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PubMed1998

Ligand binding and modulation of cyclic AMP levels depend on the chemical nature of residue 192 of the human cannabinoid receptor 1.

The human cannabinoid receptor associated with the CNS (CB1) binds delta9-tetrahydrocannabinol, the psychoactive component of marijuana, and other cannabimimetic compounds. This receptor is a member of the seven transmembrane domain G protein-coupled receptor family and mediates its effects through inhibition of adenylyl cyclase. An understanding of the molecular mechanisms involved in ligand binding and receptor activation requires identification of the active site residues and their role. Lys192 of the third transmembrane domain of the receptor is noteworthy because it is the only nonconserved, charged residue in the transmembrane region. To investigate the properties of this residue, which are important for both ligand binding and receptor activation, we generated mutant receptors in which this amino acid was changed to either Arg (K192R), Gln (K192Q), or Glu (K192E). Wild-type and mutant receptors were stably expressed in Chinese hamster ovary cells and were evaluated in binding assays with the bicyclic cannabinoid CP-55,940 and the aminoalkylindole WIN 55,212-2. We found that only the most conservative change of Lys to Arg allowed retention of binding affinity to CP-55,940, whereas WIN 55,212-2 bound to all of the mutant receptors in the same range as it bound the wild type. Analysis of the ligand-induced inhibition of cyclic AMP production in cells expressing each of the receptors gave an EC50 value for each agonist that was comparable to its binding affinity, with one exception. Although the mutant K192E receptor displayed similar binding affinity as the wild type with WIN 55,212-2, an order of magnitude difference was observed for the EC50 for cyclic AMP inhibition with this compound. The results of this study indicate that binding of CP-55,940 is highly sensitive to the chemical nature of residue 192. In contrast, although this residue is not critical for WIN 55,212-2 binding, the data suggest a role for Lys192 in WIN 55,212-2-induced receptor activation.

Amino Acid Sequence↗
PubMed2003

Antagonism between the anti-inflammatory activity of the cannabinoid WIN 55212-2 and SR 141716A.

The CB1/CB2 receptor agonist WIN 55212-2 (0.75 mg/kg, i.v.) caused a significant reduction in neurogenic plasma extravasation induced by electrical stimulation of the saphenous nerve in anesthetized rats; WIN 55212-2 at 2.5-10 mg/kg, s.c., also produced a significant reduction in the carrageenan-induced paw edema in conscious rats. The selective CB1 antagonist SR 141716A (0.075-0.75 mg/kg i.v.) antagonized the WIN 55212-2 effects in the plasma extravasation model and antagonized the WIN 55212-2 (2.5 mg/kg, s.c.)-induced decreases in rectal temperature and increases in tail-flick latencies. However, SR 141716A (10 mg/kg, p.o.) failed to antagonize the effects of Win 55212-2 (2.5 mg/kg, s.c.) in the carrageenan model, suggesting that cannabinoid receptors found in the periphery may be able to modulate inflammatory processes in rats.

Animals↗
PubMed2006

Rimonabant: a cannabinoid receptor blocker for the treatment of metabolic and cardiovascular risk factors.

AIMS: The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence. DATA SYNTHESIS: Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date. CONCLUSION: Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors.

Cannabinoid Receptor Antagonists↗
PubMed2006

Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide].

The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat), and inflammatory pain (complete Freund's adjuvant injection in the rat). In the formalin model, administration of AM404 (1-10 mg/kg i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB(1) cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg/kg i.p.) but not by the CB2 antagonist SR144528 (1 mg/kg i.p.) or the vanilloid antagonist capsazepine (30 mg/kg i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury and complete Freund's adjuvant model, daily treatment with AM404 (1-10 mg/kg s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg/kg i.p.) and was accompanied by decreased expression of cyclooxygenase-2 and inducible nitric-oxide synthase in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.

