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At least 613 records · Page 34Linked to original sources
PubMed1993

Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N,N-diallyl-tyrosine-Aib-phenylalanine-leucine, ICI 174,864 or naloxone in mice.

Previous studies showed that cannabinoids administered intrathecally (i.t.) produced antinociception and synergism with the antinociceptive effects of morphine. Low doses of naloxone that appear selective for the mu receptor failed to block the antinociceptive effect of the cannabinoids. The present studies evaluated the interaction of the cannabinoids with kappa and delta opioid antagonists and agonists. Antinociception produced by delta 9 tetrahydrocannabinol (THC) and delta 8-THC (i.v., ED80 doses) was blocked by the kappa antagonist, nor-BNI (10 and 20 micrograms/mouse). The effects of CP 55,940 administered i.v. were blocked by norbinaltorphimine (nor-BNI; i.v. but not i.t.). The delta antagonist, N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864; 10 micrograms/mouse administered i.t.), failed to block the effects of any of the cannabinoids administered i.v. Nor-BNI administered i.t. blocked the antinociception produced by the cannabinoids (administered i.t., ED80 doses). The AD50s generated for nor-BNI vs. i.t. administered delta 9-THC, delta 8-THC, levonantradol and CP 55,940 were 3.5, 1.1, 3.8 and 4.5 micrograms/mouse, respectively. Nor-BNI (10 micrograms/mouse i.t.) shifted the dose-effect curve for delta 9-THC to the right in a parallel manner. delta 9-THC was additive with the kappa agonist, U50,488H, whereas delta 9-THC produced a parallel 37-fold shift to the left in the dose-effect curve of the delta agonist, DPDPE. Nor-BNI (70 micrograms/mouse i.c.v.) or ICI 174,864 (10 micrograms/mouse i.t.) failed to block the effects of the cannabinoids administered i.t. The exact nature of the nor-BNI/cannabinoid interaction is yet to be determined.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2006

The pharmacology of cannabinoid receptors and their ligands: an overview.

Mammalian tissues express at least two cannabinoid receptor types, CB1 and CB2, both G protein coupled. CB1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors occur mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous agonists for cannabinoid receptors also exist, and are all eicosanoids. The first-discovered of these 'endocannabinoids' was arachidonoylethanolamide and there is convincing evidence that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors. Certain cannabinoids also appear to have TRPV1-like and/or non-CB1, non-CB2, non-TRPV1 targets. Several CB1- and CB2-selective agonists and antagonists have been developed. Antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. 'Neutral' cannabinoid receptor antagonists have also been developed. CB1 and/or CB2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB1, CB2 or CB1/CB2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis. We have recently discovered the presence of an allosteric site on the CB1 receptor. Consequently, it may also prove possible to enhance 'autoprotective' effects of released endocannabinoids with CB1 allosteric enhancers or, indeed, to reduce proposed 'autoimpairing' effects of released endocannabinoids such as excessive food intake with CB1 allosteric antagonists.

Animals↗
PubMed2004

Cannabinoid signaling in glial cells.

The cannabinoid signaling system is composed of cannabinoid (CB) receptors, their endogenous ligands, the endocannabinoids, and the enzymes that produce and inactivate them. It is well known that neurons communicate between each other through this signaling system. Delta 9-tetrahydrocannabinol, the main psychoactive compound of marijuana, interacts with CB receptors, impinging on this communication and inducing profound behavioral effects such as memory impairment and analgesia. Recent evidence suggests that glial cells also express components of the cannabinoid signaling system and marijuana-derived compounds act at CB receptors expressed by glial cells, affecting their functions. This review summarizes this evidence, discusses how glial cells might use the cannabinoid signaling system to communicate with neighboring cells, and argues that nonpsychotropic cannabinoids, both marijuana-derived and synthetic, likely constitute lead compounds for therapy aimed at reducing acute and chronic neuroinflammation, such as occurs in multiple sclerosis.

Animals↗
PubMed2003

Tolerance to the memory disruptive effects of cannabinoids involves adaptation by hippocampal neurons.

