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At least 1,297 records · Page 72Linked to original sources
PubMed1999

Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study.

In situ hybridization histochemistry was used to show the distribution of messenger RNA for central cannabinoid CB 1 receptors in dorsal root ganglia of the rat. CB1 messenger RNA was highly expressed in neuronal subpopulations of rat dorsal root ganglia. The phenotypes of neurons that express messenger RNA for CB1 were subsequently examined by combining a 35S-labeled ribonucleotide probe for CB1 messenger RNA with digoxigenin-labeled riboprobes for preprotachykinin A (substance P precursor), alpha-calcitonin gene-related peptide and preprosomatostatin (somatostatin precursor) messenger RNAs. Qualitative examination revealed expression of CBI messenger RNA predominantly in medium-and large-sized cells distributed throughout the dorsal root ganglia. The majority of neurons expressing substance P messenger RNA were CB1 messenger RNA negative and smaller in size than the CB1 messenger RNA-positive cells. Only 13% of substance P messenger RNA-positive cells expressed CB1 messenger RNA. A similar degree of co-localization was observed with alpha-calcitonin gene-related peptide: 10% of cells expressing messenger RNA for this neuropeptide were CB1 messenger RNA positive. Co-localization of CB1 and somatostatin messenger RNAs was observed in less than 0.5% of somatostatin messenger RNA-positive cells. The data suggest that subpopulations of neurons in rat dorsal root ganglia are capable of synthesizing cannabinoid receptors and inserting them on terminals in the superficial dorsal horn. These findings provide anatomical evidence for cannabinoid modulation of primary afferent transmission. Although an anatomical basis for cannabinoid-mediated suppression of release of neurogenic peptides from nociceptive primary afferents is provided, our results demonstrate that the majority of CB messenger RNA-positive neurons in the dorsal root ganglia contain transmitters and/or neuromodulators other than the neuropeptides examined herein.

Animals↗
PubMed1998

Cannabinoid receptors and their endogenous agonists.

Marijuana has been in use for over 4000 years as a therapeutic and as a recreational drug. Within the past decade, two cannabinoid receptor types have been identified, their signal transduction characterized, and an endogenous lipid agonist isolated from mammalian tissues. The CB1 cannabinoid receptor is widely distributed in mammalian tissues, with the highest concentrations found in brain neurons. CB1 receptors are coupled to modulation of adenylate cyclase and ion channels. The CB2 receptor is found in cells of the immune system and is coupled to inhibition of adenylate cyclase. Both receptor types selectively bind delta 9-THC, the active principle in marijuana, and anandamide (arachidonylethanolamide), an endogenous cannabimimetic eicosanoid. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity, mice with genetic deletion of the cannabinoid receptors, and receptor-specific antibodies, which should help in providing a better understanding of the physiological role of the cannabinoid receptors.

Animals↗
PubMed1997

Changes in rat spleen cannabinoid receptors after chronic CP-55,940: an autoradiographic study.

We examined whether cannabinoid receptor density changes in the rat spleen after in vivo chronic exposure to cannabinoids. Rats received daily injections of 0.4 mg/kg IP of the synthetic cannabinoid receptor ligand CP-55,940 for 11 days. One h after the last injection on day 11, the rats were killed and spleen coronal sections were processed for receptor binding autoradiography with 10 nM of [3H]CP-55,940 in the absence or presence of unlabeled CP-55,940 (10 microM). Densitometric analysis of the autoradiograms showed significant loss of [3H]CP-55,940 binding of about 42% in chronic cannabinoid-treated, tolerant rats. Our findings indicate that cannabinoid receptors basically present in immune spleen cells are down-regulated by chronic exposure to cannabinoids, suggesting a role in immune modulation and in the impairment of immune function.

Animals↗
PubMed2006

Pathophysiology and treatment of pain in joint disease.

Deep somatic pain originating in joints and tendons is a major therapeutic challenge. Spontaneous pain and mechanical hypersensitivity can develop as a consequence of sensitization of primary afferents directly involved in the inflammatory process, but also following sensitization of neuronal processing in the spinal cord (central sensitization) or higher centres. Inflammatory pain is linked to sensitization of sensory proteins at the nociceptive endings whereas pain originating from nerve damage (neuropathic pain) has been linked to changes in axonal ion channels producing ectopic discharge in nociceptors as a source of pain. New targets for analgesic therapy include sensory proteins at the nociceptive nerve endings such as the activating TRPV and ASIC channels, but also inhibitory opioid and cannabinoid receptors. Therapeutic targets are also found among the axonal channels that set membrane potential and modulate discharge frequency such as voltage sensitive sodium channels and various potassium channels.

