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PubMed2004

CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat.

RATIONALE: Addictive drugs have a number of commonalities in animal behavioral models. They lower intracranial self-stimulation (ICSS) thresholds, support self-administration, and produce conditioned place preference (CPP). However, cannabinoids appear atypical as drugs of abuse, since there are controversial data in the literature concerning their reinforcing properties. OBJECTIVES: The aim of the present study was to examine the effects of cannabinoids on brain reward using the rate-frequency curve shift paradigm of ICSS. METHODS: Male Sprague-Dawley rats were implanted with electrodes into the medial forebrain bundle (MFB). Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain stimulation reward thresholds stabilized rats received intraperitoneal (IP) injections of the potent CB1 receptor agonists WIN 55,212-2 (graded doses 0.1, 0.3, 1 and 3 mg/kg), CP 55,940 (graded doses 10, 30, 56 and 100 microg/kg), or HU-210 (graded doses 10, 30, 100 microg/kg). RESULTS: With the exception of the highest dose of all cannabinoid agonists tested, which significantly increased the threshold frequency required for MFB ICSS, all other doses of the tested drugs did not affect ICSS thresholds. The CB1 receptor antagonist SR141716A reversed the actions of WIN 55,212-2 and CP 55,940, but not HU-210. However, the selective CB1 cannabinoid receptor antagonist AM 251 counteracted the effect of HU-210. Both CB1 receptor antagonists, at the doses used in the present study, did not affect reward thresholds by themselves. CONCLUSIONS: The present results indicate that cannabinoid agonists do not exhibit reinforcing properties in the ICSS paradigm, but rather have an inhibitory influence on reward mechanisms. The results suggest that the anhedonic effects of cannabinoids are probably mediated by cannabinoid CB1 receptors.

Animals↗
PubMed2006

The agonists for nociceptors are ubiquitous, but the modulators are specific: P2X receptors in the sensory neurons are modulated by cannabinoids.

P2X2 and P2X3 receptors expressed in mammalian sensory neurons participate in nociception. Cannabinoid receptors modulate nociceptive processing in various models of pain. They are also expressed in nociceptive sensory neurons. We have examined the effect of cannabinoids on the slow P2X2 and P2X2/3 receptors in the cells isolated from nodosal and dorsal root ganglia of rat. The study was carried out by means of the whole-cell patch clamp and rapid superfusion methods. We have found that both endogenous and synthetic cannabinoids (anandamide, WIN55,212-2, and (R)-(+)-methanandamide) inhibit the slow response to ATP mediated by P2X2 and P2X2/3 receptors in a majority of tested neurons. This inhibition was significant but only partial: anandamide (0.5-1 microM) inhibited the response to 51+/-21% of control. In the remaining minority of tested neurons, the response was transiently facilitated. The effect of cannabinoids appears to be mediated via cannabinoid CB(1) receptors: it was reversibly inhibited by selective CB(1) antagonist, SR141716A (10 microM). Introduction of cyclic AMP (0.5 mM) into the cell potently facilitated the inhibitory effect of cannabinoids: the ATP-activated current was inhibited to 13+/-10% of control. These data indicate that cannabinoids may inhibit nociceptive responses produced by P2X receptors.

Adenosine Triphosphate↗
PubMed2003

[Therapeutic use of cannabinoids in neurology].

This review gives insight into the potential therapeutical role of cannabinoids in neurology. Preclinical data are presented which could give a rationale for the clinical use of cannabinoids in the fields of multiple sclerosis, spasticity, epilepsy, movement disorders, and neuroprotection after traumatic head injury or ischemic stroke. Besides, clinical data (case reports, open-label and randomised controlled studies) dealing with the therapeutical use of cannabinoids in these fields are reported and discussed. At present, clinical data are insufficient to recommend the use of cannabinoids in any neurological disease as standard therapy. Several questions still have to be answered (which cannabinoid? which way of administration? stimulation of endogenous cannabinoids? separation between desired and undesired effects?), and controlled studies are still needed to clarify the potential therapeutical role of cannabinoids in neurology.