The effects of chronic exposure to cannabinoids on short-term memory in rats were assessed during repeated daily injections of an initially debilitating dose (3.75 mg/kg) of the potent CB1 cannabinoid receptor ligand, WIN 55,212-2. Delayed nonmatch to sample (DNMS) performance was assessed over a 35-day exposure period in which performance was initially disrupted during the first 21 days of exposure but recovered by day 30 and was stable at pre-drug levels for 5 days thereafter. Withdrawal was precipitated by injections of the CB1 receptor antagonist SR141716A and transiently reduced performance for 2 days but was restabilized to pre-drug levels within 3-4 days. Concomitant recording from identified CA1 and CA3 hippocampal neurons demonstrated a marked correspondence in the time course of suppression of peak firing in the sample and delay phases of the task to the drug-induced performance deficits over the same days of exposure. Hippocampal encoding of task-relevant events and performance levels "tracked" each other on a daily basis throughout the chronic cannabinoid treatment and withdrawal regimen. However, hippocampal neuronal activity in the nonmatch phase of the task was unaffected by the chronic cannabinoid treatment or withdrawal, suggesting that only a select population of hippocampal neurons and synapses are involved in cannabinoid-sensitive short-term memory processes.

Action Potentials↗
PubMed2003

CB1 cannabinoid receptor activation inhibits a neural correlate of song recognition in an auditory/perceptual region of the zebra finch telencephalon.

A notable consequence of CB1 cannabinoid receptor activation in vertebrates is an impairment of cognitive function related to learning and short-term memory. The mechanisms of this impairment remain unclear, but one possibility is that cannabinoids influence encoding of stimuli at sensory and/or perceptual levels. Here, by treating zebra finches with the cannabinoid agonist WIN55212-2 and then measuring expression of the transcription factor zenk following presentation of novel zebra finch song, we show that cannabinoid receptor activation differentially influences zenk expression in sensory versus perceptual regions of the songbird auditory telencephalon. That is, WIN55212-2 dose-dependently inhibited zenk expression in a region for auditory perception (NCM, the caudomedial neostriatum), but had no effect on zenk expression in the primary auditory area, the Field L complex. The inhibitory effects of WIN55212-2 on zenk expression in NCM were reversed by coadministration of the CB1-selective antagonist SR141716A. Moreover, we found that the habituation of the NCM zenk response to repeated presentation of the same song, a well-established neural correlate of song recognition, was blocked when birds were treated with WIN55212-2 during habituation trials. Our data suggest that activation of CB1 cannabinoid receptors can selectively influence perceptual and mnemonic aspects of auditory experience.

Animals↗
PubMed1995

2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.

The effects of anadamide, 2-arachidonoylglycerol and related compounds on the specific binding of a radiolabeled cannabinoid receptor ligand,[3H]CP55940, to synaptosomal membranes were examined. Anandamide, an endogenous cannabinoid receptor ligand, reduced the specific binding of [3H]CP55940 to synaptosomal membranes in a dose-dependent manner: the Ki value was 89 nM. 2-Arachidonoylglycerol was also shown to bind appreciably to the cannabinoid receptor in competitive inhibition experiments. The apparent binding affinity was markedly increased when the binding assay was carried out in the presence of the esterase inhibitor DFP or at 0 degrees C. Free arachidonic acid and N-palmitoylethanolamine were almost inactive in terms of binding to the cannabinoid receptor in synaptosomal membranes. 2-Arachidonoylglycerol may be an endogenous cannabinoid receptor ligand in the brain.

Animals↗
PubMed1998

Function of cannabinoid receptors in the neuroendocrine regulation of hormone secretion.

Marijuana and its cannabinoid constituents have profound effects on anterior pituitary hormone secretion. Exposure to delta 9-tetrahydrocannabinol inhibits gonadotropin, prolactin, growth hormone, and thyroid-stimulating hormone release and stimulates the release of corticotropin. Consequently, cannabinoid exposure could have profound effects on the function of the reproductive system, lactation, metabolism, and on the endocrine stress axis. The acute effects of cannabinoids on the endocrine system are consistent with its actions on brain neurotransmitter systems involved in the regulation of neuropeptides that modulate anterior pituitary hormone secretion. Although cannabinoid receptors appear to play a major role in the ability of cannabinoids to influence hormone release, much remains to be learned concerning their function in the neuroendocrine regulation of hormone secretion.