Animals↗
PubMed1997

Inhibition of protein kinase A and cyclic AMP response element (CRE)-specific transcription factor binding by delta9-tetrahydrocannabinol (delta9-THC): a putative mechanism of cannabinoid-induced immune modulation.

Delta9-Tetrahydrocannabinol (delta9-THC) binding to cannabinoid receptors induces an inhibition in adenylate cyclase activity through the engagement of a pertussis toxin-sensitive GTP-binding protein. In this study we investigated the ramifications of decreased cyclic AMP (cAMP) formation by delta9-THC on signaling events through the cAMP pathway distal to adenylate cyclase in mouse splenocytes. Delta9-THC treatment produced a marked and concentration-related decrease in forskolin-inducible protein kinase A (PKA) activity. This decrease in kinase activity was due to an inhibition in cAMP formation and not through a direct effect on the kinase as evidenced by the fact that PKA activity could not be modulated directly by delta9-THC in the presence of exogenous cAMP. One of the primary roles of PKA in this signaling pathway is to activate transcription factors for subsequent binding to cAMP response elements (CRE) present in the promoter region of cAMP-responsive genes. In the present studies, we observed that forskolin treatment of splenocytes resulted in a rapid activation of trans-acting factor binding to the CRE, which peaked at 30-60 min and whose binding was repressed concentration dependently in the presence of delta9-THC. As with forskolin, mitogenic stimulation including anti-CD3 mAb or phorbol ester plus ionomycin treatment of splenocytes induced CRE binding activity, which was maximal around 60 min and was suppressed by delta9-THC treatment. In conclusion, these data indicate that cAMP-mediated signal transduction is inhibited by delta9-THC and consequently leads to a decrease in the activation of transcription factors that bind to CRE regulatory sites.

Animals↗
PubMed2003

The spontaneously hypertensive-rat as an animal model of ADHD: evidence for impulsive and non-impulsive subpopulations.

Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric syndrome, affecting human infants and adolescents. Two main behavioural features are reported: (1). impaired attention and (2). an impulsive-hyperactive behavioural trait. The latter has been studied in a series of experiments, using the spontaneously hypertensive-rat (SHR) strain (which is regarded as a validated animal model for ADHD) in operant tasks. Food-restricted SHRs and their Wistar-Kyoto (WKY) controls were tested during adolescence (i.e. post-natal days 30-45), in operant chambers provided with two nose-poking holes. Nose-poking in one hole (H1) resulted in the immediate delivery of a small amount of food, whereas nose-poking in the other hole (H5) delivered a larger amount of food after a delay, which was increased progressively each day (0-100 s). As expected, all animals showed a shift in preference from the large (H5) to the immediate (H1) reinforcer as the delay length increased. Impulsivity can be measured by the steepness of this preference-delay curve. The two strains differed in home-cage circadian activity, SHRs being more active than WKYs at several time-points. During the test for impulsivity, inter-individual differences were completely absent in the WKY strain, whereas a huge inter-individual variability was evident for SHRs. On the basis of the median value of average hole-preference, we found an 'impulsive' SHR subgroup, with a very quick shift towards the H1 hole, and a flat-slope ('non-impulsive') SHR subgroup, with little or no shift. The impulsive subpopulation also presented reduced noradrenaline levels in both cingulated and medial-frontal cortex, as well as reduced serotonin turnover in the latter. Also, cannabinoid CB1 receptor density resulted significantly lower in the prefrontal cortex of impulsive SHRs, when compared to both the non-impulsive subgroup and control WKYs. Interestingly, acute administration of a cannabinoid agonist (WIN 55,212, 2 mg/kg s.c.) normalized the impulsive behavioural profile, without any effect on WKY rats. Thus, two distinct subpopulations, differing for impulsive behaviour and specific neurochemical parameters, were evidenced within adolescent SHRs. These results support the notion that a reduced cortical density of cannabinoid CB1 receptors is associated with enhanced impulsivity. This behavioural trait can be positively modulated by administration of a cannabinoid agonist. Present results confirm and extend previous literature, indicating that adolescent SHRs represent a suitable animal model for the preclinical investigation of the early-onset ADHD syndrome.