Analgesics↗
PubMed1996

Studies on the thermotropic effects of cannabinoids on phosphatidylcholine bilayers using differential scanning calorimetry and small angle X-ray diffraction.

We have studied the thermotropic properties of a wide variety of cannabinoids in DPPC bilayers. The molecules under study were divided into four classes: (a) classical cannabinoids possessing a phenolic hydroxyl group; (b) delta9-THC metabolites with an additional hydroxyl group on the C ring; (c) non-classical cannabinoids, and (d) cannabinoids with a protected phenolic hydroxyl group. The results showed that the first three groups have similar effects on the thermotropic properties of DPPC bilayers up to x = 0.05 (molar ratio) and that these effects do not parallel their biological activity. For concentrations less than x = 0.01, cannabinoids affect mainly the pretransition temperature in a progressive manner until its final abolishment. At x = 0.05, they further affect the main phase transition by lowering its phase transition temperature and broadening its half width. At high concentrations the thermograms have multiple components, indicating that membranes are no longer homogeneous but rather consist of different domains. At these concentrations cannabinoids with more hydroxyl groups give simpler thermograms. Low concentrations of cannabinoids in group d affect significantly the pretransition temperature, while high concentrations affect only marginally the main phase transition by slightly lowering its temperature and broadening its half width. These results point out the importance of the phenolic hydroxyl group in inducing membrane perturbations. The d-spacing data from our small angle X-ray diffraction experiments show that delta8-THC produces significant structural changes in the lipid bilayer, including the gel-phase tilting angle, the intermolecular cooperativity and the gauche:trans conformer ratio. Conversely, the inactive analog Me-delta8-THC does not cause drastic changes to the bilayer structure.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Expression of a cannabinoid receptor in baculovirus-infected insect cells.

A cannabinoid receptor recombinant baculovirus (AcNPV-THCR) has been constructed and employed to express rat neural cannabinoid receptors. Northern analysis of total RNA from Spodoptera frugiperda (Sf9) insect cells infected with AcNPV-THCR revealed novel hyper-production of a 3.3 kb transcript when probed with nick-translated rat cannabinoid receptor cDNA. Optimal viral protein expression was observed in 35S-metabolically labeled AcNPV-THCR-infected Sf9 cells at a multiplicity of infection of 2.5. Transmission electron microscopy of AcNPV-THCR-infected Sf9 cells showed extensive membrane perturbation and electron-dense cytoplasmic perinuclear accumulation, indicative of receptor glycoprotein expression. Immunofluorescence staining using antiserum produced to a fusion protein consisting of the external domain of the cannabinoid receptor and hepatitis B core antigen revealed cannabinoid receptor expression in AcNPV-THCR-infected Sf9 cells. Scatchard-Rosenthal analysis of [3H]CP55,940 receptor binding indicated a Kd of 3.4 nM and a Bmax equal to 3.17 pmol/mg protein. Western immunoblotting performed on AcNPV-THCR-infected Sf9 cell lysates revealed immunoreactive bands with relative molecular weights ranging from 45 to 79 kDa. The predominant species (55 kDa) exhibited a relative molecular weight consistent with that predicted for the translational product obtained from the cannabinoid receptor cDNA coding sequence. In vitro translation using AcNPV-THCR mRNA also yielded a 55 kDa immunoreactive species. These data indicate that the baculovirus expression system is a viable means of expressing relatively large quantities of cannabinoid receptor recombinant protein.

Animals↗
PubMed1996

Local pressure application of cannabinoid agonists increases spontaneous activity of rat substantia nigra pars reticulata neurons without affecting response to iontophoretically-applied GABA.