Animals↗
PubMed2005

Effects of cannabinoids on neurotransmission.

The CB1 cannabinoid receptor is widely distributed in the central and peripheral nervous system. Within the neuron, the CB1 receptor is often localised in axon terminals, and its activation leads to inhibition of transmitter release. The consequence is inhibition of neurotransmission via a presynaptic mechanism. Inhibition of glutamatergic, GABAergic, glycinergic, cholinergic, noradrenergic and serotonergic neurotransmission has been observed in many regions of the central nervous system. In the peripheral nervous system, CB1 receptor-mediated inhibition of adrenergic, cholinergic and sensory neuroeffector transmission has been frequently observed. It is characteristic for the ubiquitous operation of CB1 receptor-mediated presynaptic inhibition that antagonistic components of functional systems (for example, the excitatory and inhibitory inputs of the same neuron) are simultaneously inhibited by cannabinoids. Inhibition of voltage-dependent calcium channels, activation of potassium channels and direct interference with the synaptic vesicle release mechanism are all implicated in the cannabinoid-evoked inhibition of transmitter release. Many presynaptic CB1 receptors are subject to an endogenous tone, i.e. they are constitutively active and/or are continuously activated by endocannabinoids. Compared with the abundant data on presynaptic inhibition by cannabinoids, there are only a few examples for cannabinoid action on the somadendritic parts of neurons in situ.

Acetylcholine↗
PubMed1995

Inhibition of long-term potentiation in rat hippocampal slices by anandamide and WIN55212-2: reversal by SR141716 A, a selective antagonist of CB1 cannabinoid receptors.

It has been reported previously that delta 9-tetrahydrocannabinol and the synthetic cannabinoid agonist HU-210 [(--)-11-OH-delta 8-dimethylheptyl tetrahydrocannabinol] prevent long-term potentiation (LTP) induction in rat hippocampal slices. In this study we confirm that both WIN55212-2 ¿R-(+)-(2,3-dihydro-5-methyl-3-[¿4-morpholinyl¿ methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl) (1-naphtalenyl) methanone monomethanesulphonate¿ (3 and 10 microM), another synthetic cannabinoid agonist, and anandamide (10 microM), considered to be the endogenous ligand of cannabinoid receptors, inhibit LTP formation in the Schaffer collateral-CA1 field complex. In addition, we show that SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide hydrochloride] at 0.1-10 microM, a potent and selective antagonist of CB1 cannabinoid receptors, concentration-dependently reversed the inhibition of LTP induced by both WIN55212-2 and anandamide. These data indicate that cannabinoid receptor agonists inhibit hippocampal LTP formation through CB1 receptor activation and that anandamide could be a candidate for an endogenous neuromessenger involved in memory processes.

Animals↗
PubMed2006

Cannabinoids, electrophysiology, and retrograde messengers: challenges for the next 5 years.

Most of the behavioral effects of cannabis and its active ingredients, the cannabinoids (delta9THC being the most abundant of these), appear to be mediated by cannabinoid receptors. Endogenous cannabinoids (endocannabinoids) are lipid mediators that activate these same cannabinoid receptors. Elegant work from several laboratories over the past 5 years has established that endocannabinoids, possibly acting as retrograde messengers, mediate several forms of neuronal plasticity. Endocannabinoid-mediated neuronal plasticity is common, apparently occurring at all neurons that express cannabinoid receptors. Thus, it is likely that delta9THC produces its effects by interacting with endocannabinoid-mediated neuronal plasticity, though whether it does so cooperatively or antagonistically remains an open question. In this review we will briefly discuss the work establishing endocannabinoids as mediators of neuronal plasticity and then present evidence that a major effect of delta9THC may be to antagonize the actions of endocannabinoids.

Animals↗
PubMed1999

Local administration of delta9-tetrahydrocannabinol attenuates capsaicin-induced thermal nociception in rhesus monkeys: a peripheral cannabinoid action.