Animals↗
PubMed2003

Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response.

Endocannabinoid signaling processes are present in diverse organisms and in organisms 500 million years divergent in evolution. Cannabinoid receptor-1 expression (CB1), anandamide, and anandamide amidase have been found in invertebrates. Furthermore, this signaling system is coupled to constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO) release in both vertebrates and invertebrates, thereby regulating neural, immune, and vascular-like functions in these divergent organisms. In human endothelial cells from various blood vessels, CB1 immunoreactive components are present as is its coupling to anandamide-stimulated cNOS-derived NO production, which exerts an autoregulatory role on cNOS release. The modulation of vascular diameter and vascular tone represents a crucial point of interest in these pathways, and interactions between NO and the sympathetic nerve system are of importance, i.e, norepinephrine. Here, a possible association of NO and endocannabinoid signaling with the relaxation response, a physiological counterpart of the stress response, may exist.

Animals↗
PubMed2003

Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation.

Mammalian fertility absolutely depends on synchronized development of the blastocyst to the stage when it is competent to implant, and the uterus to the stage when it is receptive to implantation. However, the molecular basis for the reciprocal interaction between the embryo and the uterus remains largely unexplored. One potentially important mechanism involves signaling between an evolutionarily conserved G protein-coupled protein cannabinoid receptor, CB1, that is expressed at high levels on the surface of the trophectoderm and anandamide (N-arachi-donoylethanolamine), an endocannabinoid ligand found to be produced at higher levels by the uterus before implantation and then down-regulated at the time of implantation. Using genetic, pharmacological, and physiological approaches, we show here that anandamide within a very narrow range regulates blastocyst function and implantation by differentially modulating mitogen-activated protein kinase signaling and Ca2+ channel activity via CB1 receptors. Anandamide at a low concentration (7 nM) induces extracellular regulated kinase phosphorylation and nuclear translocation in trophectoderm cells without influencing Ca2+ channels, and renders the blastocyst competent for implantation in the receptive uterus. In contrast, anandamide at a higher concentration (28 nM) inhibits Ca2+ channel activity and blastocyst competency for implantation without influencing mitogen-activated protein kinase signaling. Besides uncovering a potentially important regulatory mechanism for synchronizing blastocyst and uterine competency to implantation, this observation has high clinical relevance, because elevated levels of anandamide induce spontaneous pregnancy loss in women.

Animals↗
PubMed2002

(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens.

The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Delta(9)-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB(1) receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB(1) receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 microM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a K(B) value (120.3 nM) well below its reported cannabinoid receptor CB(1)/CB(2) K(i) values. Cannabidiol (10 microM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; K(B)=34 nM) and [D-Ala(2), NMePhe(4), Gly-ol]enkephalin (DAMGO; K(B)=5.6 microM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to beta, gamma-methyleneadenosine 5'-triphosphate. At 3.16-10 microM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB(1) or CB(2) receptors.

Adenosine Triphosphate↗
PubMed1995

Expression of cannabinoid receptor mRNA in murine and human leukocytes.

delta 9-tetrahydrocannabinol, the major psychoactive cannabinoid of marijuana modulates immune cells in vivo and in vitro. It is possible that the drug exerts it's effect either by inserting into and disrupting the cell membrane (nonreceptor mechanism) or by binding to a cannabinoid receptor moiety and thus altering cell function through some form of signal transduction. In the present study, we confirm and extend the findings that mouse and human immune cells express specific cannabinoid binding sites and cannabinoid receptor mRNA. Reverse transcription-polymerase chain reaction analysis showed the presence of receptor mRNA not only in the neuroblastoma cell line (N18TG-2), but also in mouse splenocytes and in cell lines such as NKB61A2 (a mouse natural killer-like), CTLL2 (a mouse IL2-dependent T cell), THP-1 (a human monocytic cell) and Raji (a human B cell) but not in Jurkat (a human T cell). Furthermore, the receptor mRNA was expressed in purified populations of resting splenic T and B lymphocytes but not in resting populations of enriched splenic macrophages. Finally, LPS-stimulated Raji and PMA-stimulated THP-1 human cell lines showed increased levels of the cannabinoid receptor mRNA. These results suggest cannabinoid receptors have biological relevance in lymphoid cells because: receptor mRNA is detected in some resting immune cells but not others and the mRNA increases during cell activation. The major psychoactive component of marijuana, delta9-tetrahydrocannabinol (THC), has been shown to modulate human and mouse immune responses both in vitro and in vivo (1,2).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940 in male rats.