Animals↗
PubMed2005

Effect of delta9-tetrahydrocannabinol on phosphorylated CREB in rat cerebellum: an immunohistochemical study.

Several converging lines of evidence indicate that drugs of abuse may exert their long-term effects on the central nervous system by modulating signaling pathways controlling gene expression. Cannabinoids produce, beside locomotor effects, cognitive impairment through central CB1 cannabinoid receptors. Data clearly indicate that the cerebellum, an area enriched with CB1 receptors, has a role not only in motor function but also in cognition. This immunohistochemical study examines the effect of delta9-tetrahydrocannabinol (delta9-THC), the principal psychoactive component of marijuana, on the levels of phosphorylated CREB (p-CREB) in the rat cerebellum. Acute treatments with delta9-THC at doses of 5 or 10 mg/kg induced a significant increase of p-CREB in the granule cell layer of the cerebellum, an effect blocked by the CB1 receptor antagonist SR 141716A. Following chronic delta9-THC administration (10 mg/kg/day for 4 weeks), the density of p-CREB was markedly attenuated compared to controls, and this attenuation persisted 3 weeks after withdrawal from delta9-THC. These data provide evidence for the involvement of cerebellar granule cells in the adaptive changes occurring during acute and chronic delta9-THC exposure. This might be a mechanism by which delta9-THC interferes with motor and cognitive functions.

Analysis of Variance↗
PubMed2006

New and emerging treatment options for neuropathic pain.

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain (NP). As a result, a corresponding wide range of treatments have been employed to treat patients with NP, including antiepileptic drugs, opioid analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, N-methyl-D-aspartate receptor antagonists, cholecystokinin receptor antagonists, adenosine, lipoic acid, cannabinoids, isosorbide dinitrate, dronabinol, capsaicin, protein kinase C inhibitors, aldose reductase inhibitors, and VR-1 receptor modulators. Many of these compounds are limited by marginal efficacy and clinically significant adverse events; few have been evaluated in well-controlled, large-scale clinical trials. At present, the only agents approved for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia are lidocaine patches 5%, duloxetine, gabapentin, and pregabalin. Of these, only pregabalin is indicated for both conditions.

Diabetic Neuropathies↗
PubMed2006

mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis.

Several studies have described functional interactions between opioid and cannabinoid receptors; the underlying mechanism(s) have not been well explored. One possible mechanism is direct receptor-receptor interactions, as has been demonstrated for a number of G-protein-coupled receptors. In order to investigate interactions between opioid and cannabinoid receptors, we epitope tagged mu, delta and kappa opioid receptors with Renilla luciferase and CB1 cannabinoid or CCR5 chemokine receptors with yellow fluorescent protein and examined the extent of substrate hydrolysis induced bioluminescence resonance energy transfer (BRET) signal. We find that coexpression of opioid receptors with cannabinoid receptors, but not with chemokine receptors, leads to a significant increase in the level of BRET signal, suggesting that the opioid-cannabinoid interactions are receptor specific. In order to examine the implications of these interactions to signaling, we used GTPgammaS binding and mitogen-activated protein kinase (MAPK) phosphorylation assays and examined the effect of receptor activation on signaling. We find that the mu receptor-mediated signaling is attenuated by the CB1 receptor agonist; this effect is reciprocal and is seen in heterologous cells and endogenous tissue expressing both receptors. In order to explore the physiological consequences of this interaction, we examined the effect of receptor activation on the extent of Src and STAT3 phosphorylation and neuritogenesis in Neuro-2A cells. We find that the simultaneous activation of mu opioid and CB1 cannabinoid receptors leads to a significant attenuation of the response seen upon activation of individual receptors, implicating a role for receptor-receptor interactions in modulating neuritogenesis.

Cells, Cultured↗
PubMed2000

Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice.