RATIONALE: Cannabinoids can reduce nociceptive responses by acting on peripheral cannabinoid receptors in rodents. OBJECTIVES: The study was conducted to evaluate the hypothesis that local administration of delta9-tetrahydrocannabinol (delta9-THC) can attenuate capsaicin-induced nociception in rhesus monkeys. METHODS: Capsaicin (100 microg) was applied locally in the tail of rhesus monkeys to evoke a nociceptive response, thermal allodynia, in normally innocuous 46 degrees C water. delta9-THC (10-320 microg) was coadministered with capsaicin in the tail to assess local antinociceptive effects. In addition, a local antagonism study was performed to confirm the selectivity of delta9-THC action. RESULTS: delta9-THC dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by small doses (10-100 microg) of the cannabinoid CB1 antagonist, SR141716A, applied in the tail. However, 100 microg SR141716A injected subcutaneously in the back did not antagonize local delta9-THC. CONCLUSIONS: These results indicate that the site of action of locally applied delta9-THC is in the tail. It provides functional evidence that activation of peripheral cannabinoid CB1 receptors can attenuate capsaicin-induced thermal nociception in non-human primates and suggests a new approach for cannabinoids in pain management.

Analgesics, Non-Narcotic↗
PubMed2001

Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats.

RATIONALE: Delta9-tetrahydrocannabinol (Delta9-THC), the main psychoactive ingredient of marijuana, as well as synthetic cannabinoid (CB1) receptor agonists, has led to negative or equivocal results when tested with the intravenous self-administration procedure, the best validated behavioural model for evaluating abuse liability of drugs in experimental animals. We recently reported, however, that the synthetic CB1 receptor agonist WIN 55,212-2 is intravenously self-administered by drug-naive mice and that its self-administration is blocked by the cannabinoid CB1 receptor antagonist SR 141716A. OBJECTIVE: To assess a reliable model of cannabinoid intravenous self-administration in rats. Long Evans male rats were allowed the opportunity to self-administer WIN 55,212-2 at doses ranging from 6.25 to 50 microg/kg per injection, under a fixed-ratio 1 (FR1) schedule of reinforcement and nose-pokes as the operant responses. The effect of either a change in the unit drug dose available or a pretreatment with the specific CB1 receptor antagonist SR 141716A were then investigated (maintenance phase). Finally, the extinction of the self-administration behaviour was evaluated. RESULTS: Response rate depended on the drug dose available, with maximum rates occurring at 12.5 microg/kg per injection. Response rate increased following pretreatment with the specific CB1 receptor antagonist, SR 141716A. Moreover, operant behaviour rapidly extinguished following both the substitution of saline or vehicle for cannabinoid and the disconnection of the drug delivery pumps. CONCLUSION: Rats will intravenously self-administer the synthetic CB1 receptor agonist WIN 55,212-2 under specific experimental conditions, thus allowing further investigation of the neurobiological mechanisms underlying cannabinoid-taking behaviour.

Analgesics↗
PubMed2005

[Endogenous cannabinoid system. Effect on neuronal plasticity and pain memory].

AIM: The aim of this study was to evaluate the role of the endogenous cannabinoid system in controlling neuroplasticity. METHODS: The pain threshold for electrical stimuli was determined in transgenic mice lacking the cannabinoid receptor type 1 (CB1(-/-)) and in the corresponding respective wild-type animals. Electrophysiological experiments were performed in prepared brain slices to test the effect of endogenous and exogenous cannabinoids on synaptic transmission and long-term potentiation (LTP) in the amygdala. RESULTS: The pain threshold was nearly identical in both groups for the first pain induction; however, with repeated pain induction it decreased to a significantly greater extent in the CB1(-/-) mice than in the wild-type animals. Synoptic transmission and the inducibility of LTP were not influenced by the acute pharmacological blockade of CB1 receptors, but inhibited by the CB1 agonist WIN55,212-2. CONCLUSION: The endogenous cannabinoid system is involved in the control of neuroplasticity as part of pain processing . Cannabinoids prevent the formation of LTP in the amygdala via activation of CB1 receptors. Synoptic transmission and the inducibility of LTP were not influenced by the acute pharmacological blockade of CB1 receptors, but inhibited by the CB1 agonist Win55,212-2.

Cannabinoids↗
PubMed2005

[Cannabinoids--signal transduction and mode of action].