We have studied the possible interaction between three selective opioid-receptor antagonists, nor-binaltorphimine (NB: kappa) (5 mg/kg), cyprodime (CY: mu) (10 mg/kg) and naltrindole (NTI: delta) (1 mg/kg), and the cannabinoid receptor agonist CP 55,940, in the modulation of anxiety (plus-maze) and adrenocortical activity (serum corticosterone levels by radioimmunoassay) in male rats. The holeboard was used to evaluate motor activity and directed exploration. CP 55,940 (75 microg/kg, but not 10 microg/kg) induced an anxiogenic-like effect, which was antagonised by NB. The other effects of CP 55,940 (75 microg/kg), a decreased holeboard activity and stimulation of adrenocortical activity, were not antagonised by any of the three opioid receptor antagonists. CY and NTI, when administered alone, induced marked reductions in motor activity, anxiogenic-like effects and stimulation of adrenocortical activity. The selective kappa-opioid receptor antagonist NB, on its own, did not modify the level of anxiety but stimulated adrenocortical activity. We provide the first pharmacological evidence about the involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940.

Animals↗
PubMed2004

Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons.

Endocannabinoids may serve as retrograde messengers to inhibit neurotransmitter release during depolarization-induced suppression of inhibition (DSI) or excitation (DSE). We therefore tested whether endocannabinoids inhibit N-type voltage-dependent Ca2+ channels by activating G(i/o)-protein-coupled CB1 cannabinoid receptors (CB1R)--a possible mechanism underlying DSI/DSE. Three putative endocannabinoids [2-arachidonylglycerol (2-AG), 2-arachidonyl glycerol ether (2-AGE), and anandamide (AEA)] and the cannabimimetic aminoalkylindole WIN 55,212-2 (WIN) inhibited whole-cell Ca2+ currents in rat sympathetic neurons previously injected with cDNA encoding a human CB1R. Agonist-mediated Ca2+ current inhibition was blocked by a selective CB1R antagonist [SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride] and pertussis toxin (PTX) pretreatment. The rank order of potency was WIN (IC50=2 nM)>2-AGE (350 nM) approximately 2-AG (480 nM)>AEA (approximately 3 microM), with each agonist displaying similar efficacy (approximately 50% maximal inhibition). Increasing CB1R expression level significantly enhanced AEA potency. AEA (10 microM) also inhibited Ca2+ channels in a voltage-independent, CB1R-independent, and PTX-insensitive manner, whereas 2-AG and 2-AGE were devoid of this activity. All three endocannabinoids activated G-protein-coupled inwardly rectifying potassium (GIRK) channels, GIRK1/4, heterologously expressed in sympathetic neurons. These results suggest a mechanism by which endocannibinoids might influence presynaptic function.

Animals↗
PubMed2005

The modulation of Ca2+ and K+ channels but not changes in cAMP signaling contribute to the inhibition of glutamate release by cannabinoid receptors in cerebrocortical nerve terminals.

