SEARCH · PubMed Health

Results for “Cannabinoids”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources

PubMed1991

Modeling the cannabinoid receptor: a three-dimensional quantitative structure-activity analysis.

The structure-activity relationship studies that have been reported for cannabinoids suggest that 1) the conformation of the C-ring at the C9 position, 2) the A-ring phenolic hydroxyl, and 3) the hydrophobic side chain are important determinants for the production of analgesia, as well as other cannabinoid effects. However, either these previous structure-activity studies described for cannabinoid compounds have not been quantitative in nature or the prediction of the activity of known and unknown compounds based on molecular structure has not been tested in a comprehensive manner. In this study we describe a three-dimensional molecular modeling program using comparative molecular field analysis to derive quantitative structure-activity relationships fitting pharmacological potencies and binding affinities of cannabinoids. The analysis has proven to accurately fit the pharmacological activity of cannabinoid analogs, with cross-validated r2 values of greater than 0.3 and final analysis r2 values of greater than 0.88. Additionally, this study has further characterized the steric and electrostatic properties that account for the variations in their potency. The results from this study indicate that steric repulsion behind the C-ring is associated with decreased predicted binding affinity and pharmacological potency. On the other hand, the steric bulk of a side chain that is extended up to seven carbons contributes to predictions of increased binding affinity and potency. The electrostatic fields of cannabinoid analogs also contribute to the predicted in vitro and in vivo potencies. If the biological activities we have investigated are assumed to be the result of interaction with a single binding site, this method indicates the structural and physicochemical properties necessary for binding to the receptor and producing an effect. By defining cannabinoid binding affinity and behavioral activity pharmacophores, this method can be used for designing cannabinoid agonists and it is capable of predicting the activity of unknowns, thereby serving to facilitate rational drug design.

Animals↗

PubMed1995

Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process.

Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (IA) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on IA. The specific issue of whether cannabinoid receptor modulation of voltage-dependent IA acts via a cAMP-dependent process was investigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cyclase stimulant forskolin, produced concentration-dependent shifts in IA that were opposite those produced by cannabinoid receptor ligands. Moreover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also produced a marked negative shift in the steady-state voltage dependence of IA and increased the effect of forskolin on IA. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased IA via a decrease in steady-state voltage-dependent inactivation of IA. WIN 55,212-2 also reversed the effects of forskolin on IA. The electrophysiological studies were paralleled by direct assays of cAMP in these cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that pertussis toxin-sensitive cannabinoid receptor-mediated changes in IA were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of IA conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.

1-Methyl-3-isobutylxanthine↗

PubMed2006

Cannabinoid receptor agonists inhibit Ca(2+) influx to synaptosomes from rat brain.

We examined the effects of cannabinoid receptor agonists on (45)Ca(2+) uptake in rat brain synaptosomes. A cannabinoid receptor agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited (45)Ca(2+) uptake in rat synaptosomes. Only an endogenous cannabinoid receptor agonist, anandamide, dose-dependently inhibited (45)Ca(2+) uptake in rat synaptosomes, but not an endogenous cannabinoid receptor agonist, palmitoylethanolamide. Only a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A), reversed the inhibitory effect of these WIN 55212-2 and anandamide on (45)Ca(2+) uptake in rat synaptosomes, but not a cannabinoid CB2 receptor antagonist, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] (SR 144528). The inhibitory effects of WIN 55212-2 and anandamide on (45)Ca(2+) uptake in rat synaptosomes were reversed by the pretreatment of a voltage-sensitive A-type K(+) channel blocker, dendrotoxin, but no other type of K(+) channel blockers, i.e. iberiotoxin, charybdotoxin or glibenclamide. These findings suggest that cannabinoid receptors inhibit Ca(2+) influx into rat brain nerves via the activation of CB1 receptors and the opening of voltage-sensitive A-type K(+) channels.

Amides↗

PubMed2006

Methods evaluating cannabinoid and endocannabinoid effects on gastrointestinal functions.