The therapeutic use of cannabinoids, the components of cannabis sativa L., was investigated in numerous researches in detail. Animal studies revealed that cannabinoid receptor agonists alter pain-associated behaviour, have immune-suppressive properties, suppress tumor growth, modulate sensitisation processes and influence memory and learning. Those effects are mediated by two membrane-bound cannabinoid receptors and as mechanisms of signal transduction blockade of ion channels, inhibition of adenylate cyclase and retrograde inhibition of neurotransmitter release are currently being discussed. In clinical studies oral administration of cannabinoids indicated beneficial results during the therapy of multiple sclerosis, weight loss, nausea and vomiting due to chemotherapy, and intractable pruritus. However, therapy of chronic pain conditions revealed conflicting results and unequivocal success could not have been delivered due to unwanted side effects. Further multicentre studies are required to estimate cannabinoids as novel therapeutic tools for the treatment of chronic pain.

Animals↗
PubMed1993

In vitro reinforcement of hippocampal bursting by the cannabinoid receptor agonist (-)-CP-55,940.

Involvement of cannabinoid receptors in behavioral reinforcement is suggested by widespread human use of marihuana, although animal tests of cannabinoid reinforcement have produced mixed results. Cannabinoid receptors are found in high density in rat hippocampus and other brain areas. Using the hippocampal-slice preparation, we attempted to demonstrate in vitro reinforcement of CA1 bursting with local micropressure applications of the high-affinity synthetic cannabinoid receptor agonist (-)-CP-55,940. Approximately 60% of the tested neurons showed increased burst activity after a series of brief, burst-contingent applications of (-)-CP-55,940 at pipette concentrations of 5 and 10 microM. Identical microinjections of (-)-CP-55,940 administered independently of cellular activity did not increase and usually suppressed hippocampal bursting. Since general stimulation of CA1 activity by (-)-CP-55,940 can thus be ruled out, we conclude that burst-contingent applications of a cannabinoid receptor agonist can reinforce hippocampal firing in vitro.

Action Potentials↗
PubMed1995

Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens.

The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoy)indole, produced a dose-related inhibition of electrically evoked contractions of the mouse vas deferens, with IC50 values of 2.56 nM, 3.38 nM and 639 nM respectively. Kd values of the selective CB1 cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride], determined in the vas deferens from experiments with these compounds are 1.34 nM, 3.86 nM and 8.06 nM respectively, indicating their susceptibility to antagonism by SR141716A is similar to that of their parent compound, the CB1 cannabinoid receptor agonist WIN 55,212-2 ¿(R)-(+)-[2,3-dihydro-5-methyl-3-[4-methylino)methyl]pyrrolo-[1,2, 3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone}. SR141716A (100 nM) had no effect on the actions of two non-cannabinoid receptor agonists, morphine and clonidine. These results provide strong support for the hypothesis that 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoyl)indole are cannabinoid receptor agonists and confirm that the WIN 55,212-2 molecule can be modified considerably without detectable loss of cannabinoid activity.

Animals↗
PubMed1996

Electrophysiological effects of a cannabinoid on neural activity in the globus pallidus.

The globus pallidus contains a dense distribution of cannabinoid receptors and appears to be a site of action of cannabinoids in the production of catalepsy. Single unit electrophysiology was used to explore the role of cannabinoid receptors in the globus pallidus of the rat. Intravenous injections of the potent and selective synthetic cannabinoid (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl) methanone (WIN 55,212-2; up to 0.5 mg/kg, i.v.) inhibited the spontaneous firing of neurons in the globus pallidus. In a second set of experiments, WIN 55,212-2 antagonized the inhibition of pallidal firing produced by electrical stimulation of the striatum. The pharmacological specificity of the effects of WIN 55,212-2 on basal and evoked activity in the globus pallidus was demonstrated by the lack of effect of the inactive enantiomer WIN 55,212-3. These results indicate that cannabinoids may produce functionally opposite effects on spontaneous and evoked activity in the globus pallidus: a decrease in spontaneous firing and a decrease in the inhibition of firing produced by the striatopallidal projection.

Action Potentials↗
PubMed1994

SR141716A, a potent and selective antagonist of the brain cannabinoid receptor.

SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the peripheral cannabinoid receptor. In vitro, SR141716A antagonises the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes. After intraperitoneal or oral administration SR141716A antagonises classical pharmacological and behavioural effects of cannabinoid receptor agonists. This compound should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.

Animals↗