Previous studies have shown that mice primed with Corynebacterium parvum produce higher levels of inflammatory cytokines than unprimed mice upon challenge with lipopolysaccharide (LPS). Herein, we describe experiments in which two cannabinoid (CB) agonists, WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone) and HU-210 [(-)-11-hydroxy-delta(8) tetrahydrocannabinol-dimethylheptyl], were examined for their effects on LPS-induced cytokines in C. parvum-primed and unprimed mice. These agonists have been reported to bind selectively to the CB2 and CB1 receptor subtypes, respectively. WIN 55212-2 (3.1-50 mg/kg i.p.) and HU-210 (0.05-0.4 mg/kg i.p.) decreased serum tumor necrosis factor-alpha and interleukin-12 (IL-12) and increased IL-10 when administered to mice before LPS. The drugs also protected C. parvum mice (but not unprimed mice) against the lethal effects of LPS. The protection afforded to C. parvum mice could not be attributed to the higher levels of IL-10 present in these mice after agonist treatment. The WIN 55212-2- and HU-210-mediated changes in the responsiveness of mice to LPS were antagonized by SR141716A [N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2, 4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor antagonist, but not by SR144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2. 1]heptan-2-yl]5-(4-choro-3-methylphenyl)-1-(4-methylbenzyl)p yrazole-3 -carboxamide], a selective antagonist at the CB2 receptor. Therefore, both CB agonists modulated LPS responses through the CB1 receptor. Surprisingly, SR141716A itself modulated cytokine responses in a manner identical with that of WIN 55212-2 and HU-210 when administered alone to mice. The agonist-like effects of SR141716A, which were more striking in unprimed than in primed mice, suggested that the antagonist also could function as a partial agonist at the CB1 receptor. Our findings indicate a role for the CB1 receptor subtype in cytokine modulation by CB ligands.

Animals↗
PubMed1995

Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.

Mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play important roles in tissue inflammation and in neuroimmune interactions. Very little is known about endogenous molecules and mechanisms capable of modulating mast cell activation. Palmitoylethanolamide, found in peripheral tissues, has been proposed to behave as a local autacoid capable of downregulating mast cell activation and inflammation. A cognate N-acylamide, anandamide, the ethanolamide of arachidonic acid, occurs in brain and is a candidate endogenous agonist for the central cannabinoid receptor (CB1). As a second cannabinoid receptor (CB2) has been found in peripheral tissues, the possible presence of CB2 receptors on mast cells and their interaction with N-acylamides was investigated. Here we report that mast cells express both the gene and a functional CB2 receptor protein with negative regulatory effects on mast cell activation. Although both palmitoylethanolamide and anandamide bind to the CB2 receptor, only the former downmodulates mast cell activation in vitro. Further, the functional effect of palmitoylethanolamide, as well as that of the active cannabinoids, was efficiently antagonized by anandamide. The results suggest that (i) peripheral cannabinoid CB2 receptors control, upon agonist binding, mast cell activation and therefore inflammation; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for the CB2 receptor on mast cells; (iii) modulatory activities on mast cells exerted by the naturally occurring molecule strengthen a proposed autacoid local inflammation antagonism (ALIA) mechanism; and (iv) palmitoylethanolamide and its derivatives may provide antiinflammatory therapeutic strategies specifically targeted to mast cells ("ALIAmides").

Amides↗
PubMed2002

Modulation of the release of endogenous gamma-aminobutyric acid by cannabinoids in the guinea pig ileum.

Interactions between cannabinoid CB(1) and GABA receptors and ligands were investigated in the myenteric plexus-longitudinal muscle of the guinea pig ileum. Electrically evoked contractions of the myenteric plexus-longitudinal muscle were inhibited by the cannabinoid receptor agonist CP55,940 ((-)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), the GABA(B) receptor agonist, baclofen (4-amino-3-(chlorophenyl) butanoic acid), or exogenous GABA. Electrically evoked contractions of the myenteric plexus-longitudinal muscle were also inhibited by the addition of the GABA releasing agent ethylenediamine. CP55,940 (1 nM) or the endogenous cannabinoid anandamide (arachidonyl ethanolamide, 1 microM) reduced the inhibition produced by ethylenediamine, while in contrast, anandamide (10 microM) significantly increased the inhibition produced by ethylenediamine. The results suggest that while there is no interaction between cannabinoid CB(1) and GABA(B) receptors in the myenteric plexus-longitudinal muscle of the guinea pig, cannabinoid CB(1) receptor stimulation reduces the ethylenediamine-evoked GABA release. In addition, anandamide at higher concentrations also potentiates the inhibitory effect of ethylenediamine at least partly by stimulating vanilloid receptors.

Animals↗
PubMedDate not supplied

[Cannabinoid system and neuroinflammation:therapeutic perspectives in multiple sclerosis].