This chapter briefly describes the physiological neural mechanisms by which diverse neurotransmitter receptor systems control several aspects of gastrointestinal functions such as motility, secretion, feeding, and emesis. The current techniques used to study the effects of cannabinoids on these gastrointestinal functions are then sequentially described, starting with isolated gastrointestinal muscle preparations and ultimately evolving to whole animal models. Both delta9-tetrahydrocannibinol (delta9-THC) and well-studied representatives of other classes of exogenous cannabinoid CB1/CB2 receptor agonists inhibit gastrointestinal motility, peristalsis, defecation, and secretions via cannabinoid CB1 receptors since the CB1 (SR141716A)- and not the CB2 (SR144528)-receptor antagonist reverses these effects in a dose-dependent manner. In addition, exogenous cannabinoids inhibit vomiting produced by diverse emetic stimuli in a SR141716A-sensitive manner in different animal models of emesis. Often these cannabinoids produce hyperphagic effects under laboratory conditions in most human and animal models of feeding. Administration of SR141716A by itself can produce effects opposite to cannabinoid agonists (e.g., increases in gastrointestinal motility and secretions, hyperphagia and vomiting), which suggests an important role for endocannabinoids in these gastrointestinal functions. Indeed, the presence of cannabinoid CB1 receptor markers, endocannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG), their metabolic enzymes, and an endocannabinoid reuptake system have been confirmed in the gastrointestinal tract (GIT). The well-studied endocannabinoid anandamide also seems to reduce both gastrointestinal motility and secretion while producing hyperphagia. On the other hand, while the less well-investigated endocannabinoid 2-AG is a potent emetogen, anandamide may possess weak antiemetic activity.

Animals↗

PubMed2006

Miniature synaptic events elicited by presynaptic Ca2+ rise are selectively suppressed by cannabinoid receptor activation in cerebellar Purkinje cells.

Activation of cannabinoid receptors suppresses neurotransmitter release in various brain regions. In cerebellar Purkinje cells (PCs), cannabinoid agonists suppress both EPSC and IPSC evoked by stimulating the corresponding inputs. However, cannabinoid agonists suppress miniature IPSC (mIPSC) but not miniature EPSC (mEPSC) at normal external Ca2+ concentration ([Ca2+]o). Therefore, cannabinoid agonists are thought to suppress release machinery for IPSCs but not that for EPSCs. Here we investigated the possible cause of this difference and found that cannabinoid agonists selectively suppressed Ca2+-enhanced miniature events. A cannabinoid agonist, WIN55,212-2 (5 microM), did not affect mEPSC frequency with 2 mM extracellular Ca2+ (Ca2+(o)). However, WIN55,212-2 became effective when mEPSC frequency was enhanced by elevation of presynaptic Ca2+ level by perfusion with 5 mM Ca2+(o) or bath application of A23187, a Ca2+ ionophore. In contrast, WIN55,212-2 suppressed mIPSC frequency with 2 mM Ca2+(o), but it became ineffective when the presynaptic Ca2+ level was lowered by perfusion with a Ca2+-free solution containing BAPTA-AM. Experiments with systematic [Ca2+]o changes revealed that mIPSC but not mEPSC regularly involved events elicited by presynaptic Ca2+ rise with 2 mM Ca2+(o). Importantly, Ca2+-enhancement of mEPSC and mIPSC was not attributable to activation of voltage-dependent Ca2+ channels. Activation of GABAB receptor or group III metabotropic glutamate receptor, which couple to G(i/o)-protein, also preferentially suppressed Ca2+-enhanced miniature events in PCs. These results suggest that the occurrence of Ca2+-enhanced miniature events at normal [Ca2+]o determines the sensitivity to the presynaptic depression mediated by cannabinoid receptors and other G(i/o)-coupled receptors in PCs.

Animals↗

PubMed2003

Cannabinoids and memory: animal studies.

This review will consider studies concerning the effects of cannabinoid receptor agonists and antagonists on memory in laboratory animals. Two subtypes of cannabinoid receptors have been identified to date: the central CB1 subtype and the peripheral CB2 subtype. The receptor which specifically binds Delta9-tetrahydrocannabinol (Delta9-THC) and related compounds in rat and human brain has been discovered and cloned by a number of researchers. This cannabinoid receptor is localized with high concentrations in different brain areas, including hippocampus and amygdala, which play an important role in the modulation of memory. In recent years evidence has been obtained that cannabinoids influence memory processes. It has been shown, for example, that Delta9-THC impairs memory in rats, mice and monkeys tested in a variety of experimental conditions (radial maze, instrumental discrimination tasks, Morris water maze, etc.). In some of these researches the effect of Delta9-THC was antagonized by the CB1 receptor antagonist SR 141716A, showing the involvement of this subtype of cannabinoid receptor in its effect. Anandamide, arachidonylethanolamide, was recently discovered as the first endogenous ligand for the cannabinoid receptor. It has been reported to stimulate CB1 receptors and to mimic the pharmacological effects of cannabinoids. Experiments carried out by our group have shown that anandamide impairs memory consolidation in random bred mice (CD1), exerts genotype-dependent influences on memory in inbred strain of mice (C57 BL/6 and DBA/2), and that opioid and dopaminergic systems might be involved in its effects.

