induce maximal IL-2 secretion elicited a marked suppression in the production of this cytokine when cultured in the presence of cannabinol. Moreover, cannabinol-mediated enhancement of IL-2 secretion by splenocytes was attenuated to various degrees by staurosporine, Ro-31-8220, and KN93. These results suggest that the enhancement of IL-2 secretion by cannabinol is associated with an increase in ERK mitogen-activated protein kinase, which is protein kinase C and calmodulin-kinase dependent.
Cannabinol or cannabigerol was administered to cats topically in doses of 250, 500 and 1000 micrograms as a single drop or chronically via osmotic minipumps (20 micrograms hr-1) over a period of 9 days. While cannabinol had a modest effect on intraocular pressure after a single dose, it caused a more significant reduction in ocular tension during chronic administration. Cannabigerol had similar effects, but the magnitude of response to its chronic administration was greater. Cannabinol but not cannabigerol caused conjunctival erythema and hyperemia. After systemic administration of cannabinol (20, 40 or 80 mg kg-1) to rats, 8-13 Hz polyspike discharges appeared in the electrocorticogram during wakefulness and during rapid eye movement sleep episodes. Cannabigerol (10, 30 and 100 mg kg-1) lacked this effect. These results indicate that chronic administration of these cannabinoids lowers ocular tension considerably. Like marihuana and delta-9-tetrahydrocannabinol, cannabinol produced both ocular toxicity and neurotoxicity. As cannabigerol lacked these toxicities, it appears that the ocular hypotensive effect of this cannabinoid is somewhat dissociable from both the adverse central and ocular effects accompanying marihuana intake.
The present experiments examined the cannabimimetic potential of cannabinol on its own as well as its interaction with delta 9-tetrahydrocannabinol (delta 9-THC) in vivo. Thus, cannabinol, as evaluated by repeated test procedures using drug-discrimination methodology (Hiltunen and Järbe, 1986; Järbe, Swedberg and Mechoulam, 1981) was found to substitute for the stimulus effects induced by delta 9-THC in both rats (delta 9-THC cue = 3 mg/kg) and pigeons (delta 9-THC cue = 0.56 mg/kg), though, relatively larger doses were required in the latter species (ED50 for cannabinol being 8.4 mg/kg, and 14.1 mg/kg at the time of maximum effect in rats and pigeons, respectively). When administered together, cannabinol added to the cue effects of delta 9-THC as shown by an increase in the percentage of responding appropriate to the drug, the effect appearing more pronounced in rats than in pigeons; no apparent change in the duration of the effect was indicated by the results obtained. Unconditioned effects of drug, as defined by rectal temperature recordings and open-field activity (ambulation, rearing, latency, circling, grooming, defecation and urination), as well as assessment of vocalization in rats were in keeping with the suggestion that the pharmacological profile of cannabinol is similar, though not necessarily identical, to that of tetrahydrocannabinols, such as delta 9-THC.
We previously reported that immunosuppressive cannabinoids inhibited interleukin (IL)-2 steady-state mRNA expression and secretion by phorbol-12-myristate-13-acetate plus ionomycin-activated mouse splenocytes and EL4 murine T-cells. Here we show that inhibition of IL-2 production by cannabinol, a modest central nervous system-active cannabinoid, is mediated through the inhibition of IL-2 gene transcription. Moreover, electrophoretic mobility shift assays demonstrated that cannabinol markedly inhibited the DNA binding activity of nuclear factor of activated T-cells (NF-AT) and activator protein-1 (AP-1) in a time- and concentration-dependent manner in activated EL4 cells. The inhibitory effects produced by cannabinol on AP-1 DNA binding were quite transient, showing partial recovery by 240 min after cell activation and no effect on the activity of a reporter gene under the control of AP-1. Conversely, cannabinol-mediated inhibition of NF-AT was robust and sustained as demonstrated by an NF-AT-regulated reporter gene. Collectively, these results suggest that decreased IL-2 production by cannabinol in EL4 cells is due to the inhibition of transcriptional activation of the IL-2 gene and is mediated, at least in part, through a transient inhibition of AP-1 and a sustained inhibition of NF-AT.
The in vivo liver metabolism of cannabinol has been studied in the mouse and rat by combined gas chromatography and mass spectrometry. Cannabinol glucuronide was the major metabolite of cannabinol in the mouse and was accompanied by relatively large amounts of 7-hydroxycannabinol, cannabinol-7-oic acid and their corresponding glucuronide conjugates. Lower concentrations of glucuronides were found in the rat. Two series of disubstituted metabolites were found containing either a 7-hydroxyl or a 7-carboxylic acid group and a second hydroxyl group in the 1 inch-4 inch positions of the sidechain. These were of low concentration in the mouse but higher in the rat; 1 inch-hydroxy metabolites were particularly abundant in the latter species. Also found in the rat livers were small amounts of sidechain monohydroxy metabolites and larger quantities of 4 inches, 5 inches-bisnorcannabinol-3 inches-oic acid; these were absent in the mouse. The metabolites were identified using the trimethylsilyl (TMS), [2H9] TMS and methyl ester-TMS derivatives, and by reduction of acid metabolites with lithium aluminium deuteride to the corresponding alcohols.