INTRODUCTION: The endocannabinoid system consists of cannabinoid receptors, endogenous ligands and the enzymatic elements involved in their synthesis and breakdown. AIM: To report on currently held knowledge about the functioning of the system as a modulator of the neuroinflammatory processes associated with chronic diseases such as multiple sclerosis. DEVELOPMENT: Cannabinoids are synthesised and released on demand and their production increases in times of neuroinflammation and neural damage. In this context then, their actions in the microglial cells and in the astrocytes are characterised by a lowered expression of inflammatory mediators and pro-inflammatory cytokines. Furthermore, cannabinoids can play a role as neuroprotectors by means of different types of mechanisms and, in experimental models of multiple sclerosis, they slow down the symptoms, reduce inflammation and can favour remyelination. CONCLUSIONS: The clinical use of cannabinoids or pharmacological agents that affect the endogenous cannabinoid system during inflammation of the central nervous system and in multiple sclerosis is currently under consideration and subject to debate. Detailed analysis of the results obtained over the past decade has made it possible to establish the existence of several mechanisms of action of cannabinoids in pathologies affecting the central nervous system that are accompanied by chronic inflammation. Likewise, they also clearly show that the cannabinoid system is an interesting proposal as a new therapeutic tool.

Animals↗
PubMed2002

Antinociceptive, behavioural and neuroendocrine effects of CP 55,940 in young rats.

The peripubertal period appears to be critical in relation to the abuse of cannabinoids and opioids in humans. However there is little information about the acute effects of cannabinoids and their interactions with opioids in young experimental animals. We have studied the effects of the cannabinoid agonist CP 55,940 (0.1, 0.2, 0.4 and 0.6 mg/kg) on the nociceptive responses (tail immersion test) and holeboard activity of 40-day-old rats, and the involvement of the CB(1) receptor (antagonism by SR 141716A, 3 mg/kg). The implication of the opioid system was evaluated using the opioid antagonist naloxone (1 mg/kg) and a combined treatment with subeffective doses of CP 55,940 (0.1 mg/kg) and morphine (1 mg/kg). The effects of CP 55,940 on the serum corticosterone levels (radioimmunoassay) and on the dopamine and DOPAC contents of discrete brain regions (high-performance liquid chromatography) were also assessed. The antinociceptive effect of CP 55,940 was of a similar magnitude at all the doses used. The results show the involvement of the CB(1) receptor. The cannabinoid agonist significantly depressed the holeboard activity in a dose-dependent manner. The results indicate that the CB(1) receptor is involved in the effects on motor activity but not in the effects on the exploratory activity. The behavioural effects of CP 55,940 were modulated by morphine. The cannabinoid agonist (0.6 mg/kg) induced a CB(1)-mediated increase in the serum corticosterone levels, but no effect on the dopaminergic systems of either the striatum or the limbic forebrain was found.

Analgesics↗
PubMed2001

Oleamide modulates memory in rats.

Oleamide is a recently described lipid, obtained from the cerebrospinal fluid of sleep-deprived cats. It has been observed that oleamide possesses several biological effects, such as sleep induction, and immunological suppression as well as serotonin and gamma-aminobutyric acid receptors activation. In addition, oleamide also binds to the cannabinoid receptors. In this study, we have observed that oleamide facilitates memory extinction in a passive avoidance paradigm, reduces core temperature and pain perception, but does not affect significantly locomotion. These results suggest that oleamide modulates memory processes. However, we do not know if oleamide impairs the retrieval of the memory associated to the "not go" behavior, or facilitates the fast re-learning of the "go" behavior. In addition, since these effects are also induced by marijuana and anandamide, it is very likely that oleamide may be affecting the cerebral cannabinoid system to induce its effects.

Animals↗
PubMed2001

The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan.

Cannabinoids exert most of their effects through the CB(1) receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB(1) receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB(1) receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB(1) antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of G(i/o) proteins. A role for the adaptor protein FAN in CB(1) receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB(1) receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB(1) cannabinoid receptor may signal independently of G(i/o) proteins.

Adenylate Cyclase Toxin↗
PubMedDate not supplied

[N-acylethanolamine--a new class of natural adrenotropic modulators].