Animals↗

PubMed1990

The molecular basis of cannabinoid activity.

Cannabinoids have been known to exhibit a wide variety of biological effects. Over the past fifty years numerous analogs were synthesized in an attempt to understand the structural requirements for each cannabinoid activity. Only recently, however, some important findings have focused new attention on this field of research. These findings include: (a) The development of novel "non-classical" potent cannabinoid analogs which exhibit similar pharmacological profiles with their "classical" counterparts; (b) The demonstration that there are specific cannabinoid binding sites in cell cultures as well as in mammalian brains; (c) Biophysical studies related to the interactions of cannabinoids with membranes which lead to a better understanding of those molecular properties which are required for cannabinoid activity; (d) Detailed and uniform pharmacological testing on a sizeable number of analogs allowing for a more detailed dissection of the cannabinoid effects and respective "structure activity relationships." The newly increased interest in cannabinoid research opens the door for a better understanding and potential treatment in cases of abuse as well as novel therapeutic opportunities through the design and synthesis of pharmacologically more selective analogs.

Animals↗

PubMed1991

The effects of delta 9-tetrahydrocannabinol and other cannabinoids on cAMP accumulation in synaptosomes.

The effects of delta 9-THC and other cannabinoids on cAMP levels in synaptosomes from mouse brains were investigated in order to determine whether cannabinoids produced their behavioral effects through alterations in adenylate cyclase. delta 9-THC (0.01-10 microM) did not significantly alter basal cAMP levels, whereas delta 9-THC and other cannabinoids were able to alter forskolin-stimulated cAMP levels in synaptosomes. In general, three kinds of responses were observed. Some cannabinoids displayed a modest, concentration-dependent decrease in cAMP levels, producing significant inhibition between 1-10 microM. Other cannabinoids, including delta 9-THC and delta 8-THC, appeared to produce a biphasic effect in that inhibition of cAMP was observed only at a single concentration. Finally, some analogs were unable to significantly alter forskolin-stimulated cAMP. There was not a clear relationship between the ability of the cannabinoids to alter cAMP levels in synaptosomes and the behavioral effects observed in mice. However, it was demonstrated that the analogs which are the most potent in producing cannabimimetic effects in mice were the analogs which inhibited cAMP in a concentration-dependent manner. While cannabinoids were able to alter cAMP levels in synaptosomes, the ability to alter cAMP levels does not appear to be absolutely necessary for the production of cannabinoid effects in mice.

Adenylyl Cyclases↗

PubMed2003

Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses.

Several anatomical, biochemical and pharmacological evidence support the existence of bidirectional interactions between cannabinoid and opioid systems. The present review is focused on the participation of the endogenous opioid system in the antinociceptive and emotional-like responses induced by cannabinoids, and the development of tolerance to cannabinoid pharmacological effects. Cannabinoid and opioid agonists produce antinociception by acting on similar structures within the central nervous system, and a peripheral mechanism has been also proposed for both compounds. Pharmacological studies have suggested that the endogenous opioid system could be involved in cannabinoid antinociception and the development of cannabinoid tolerance. Recent studies using knockout mice have also demonstrated the role of the opioid system in cannabinoid antinociception and tolerance, although some discrepancies with the previous pharmacological results have been reported when using knockout mice. On the other hand, cannabinoid administration can induce anxiolytic-like responses that are mediated at least in part by an endogenous opioid activity on micro- and delta-opioid receptors.

Analgesics↗

PubMed2005

Gene ancestry of the cannabinoid receptor family.

Genome sequencing projects, and their available resources, have revealed two distinct genes encoding cannabinoid receptors, CB(1) and CB(2). Biochemical evidence in support of a third cannabinoid receptor includes signal transduction events and vasodilation in the vasculature of cannabinoid receptor knockout mice after exposure to the endogenous cannabinoid, anandamide. In addition, a nonpsychoactive ingredient in marijuana, abnormal cannabidiol, which does not activate the two characterized cannabinoid receptor homologues, has been shown to induce vasodilation in the endothelium. Our work distinguishes the biochemical differences by way of a phylogenetic analysis of cannabinoid receptors. Recently a putative orthologue to CB(1) and CB(2) has been identified in the urochordate, Ciona intestinalis, indicating the presence of cannabinoid receptors previous to the evolution of vertebrates. Moreover, the Ciona sequence shares equal identity to both cannabinoid paralogous sequences and no other GPCR sequence identified in an exhaustive database search is as similar. We propose that, although an alternate cannabinergic-activating pathway may be present, it does not include a GPCR (or other receptor type) phylogenetically related to the CB(1)/CB(2)Ciona lineage.