Elfazepam (7-chloro-1-[2-(ethylsulfonyl)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4benzodiazepin-2-one) and-9-aza-cannabinol )10 hydroxy-beta-(3-methyl-2-octyl)-5',5-dimethyl-5H-1 benzopyranol 3,4-d pyridine, HC1) were administered IV to study their effects on feed intake and acid secretion in abomasal Pavlov pouches in sheep. Elfazepam and 9-aza-cannabinol increased 3-fold 3 hr postinjection feed intake and decreased abomasal acid secretion compared to saline and DMSO (dimethyl sulfoxide) control treatments. At doses which elicit feeding, 9-aza-cannabinol was a much more potent inhibitor of acid secretion than elfazepam. These results are consistent with the theory of localized hypothalamic nuclei which have roles in the control of both feed intake and gastric acid secretion. However, in contrast to feeding associated with normal hunger, the benzodiazepine and cannabinol stimulated feeding is associated with decreased gastric acid secretion.
Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as for activation of CB1- and CB2-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB1 and CB2 (Ki values of 38.0 +/- 7.2 and 26.6 +/- 5.5 nM, respectively) and to inhibit CB1-mediated adenylylcyclase with an EC50 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
The effects of the cannabinoids delta 9-tetrahydrocannabinol (THC), cannabinol and cannabidiol on the primary humoral immune response, the secondary humoral immune response and the memory aspect of humoral immunity in response to sheep red blood cell (SRBC) immunization was investigated. Mice treated with THC (10 and 15 mg/kg) during the primary immunization period exhibited a suppression of the primary humoral immune response. Mice treated with THC during the secondary immunization period showed no measurable suppression of the secondary humoral immune response to the immunizing antigen. The memory aspect of humoral immunity was assessed when treatment with cannabinoids was carried out during the primary immunization period and the ability of mice to undergo a secondary immune response was evaluated; suppression of the secondary humoral immune response was evident with THC treatment (10 and 15 mg/kg). Cannabinol and cannabidiol (10 and 25 mg/kg) treated mice showed no impairment in the ability to undergo primary or secondary immune responses with any treatment protocol. In vivo investigations of the effects of cannabinoids on the thymus were also carried out. Thymus weight and thymus cell number were depressed in mice undergoing a primary humoral immune response when treated with THC (10 and 15 mg/kg) during this period. THC treatment, however, did not alter these parameters in mice not challenged with antigen. In both challenged and unchallenged animals, cannabinol and cannabidiol did not measurably alter the thymus.
The ability of cannabinol and delta-8-tetrahydrocannabinol (delta-8-THC), two cannabinoid marihuana components, to modify delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) was investigated in mice. Reduction of DTH reactivity by cannabinol required multiple, daily, postimmunization drug administration. Neither multiple preimmunization dosings nor a single postimmunization dosing was effective. Delta-8-THC produced moderate (13-33%) suppression of DTH reactivity only upon multiple, preimmunization treatments, whereas postimmunization administration only delayed peak DTH reactivity 24 hours without altering the absolute response level. These results indicate that delta-8-THC and cannabinol possess slight to moderate activity in the suppression of DTH.
The butyl homologues of delta1-tetrahydrocannabinol, delta1-tetrahydrocannabinolic acid, cannabinol and cannabidiol have been identified in several samples of cannabis. 8 samples contained delta1-tetrahydrocannabinolic acid, one sample contained cannabinol and one sample contained both cannabinol and cannabidiol. Separation by gas chromatography and identification by gas chromotography-mass spectrometry was achieved by the preparation of trimethylsilyl, d9-trimethylsilyl, triethylsilyl and tri-n-propylsilyl derivatives.
Stable cyclic methyl- and n-butylboronates were prepared from the cannabinolic acids and used as derivatives for the characterization of these compounds by combined gas chromatography mass spectrometry. Retention times of the methylboronates were comparable with those of the trimethylsilyl derivatives. The mass spectra of these derivatives were more characteristic of the cannabinoid skeleton than were the spectra of the trimethylsilyl derivatives where fragmentation was associated with the trimethylsilyl groups. Molecular weights were lower and abundant molecular ions were obtained. These derivatives also offered the possibility of distinguishing between isomeric cannabinolic acids where only isomers possessing adjacent phenolic and carboxylic functions form cyclic boronates.
A marijuana compound, cannabinol [1], was converted to two metabolites using in vitro tissue of Pinellia ternata. The structures of the metabolites were determined to be cannabinol-O-beta-D-glucopyranoside [2] and 9'-hydroxycannabinol-O-beta-D-glucopyranoside [3] by 1H nmr and 13C nmr. From the time course experiments, 1 was absorbed rapidly in the tissues and glycosylated. Hydroxylation at the pentyl group occurred, and its metabolite was secreted in the medium.
Six acidic metabolites were isolated from rat faeces and identified by gas chromatographymass spectrometry and proton magnetic resonance. Cannabinol-7-oic acid was the most abundant acidic metabolite isolated. Others present in decreasing order of prominence were 1"-hydroxy-, 4"-hydroxy-, 3"-hydroxycannabinol-7-oic acid, cannabinol-3"-one-7-oic acid and 2"-hydroxycannabinol-7-oic acid.
Although Delta(9)-tetrahydrocannabinol (THC) produces analgesia, its effects on nociceptive primary afferents are unknown. These neurons participate not only in pain signaling but also in the local response to tissue injury. Here, we show that THC and cannabinol induce a CB(1)/CB(2) cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves. Other psychotropic cannabinoids cannot mimic this action. The vanilloid receptor antagonist ruthenium red abolishes the responses to THC and cannabinol. However, the effect of THC on sensory nerves is intact in vanilloid receptor subtype 1 gene knock-out mice. The THC response depends on extracellular calcium but does not involve known voltage-operated calcium channels, glutamate receptors, or protein kinases A and C. These results may indicate the presence of a novel cannabinoid receptor/ion channel in the pain pathway.