This study tested the hypothesis that cannabinoid agonists, applied locally into the pars reticulata of substantia nigra (SNpr), could modulate striatonigral transmission, without affecting the response of SNpr neurons to iontophoretically-applied GABA. Multibarreled glass capillary electrode assemblies were used for extracellular recording of the spontaneous electrical activity of single SNpr cells in anesthetized rats. Local pressure ejection of the cannabinoid agonists Win 55212-2 (WIN2) and CP 55940 increased SNpr spontaneous firing rate by 13-46%, similar to the effects of systemic injections. Neither WIN2 nor CP 55940 had an effect on the slowing of SNpr neuron activity in response to iontophoretic GABA. Local pressure application of Win 55212-3 (the much less active enantiomer of WIN2) produced an insignificant decrease in SNpr firing rate. Similarly, locally applied vehicle (45% 2-hydroxypropyl-beta-cyclodextrin) produced insignificant decreases in SNpr firing. A second application of cannabinoid agonist produced a much smaller effect, suggesting desensitization. Increasing the interval between CP 55940 applications to 45 min showed recovery of sensitivity to the agonist. Local application of the cannabinoid antagonist, SR 141716A, significantly decreased spontaneous cell firing by 34%. CP 55940, when given immediately following or concurrently with the antagonist application failed to produce the expected increase in discharge rate over baseline. A second application of CP 55940 45 min later produced a 26% increase in firing rate. Bicuculline methiodide (BMI) was applied locally causing a significant increase in SNpr cell firing. CP 55940, when locally administered concurrently with bicuculline methiodide, had no further effect on the firing rate of the cell. Based on the reported presynaptic localization of cannabinoid receptors in SNpr, these findings suggest that cannabinoids act within the SNpr to modulate striatonigral neurotransmission presynaptically. The effect of SR 141716A suggests that an endogenous cannabinoid may mediate striato-nigral transmission.

Action Potentials↗
PubMed1994

Blockade of cannabinoid-induced antinociception by naloxone benzoylhydrazone (NalBZH).

We have recently shown that the antinociceptive effects, but not other behavioral effects of the intrathecally administered, but not intracerebroventricularly administered, cannabinoids, are blocked by the kappa antagonist, nor-binaltorphimine. We employed naloxone benzoylhydrazone, a kappa3 agonist, and kappa1, mu, and delta antagonist, to better characterize the interaction of cannabinoids with kappa receptors. Naloxone benzoylhydrazone blocked the antinociceptive effects of both intrathecally and intracerebroventricularly administered cannabinoids. Because the cannabinoids are not blocked by mu and delta antagonists, the effects of naloxone benzoylhydrazone are presumed to occur through interaction with kappa receptors. Because the data indicate that naloxone benzoylhydrazone does not block kappa3 receptors, the data indicate that the cannabinoids may interact with kappa1 receptors in the production of antinociception. However, differences in the profile of activity of naloxone benzoylhydrazone and the cannabinoids at kappa receptors exist. Thus, the exact nature of the interaction of the cannabinoids and the kappa receptors to be elucidated.

Analgesics↗
PubMed1993

Developmental expression of cannabinoid receptor mRNA.

Cloning of the cannabinoid receptor affords the opportunity to examine its developmental expression. Other G-protein-coupled receptor systems, those for the opioids for example, exhibit distinct ontogenies. For the initial study, therefore, cannabinoid receptor mRNA expression was assessed in rat pups postnatal days 3, 5, 8, 10, 12, 15, 18 and 21. The brains were grossly dissected into cerebellum/brainstem and forebrain, and total RNA was extracted by a modified acid-extraction method. Expression of the cannabinoid receptor was analyzed by two methods: polymerase chain reaction (PCR) and Northern blot analysis. Oligonucleotide primers based on bp 1-21 and bp 824-843 on the opposite strand were chosen for use in the PCR. The probe used in the Northern blot analysis was a full length cDNA corresponding to the rat cannabinoid receptor and was cloned in our lab based on published sequence information. Our results indicate that by postnatal day 3, cannabinoid receptor mRNA can be detected in the brain. Our results further indicate that cannabinoid mRNA expression steadily increases in the cerebellum/brainstem until postnatal days 18-21, while expression in the forebrain does not change. The findings from the present study indicate that cannabinoid receptor mRNA is present in very young rats. Our data also suggest, however, regional differences in the relative expression of message which may parallel cerebellar proliferation and organization.