Animals↗

PubMed2000

CB1 cannabinoid receptor expression in brain regions associated with zebra finch song control.

Cannabinoids have been used for millennia through various preparations of Cannabis sativa. Despite this long history of use, the physiological significance of cannabinoid signaling in the vertebrate CNS is not well understood. High CB1 cannabinoid receptor densities in mammalian telencephalon and the results of behavioral studies suggest that cannabinoids play a role in cognitive function, learning, and memory. Since a network of discrete brain regions in zebra finch telencephalon controls song learning, we hypothesized that cannabinoid signaling may be relevant to songbird vocal development and behavior. Radioligand binding experiments using the cannabinoid agonist [3H]CP-55940 allowed identification of a dense population of high-affinity cannabinoid binding sites in zebra finch neuronal membranes. Northern blotting and RT-PCR experiments demonstrated expression of a predominant zebra finch CB1 mRNA of approximately 5.5 kb. Expression of this CB1 mRNA appears to change over the course of vocal development within the caudal telencephalon. As zebra finch caudal telencephalon contains the higher vocal center (HVC) and the robust nucleus of the archistriatum (RA), regions involved in song learning and production, we further investigated CB1 expression in these areas using in situ hybridization. In situ hybridization revealed that CB1 mRNA is expressed at high levels within both HVC and RA. Overall, these data demonstrate the presence of CB1 signaling systems within songbird telencephalon, notably within regions known to be involved in song learning and production. High-level CB1 expression in song regions suggests a potential role for cannabinoid signaling in zebra finch vocal development.

Animals↗

PubMed2001

Sex differences in antinociceptive and motoric effects of cannabinoids.

Cannabinoids are currently used for the treatment of excessive weight loss and nausea; however, there are very few studies that have examined cannabinoid effects in females of any species. A previous study has shown that there are sex differences in cannabinoid pharmacokinetics in rats, suggesting that there could be sex differences in cannabinoid-induced behaviors. To address this issue, Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol (natural cannabinoids) or (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP55940, a synthetic cannabinoid) was administered i.p. to male and female Sprague-Dawley rats, who were tested on the 50 degrees C warm water tail withdrawal, paw pressure, catalepsy bar and spontaneous locomotor activity tests at various times post-injection. At the doses tested, all three cannabinoid agonists produced greater effects in females than males in two or more behavioral tests. This study demonstrates that there are sex differences in the behavioral effects of cannabinoids in the rat.

Analgesics↗

PubMed2003

Differential distribution of functional cannabinoid CB1 receptors in the mouse gastroenteric tract.

Recently, the gastrointestinal pharmacology of cannabinoid CB(1) receptors has been extensively explored. We employed western blotting and immunohistochemistry techniques to study the distribution of the cannabinoid CB(1) receptor protein in the mouse gastroenteric tract. The cannabinoid CB(1) receptor peptide was detected by western blotting only in its glycosylated form (63 kDa) with a significant differential distribution. The highest levels of expression were detected in the stomach and in the colon, while the pyloric valve was devoid of any cannabinoid CB(1) receptor protein. The immunohistochemical study showed intense cannabinoid CB(1) receptor immunoreactivity in ganglia subadjacent to the gastric epithelium and in the smooth muscle layers of both the small and large intestine. Only the small intestine showed (-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)-phenyl]-4-(3-hydroxylpropyl) cyclohexan-1-ol) ([3H]CP 55,940) specific binding (27%). These receptors mediated pharmacologically significant effects since the cannabinoid CB(1) receptor agonist R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU 210) dose dependently inhibited gastrointestinal transit up to 70%, while the cannabinoid CB(1) receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR 141716A) increased gastrointestinal transit. Moreover, the dose of 0.3 microg/kg of HU 210, devoid per se of any activity on mouse intestinal propulsion, blocked the increased gastroenteric transit induced by the cannabinoid CB(1) antagonist SR 141716A.