N-acyl-ethanolamines (NAE) belong to the new class of naturally occurring biologically active regulators. Anandamide--a well known representative of NAEs--is an agonist of central (CB1) and peripheral (CB2) cannabinoid receptors. Adrenal cortex contains the CB2 receptor. The aim of present work is to investigate the influence of saturated and polyunsaturated NAEs on the corticosteroid synthesis in adrenal gland in vitro. It was shown that the rat adrenal gland is the main target of N-([1-14C]palmitoyl)ethanolamine incorporation. Saturated NAE enhanced the incorporation of [3H]-cholesterol into the aldosterone by 25% (p < 0.06) and corticosterone by 17% (p < 0.05) of rat adrenal slices in vitro. Mixture of polyunsaturated NAEs containing mainly 18:1w9, 18:2w6, 18:3w3, 20:1w9, 22:1w9 increased the labeling of aldosterone by 70% (p < 0.05) and corticosterone by 20% (p < 0.05). Thus, the saturated NAEs as well as polyunsaturated analogs, act by the similar manner on the corticosteroid synthesis. The fact that saturated NAEs possess poor affinity to CB receptors provides us opportunity to suggest the non-receptor mechanism of NAEs adrenotrophic action. Further we used the purified bovine serum albumin to test the binding kinetic of N-([I14C]palmitoyl)ethanolamine with its hydrophobic domains. It was found that NAEs have high affinity to hydrophobic domains of protein with K = 2.5 x 10(8) M-1. This finding could support the idea of the existence of putative allosteric modulation of regulatory protein function. It was concluded that NAEs exert a stimulatory effect on the corticosteroid synthesis in rat adrenal gland in vitro and this action do not mediated trough cannabinoid receptor.

Adrenal Glands↗
PubMed2004

Comparison of cannabinoid ligands affinities and efficacies in murine tissues and in transfected cells expressing human recombinant cannabinoid receptors.

Affinities and efficacies of several reference cannabinoid ligands were investigated at central and peripheral cannabinoid receptors in three different species (rat, mouse, and human). The tested compounds belong to different chemical classes such as classical and non-classical terpene derivatives (Delta(8)-THC, Delta(9)-THC, HU 210, CP 55,940, CP 55,244, CP 55,243 and CP 47,947), aminoalkylindole (WIN 55,212-2, WIN 55,212-3) and diarylpyrazole cannabinoids (SR 141716A, SR 144528). As cannabinoid receptors have been shown to be mainly coupled to Gi/o type G- proteins, and by using the [(35)S]-GTPgammaS nucleotide binding modulation, we characterized the functional activity of these ligands which can act as agonists (positive intrinsic activity), partial agonists (partial positive intrinsic activity), antagonists (no intrinsic activity), or inverse agonists (negative intrinsic activity). To our knowledge, some derivatives (Delta(8)-THC, WIN 55,212-3, CP 55,243 and CP 47,947) have never been characterized in [(35)S]-GTPgammaS binding assays and up to now, this study represents the largest survey of reference cannabinoids performed in unique experimental conditions and in the same laboratory.

Animals↗
PubMed2000

Acute and long-term effects of 17beta-estradiol on G(i/o) coupled neurotransmitter receptor function in the female rat brain as assessed by agonist-stimulated [35S]GTPgammaS binding.

Estrogens exert effects on mood, mental state, memory and other central nervous system (CNS) functions by modulating neurotransmitter receptor systems in the brain. Studies were designed to investigate the effect of 17beta-estradiol (E(2)) on agonist-stimulated [35S]GTPgammaS binding in membranes to assess the first step in the intracellular signal transduction cascade in a functional assay following: (1) an acute, one-time bolus subcutaneous injection, or (2) 14-day continuous exposure by a slow-release pellet implanted subcutaneously. In rats treated with E(2) acutely, the maximal response produced by activation of serotonin(1A) (5-HT(1A)) receptors was decreased approximately 25% in the hippocampus, cortex, and amygdala. Similarly, acute E(2) administration desensitized 5-HT(1B) and GABA(B) receptors in hypothalamus and cerebellum, respectively, and cannabinoid receptors in hippocampus and cortex. Although the maximal responses were decreased, acute E(2) treatment did not alter the EC(50) of any of the aforementioned receptors. The incubation of membranes prepared from the cortex of ovariectomized (OVX) rats with E(2) (1 microM) in vitro did not alter 5-HT(1A) or cannabinoid receptor-mediated [35S]GTPgammaS binding. By contrast to acute treatment in vivo, 14-day E(2) administration to OVX rats did not alter the maximal responses produced by activation of 5-HT(1A), 5-HT(1B), GABA(B), or cannabinoid receptors in any of the brain regions examined. Thus, it is concluded that acute E(2) administration in vivo modulates multiple G(i/o) coupled receptors in various regions of the female rat brain. Because these effects are observed only in vivo, it is concluded that cytosolic, nuclear and/or extraneuronal factors are required.

Animals↗