Animals↗
PubMed1993

Cannabinoids inhibit agonist-stimulated formation of inositol phosphates in rat hippocampal cultures.

The effect of cannabinoids on phosphoinositide metabolism stimulated by activation of muscarinic receptors, alpha 1-adrenoceptors or glutamate receptors was examined in rat hippocampal cultures. Carbachol stimulated phosphoinositide turnover by 5.5-fold over basal level, whereas glutamate and norepinephrine stimulated phosphoinositide turnover by 2-fold. Addition of cannabinoids, such as delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol or the psychoinactive cannabidiol inhibited formation of inositol phosphates evoked by carbachol, glutamate or norepinephrine by 55-90%. The cannabinoids alone only slightly inhibited the basal unstimulated formation of inositol phosphates. The inhibitory effect of the cannabinoids was dose-dependent and was achieved within the range of pharmacologically relevant concentrations. IC50 values for delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol and cannabidiol were 9.6 +/- 1.0, 9.7 +/- 0.3 and 7.9 +/- 0.4 microM, respectively. Pretreatment with pertussis toxin (100 ng/ml, 18 h) did not affect the carbachol-induced stimulation of phosphoinositide turnover or its inhibition by the cannabinoids. This suggests that the inhibition by the cannabinoids of the stimulated formation of inositol phosphates is not mediated through a pertussis toxin-sensitive GTP-binding protein nor through the known effect of the cannabinoids on adenylate cyclase inhibition.

Adenylate Cyclase Toxin↗
PubMed2006

The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells.

Cannabis is the most widely used illicit drug in the world. Cannabinoids are used therapeutically by some patients as they have analgesic, anti-emetic and appetite stimulant properties which palliate adverse symptoms. Use of these agents in an oncology setting raises the question of whether they act to modulate the effectiveness of concurrently administered anti-cancer drugs. The transporter, P-glycoprotein (P-gp) confers multiple drug resistance (MDR) by effluxing a diverse array of anti-cancer agents. This study was undertaken to examine the effect of cannabinoids on P-gp. Unlike the known P-gp inhibitor, PSC833, short 1h exposure to three plant-derived cannabinoids, cannabinol (CBN), cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid receptor agonist, WIN55, 212-2 (WIN) did not inhibit the efflux of the P-gp substrate Rhodamine 123 (Rh123) in either a drug-selected human T lymphoblastoid leukaemia cell line (CEM/VLB(100)) or in a mouse fibroblast MDR1 transfected cell line (77.1). However, in CEM/VLB(100) cells, prolonged 72 h exposure to the cannabinoids, THC and CBD, decreased P-gp expression to a similar extent as the flavonoid, curcumin (turmeric). This correlated with an increase in intracellular accumulation of Rh123 and enhanced sensitivity of the cells to the cytotoxic actions of the P-gp substrate, vinblastine. Taken together, these results provide preliminary evidence that cannabinoids do not exacerbate P-gp mediated MDR. Further, plant-derived cannabinoids are moderately effective in reversing MDR in CEM/VLB(100) cells by decreasing P-gp expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2.