Animals↗

PubMed2003

Pharmacological characterisation of cannabinoid receptors inhibiting interleukin 2 release from human peripheral blood mononuclear cells.

The effects of a range of cannabinoid receptor agonists and antagonists on phytohaemagglutinin-induced secretion of interleukin-2 from human peripheral blood mononuclear cells were investigated. The nonselective cannabinoid receptor agonist WIN55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate) and the selective cannabinoid CB(2) receptor agonist JWH 015 ((2-methyl-1-propyl-1H-indol-3-yl)-1-napthalenylmethanone) inhibited phytohaemagglutinin (10 microg/ml)-induced release of interleukin-2 in a concentration-dependent manner (IC(1/2max), WIN55212-2=8.8 x 10(-7) M, 95% confidence limits (C.L.)=2.2 x 10(-7)-3.5 x 10(-6) M; JWH 015=1.8 x 10(-6) M, 95% C.L.=1.2 x 10(-6)-2.9 x 10(-6) M, n=5). The nonselective cannabinoid receptor agonists CP55,940 ((-)-3-[2-hydroxy-4-(1,1-dimethyl-hepthyl)-phenyl]4-[3-hydroxypropyl]cyclo-hexan-1-ol), Delta(9)-tetrahydrocannabinol and the selective cannabinoid CB(1) receptor agonist ACEA (arachidonoyl-2-chloroethylamide) had no significant (P>0.05) inhibitory effect on phytohaemagglutinin-induced release of interleukin-2. Dexamethasone significantly (P<0.05) inhibited phytohaemagglutinin-induced release of interleukin-2 in a concentration-dependent manner (IC(1/2max)=1.3 x 10(-8) M, 95% C.L.=1.4 x 10(-9)-3.2 x 10(-8) M). The cannabinoid CB(1) receptor antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (10(-6) M) did not antagonise the inhibitory effect of WIN55212-2 whereas the cannabinoid CB(2) receptor antagonist SR144528 (N-(1,S)-endo-1,3,3-trimethyl bicyclo(2,2,1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) antagonised the inhibitory effect of WIN55212-2 (pA(2)=6.3+/-0.1, n=5). In addition, CP55,940 (10(-6) M) and Delta(9)-tetrahydrocannabinol (10(-6) M) also antagonised the inhibitory effects of WIN55212-2 (pA(2)=6.1+/-0.1, n=5 and pA(2)=6.9+/-0.2, n=5). In summary, WIN55,212-2 and JWH 015 inhibited interleukin-2 release from human peripheral blood mononuclear cells via the cannabinoid CB(2) receptor. In contrast, CP55,940 and Delta(9)-tetrahydrocannabinol behaved as partial agonists/antagonists in these cells.

Arachidonic Acids↗

PubMed1997

Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals.

We have investigated whether there are cannabinoid CB2 receptors that can mediate cannabinoid-induced inhibition of electrically evoked contractions in the mouse vas deferens or guinea-pig myenteric plexus-longitudinal muscle preparation. Our results showed that mouse vas deferens and guinea-pig whole gut contain cannabinoid CB1 and CB2-like mRNA whereas the myenteric plexus preparation seemed to contain only cannabinoid CB1 mRNA. JWH-015 (1-propyl-2-methyl-3-( -naphthoyl)indole) and JWH-051 (1-deoxy-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl+ ++), which have higher affinities for CB2 than CB1 cannabinoid binding sites, inhibited electrically evoked contractions of both tissues in a concentration related manner. This inhibition was attenuated by 31.62 nM of the cannabinoid CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride] only in the myenteric plexus preparation. Vasa deferentia from delta9-tetrahydrocannabinol-pretreated mice (20 mg/kg i.p. once daily for two days) showed reduced sensitivity to JWH-015 and JWH-051. The results suggest that these compounds exert their inhibitory effects through cannabinoid CB1 receptors in the myenteric plexus preparation, but mainly through CB2-like cannabinoid receptors in the vas deferens.

Amino Acid Sequence↗

PubMed2003

Topical cannabinoid enhances topical morphine antinociception.