Cannabinoid CB1 receptors are the most abundant G-protein-coupled receptors in the brain. Its presynaptic location suggests a role for cannabinoids in modulating the release of neurotransmitters from axon terminals by retrograde signaling. The neuroprotective effects of cannabinoid agonists in animal models of ischemia, seizures, hypoxia, Multiple Sclerosis, Huntington and Parkinson disease have been demonstrated in several reports. The proposed mechanism for the neuroprotection ranges from antioxidant effects, reduction of microglial activation and anti-inflammatory reaction to receptor-mediated reduction of glutamate release. In the present work, we analyzed the morphological changes induced by a chronic treatment with the synthetic cannabinoid receptor agonist, WIN 55,212-2, in four brain regions where the CB1 cannabinoid receptor is present in high density: the CA1 hippocampal area, corpus striatum, cerebellum and frontal cortex. After a twice-daily treatment for 14 days with the cannabinoid receptor agonist (3 mg/kg sc, each dose) to male Wistar rats (150-170 g), the expression of neurofilaments (Nf-160 and Nf-200), microtubule-associated protein-2 (MAP-2), synaptophysin (Syn) and glial fibrillary acidic protein (GFAP) was studied by immunohistochemistry and digital image analysis. Ultrastructural study of the synapses was done using electron microscopy. After the treatment, a significant increase in the expression of neuronal cytoskeletal proteins (Nf-160, Nf-200, MAP-2) was observed, but we did not find changes in the expression of GFAP, the main astroglial cytoskeletal protein. In cerebellum, there was an increase in Syn expression and in the number of synaptic vesicles, while, in the hippocampus, an increase in the Syn expression and in the thickness of the postsynaptic densities was observed. The results obtained from these studies provide evidences on the absence of astroglial reaction and a sprouting phenomena induced by the WIN treatment that might be a key contributor to the long-term neuroprotective effects observed after cannabinoid treatments in different models of central nervous system (CNS) injury reported in the literature.

Animals↗
PubMed2003

Prenatal cannabinoid and gene expression for neural adhesion molecule L1 in the fetal rat brain.

The consumption by women of cannabis derivatives during pregnancy and/or lactation affects the development of their offspring because like other psychoactive drugs, cannabinoids, the psychoactive ingredients of marijuana, can cross the placental barrier and be secreted into the maternal milk. Through this way, cannabinoids are able to affect the expression of key genes for neural developmental leading to neurotransmitter and behavioral disturbances. In this present study, we wanted to explore the influence of prenatal cannabinoid exposure on the gene expression of a key protein for brain development, the neural adhesion molecule L1, which plays an important role in processes of cell proliferation and migration, neuritic elongation and guidance, and synaptogenesis. To this end, pregnant rats were daily treated with delta9-tetrahydrocannabinol (delta9-THC) since the 5th day of gestation up to the day before birth (GD21), day at which rats were killed and their pups removed for analysis of L1-mRNA levels in different brain structures. Our results confirmed that the levels of L1 transcripts were significantly increased after prenatal delta9-THC exposure in several regions such as the fimbria, stria terminalis, stria medullaris and corpus callosum, which share the properties of being white matter regions and containing, exclusively during development, an abundant population of cannabinoid CB1 receptors, the major targets for the action of plant-derived cannabinoids. L1-mRNA levels were also increased in grey matter structures such as the septum nuclei and the habenula, but remained unchanged in most of the grey matter structures analyzed (cerebral cortex, basolateral amygdaloid nucleus, hippocampus, thalamic and hypothalamic nuclei, basal ganglia and subventricular zones) and also in a few white matter structures (fornix and fasciculus retroflexus). An important aspect of these observations is that the increase in L1-mRNA levels reached statistical significance only in the case of delta9-THC-exposed males but not in the case of delta9-THC-exposed females where only trends or no effects were detected, this supporting previous evidence on a sexual dimorphism, with greater effects in male fetuses, for the action of cannabinoids in the developing brain. In summary, cannabinoids seem to influence the expression of L1 in specific brain structures during the prenatal period, which, considering the role played by this protein in different events related to neural development, might explain the neurotransmitter and behavioral disturbances reported after prenatal consumption of marijuana.

Animals↗
PubMed2005

Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat.

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.

Analysis of Variance↗
PubMed2005

Sex differences in behavioral effects of cannabinoids.

This review summarizes the existing literature on sex differences in the effects of cannabinoid drugs on behavior, primarily in the adult rodent. These preclinical studies, taken together with preliminary reports of sex differences in cannabinoid effects in humans, suggest that sex of subject may be an important modulating factor in a variety of cannabinoid effects. When sex differences are found, females are usually more sensitive than males to cannabinoids. Both pharmacokinetic and pharmacodynamic variables may contribute to sex differences in behavioral effects of cannabinoids. Given the significant therapeutic potential of cannabinoid agonists and antagonists--as well as their widespread recreational use--it will be important to determine the reliability and functional significance of, as well as mechanisms underlying sex differences in cannabinoid effects.

Animals↗
PubMed2006

WIN 55212-2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors.

The memory deficits induced by cannabinoid agonists have been found in several behavioral paradigms. Nevertheless, there is evidence that not all types of memory are impaired after cannabinoid administration. The aim of this study was to investigate whether the cannabinoid agonist WIN 55212-2 (WIN) is able to influence the acquisition of fear conditioning using tone and contextual versions. For tone-fear conditioning, male Wistar rats were placed in the conditioning chamber and after 3 min, a sound (CS) was presented for 10s that terminated with a 1-s electric footshock (1.5 mA). For contextual-fear conditioning, a similar procedure was used but no sound was presented. Twenty-four hours after, the animals were re-exposed to the respective CS (tone or conditioning chamber) and the freezing behavior was registered. A subsequent experiment investigated a possible state-dependent effect of WIN by administering WIN or control solution 30 min before conditioning and before testing. WIN (2.5 and 5.0 mg/kg) administered i.p. 30 min before impaired contextual fear conditioning but did not modify the freezing behavior elicited by tone presentation. These animals did not show any state-dependent effects of WIN. Further, the impaired contextual conditioning was prevented by preadministration of SR141716A (1.0 mg/kg, i.p.) or SR147778 (1.0 mg/kg, i.p.), selective cannabinoid CB1 receptor antagonists. The present findings highlight that cannabinoid agonists effects are selective for the hippocampus-dependent aversive memories in rats. This effect appears to be related to the activation of CB1 cannabinoid receptors and confirms that cannabinoids might provide a novel approach for the treatment of unpleasant memories.

Analgesics↗
PubMed2005

Self-administration of cannabinoids by experimental animals and human marijuana smokers.

Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drug-naïve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans.

Animals↗
PubMed1997

Failure of cannabinoid compounds to stimulate estrogen receptors.

delta 9-Tetrahydrocannabinol (THC), the primary active compound in Cannabis sativa (marihuana), and other cannabinoid receptor agonists exert potent effects on luteinizing hormone and prolactin release in animal models and humans. Compounds possessing the tricyclic cannabinoid structure, including delta 9-THC and cannabidiol, have been reported to interact with rodent uterine estrogen receptors in ligand binding assays. The present study tested the hypothesis that cannabinoid compounds produce a direct activation of estrogen receptors. We investigated whether cannabinoid compounds exhibit estrogen-induced mitogenesis in MCF-7 breast cancer cells. Under conditions in which 10 pM estradiol promoted MCF-7 cell proliferation, no response was observed with biologically relevant concentrations (< = 10 microM) of delta 9-THC or its tricyclic analog desacetyllevonantradol. No response was observed with cannabidiol, a bicyclic cannabinoid compound that exhibits no cannabimimetic behavioral effects but has been reported to bind to the estrogen receptor in vitro. delta 9-THC also failed to antagonize the response to estradiol under conditions in which the antiestrogen LY156758 (keoxifene; raloxifene) was effective. The phytoestrogen formononetin behaved as an estrogen at high concentrations, and this response was antagonized by LY156758. We also investigated the ability of cannabinoid compounds to stimulate transcription of an EREtkCAT reporter gene transiently transfected into MCF-7 cells. Neither delta 9-THC, desacetyllevonantradol, nor cannabidiol stimulated transcriptional activity. We conclude that psychoactive or inactive compounds of the cannabinoid structural class fail to behave as agonists in appropriate assays of estrogen receptor responses in vitro.

Breast Neoplasms↗
PubMed2000

Pharmacological evaluation of aerosolized cannabinoids in mice.

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.

Administration, Inhalation↗