Opioids and cannabinoids produce antinociception through both spinal and supraspinal action. Both opioids and cannabinoids also have important peripheral action. Many previous studies indicate that systemically administered cannabinoids enhance antinociceptive properties of opioids. Experiments were conducted to test the hypothesis that topical cannabinoids would enhance the topical antinociceptive effects of morphine. Antinociception was measured in the radiant tail-flick test after immersion of the tail of mice into a solution of dimethyl sulfoxide (DMSO) containing WIN 55, 212-2, a cannabinoid agonist and morphine, an opioid agonist. Morphine and WIN 55, 212-2 produce time dependent topical analgesic effects limited to the portion of the tail exposed to drugs. WIN 55, 212-2 had a potency lower than that of morphine. The topical antinociceptive effects of WIN 55, 212-2 were blocked by systemic pretreatment of cannabinoid CB1 receptor selective antagonist, AM 251. This suggests that topical antinociceptive effects of WIN 55, 212-2 involve CB1 receptors. Combination of topical WIN 55, 212-2 with topical morphine yielded significantly greater analgesic effects than that of topical morphine alone. The ability of the CB1 receptor antagonist AM 251 to antagonize the enhancement of antinociception of morphine by WIN 55, 212-2 indicates that WIN 55, 212-2 acts through a CB1 receptor to enhance the potency of topical morphine. Additionally, spinally administered ineffective doses of WIN 55, 212-2 potentiated the antinociceptive effects of topical morphine. These results demonstrate an antinociceptive interaction between topical opioids with topical, and spinal cannabinoids. These observations are significant in using of topical combination of cannabinoid and morphine in the management of pain.

Administration, Topical↗

PubMed2001

Conditioned place preference induced by the cannabinoid agonist CP 55,940: interaction with the opioid system.

Cannabinoids appear atypical as drugs of abuse since controversial data exist concerning the ability to lower the thresholds for electrical self-stimulation (Stark and Dews, 1980; Gardner et al., 1988; Gardner, 1992) and to support self-administration (Martellotta et al., 1998; Tanda et al., 2000) or conditioned place preference in animals (Lepore et al., 1995; Parker and Gillies, 1995; McGregor et al., 1996; Sañudo-Peña et al., 1997; Chaperon et al., 1998; Hutcheson et al., 1998; Mallet and Beninger, 1998; Cheer et al., 2000; Valjent and Maldonado, 2000). Opioids and cannabinoids share some pharmacological properties (Manzanares et al., 1999). The most interactions were found in antinociception (Welch and Stevens, 1992; Smith et al., 1994) and, to a lesser extent, in drug reinforcement (Chen et al., 1990; Vela et al., 1995; Tanda et al., 1997). In the present study we asked whether: (1) a potent synthetic cannabinoid receptor agonist, [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptil)-phenyl]-trans-4-(3-hydroxy propyl) cyclohexanol] (CP 55,940) (from 10 to 40 microg/kg), which binds to the brain cannabinoid receptors with high affinity (Herkenham et al., 1991), would induce conditioned place preference, in comparison with heroin (from 0.1 to 5 mg/kg); (2) what type of receptor was involved; (3) what kind of interaction there was between the two drugs, when given in combination, on reward. CP 55,940 elicited a conditioned place preference only at a dose of 20 microg/kg similar in intensity to that of heroin (2 mg/kg). The reinforcing properties of the cannabinoid agonist were fully antagonised by pretreatment with the brain cannabinoid receptor-1 (CB(1)) antagonist, [N-piperidino-5-(4-chlorophenyl) 1-(2,4-dichloro-phenyl)-4-methyl pyrazole-3-carboxamide hydrochloride] (SR 141716A) and naloxone. The combination of CP 55,940 and heroin, at the reinforcing doses, led to a reward which did not show any additive effect. Taken together these findings are important for understanding how the cannabinoids produce reward and the interconnection of the opioid and cannabinoid system in the motivation.

Analgesics↗

PubMed2001

Cannabinoid modulation of time estimation in the rat.

Cannabinoids have been implicated in a variety of cognitive processes in humans, including attention, learning, memory, and time estimation. However, studies of the effects of cannabinoids on rodent behavior have focused on motor, learning, and memory tasks. To assess cannabinoid effects on time perception, this study examined whether systemically administered cannabinoid receptor agonists and a cannabinoid receptor antagonist influenced rats' performance of a time interval estimation task based on a fixed-interval schedule (a "peak procedure"). Both cannabinoid agonists WIN 55,212-2 and delta9-tetrahydrocannabinol shortened the modal response time, and cannabinoid antagonist SR 141716A lengthened the modal response time. Secondary measures of the shape of the response distribution were not influenced by any of the drugs, suggesting that the response distribution shifts were not artifacts of drug side effects. Therefore, these experiments argue for the involvement of endogenous cannabinoids in time estimation.

Animals↗