While cannabinoid receptors activate multiple signaling pathways in the brain, it remains unclear what influence the inhibition of adenylylcyclase has on the inhibition of glutamate release. In cerebrocortical nerve terminals, the cannabinoid receptor agonist WIN55,212-2 reduced KCl-evoked glutamate release through a mechanism that restricted the rise of cytoplasmic free Ca2+, but not the changes in plasma membrane depolarization. These effects were consistent with the inhibition of Ca2+ channels. Furthermore, WIN55,212-2 reduced 4-aminopyridine (4AP) evoked glutamate release to a larger extent by modulating the behavior of both Ca2+ and K(+)-channels. The inhibition of 4AP-evoked release was associated with a decrease in cytoplasmic free Ca2+ and in plasma membrane depolarization that was reverted by the potassium channel blocker, tetraethylammonium. Interestingly, the reduction of KCl- and 4AP-evoked release by WIN55,212-2 was independent of adenylylcyclase activity and did not affect cAMP. Forskolin and the beta-adrenergic receptor increase intrasynaptosomal cAMP and promote a PKA-dependent tetrodotoxin (TTX)-sensitive increase in the spontaneous release of glutamate. These two responses were reduced by WIN55,212-2. However, the glutamate release induced by Sp-8-Br-cAMPS, which directly activated PKA without affecting cAMP, was also similarly reduced by WIN55,212-2. Hence, we conclude that the inhibition of glutamate release by WIN55,212-2 is unrelated to changes in cAMP and that the inhibition of release that a decrease in cAMP might produce is occluded by the activation of additional pathways such as the inhibition of Ca2+ channels and/or the activation of K(+)-channels that strongly depress glutamate release.

Animals↗
PubMed2003

Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells.

Many types of neurons release endocannabinoids from their dendrites in response to elevation of intracellular calcium levels. Endocannabinoids then activate presynaptic cannabinoid receptors, thereby inhibiting neurotransmitter release for tens of seconds. A crucial step in understanding the physiological role of this retrograde signaling is to determine its sensitivity to elevations of postsynaptic calcium. Here we determine and compare the calcium dependence of endocannabinoid-mediated retrograde inhibition at three types of synapses onto cerebellar Purkinje cells. Previous studies have shown that Purkinje cell depolarization results in endocannabinoid-mediated retrograde inhibition of synapses received from climbing fibers, granule cell parallel fibers, and inhibitory interneurons. Using several calcium indicators with a range of affinities, we performed a series of in situ and in vitro calibrations to quantify calcium levels in Purkinje cells. We found that postsynaptic calcium levels of approximately 15 microM are required for half-maximal retrograde inhibition at all of these synapses. In contrast, previous studies had suggested that endocannabinoid release could occur with slight elevations of calcium above resting levels, which implies that inhibition should be widespread and continuously modulated by subtle changes in intracellular calcium levels. However, our results indicate that such small changes in intracellular calcium are not sufficient to evoke endocannabinoid release. Instead, because of its high requirement for calcium, retrograde inhibition mediated by calcium-dependent endocannabinoid release from Purkinje cells will occur under more restricted conditions and with greater spatial localization than previously appreciated.

Animals↗
PubMed1998

Biphasic effects of anandamide.

Effects of the endogenous cannabimimetic anandamide were assessed over a wide dose range in a series of physiological and behavioral assays. These included the tetrad of tests in mice commonly used to assess cannabinoid-induced effects (motor activity, ring catalepsy, hypothermia, and analgesia tests), as well as a model for agonistic behavior on dyadic interactions of singly housed males with nonaggressive group-housed partners. Anandamide-induced effects on leukocyte phagocytosis were measured in a chemiluminescence assay. Results indicated that the higher doses tested (10-100 mg/kg) produced the well-known inhibitory effects in all of the above parameters as well as inhibition of phagocytosis. The lowest dose of anandamide tested (0.01 mg/kg) stimulated behavioral activities in the open field, on the ring and aggressive behavior in timid singly housed mice. This dose of 0.01 mg/kg, also stimulated phagocytosis. We suggest several possible mechanisms to explain these findings such as a differential involvement of a Gs and a Gi protein activated at low and high doses, respectively, allosteric modulation of the cannabinoid, and activation of presynaptic cannabinoid receptors by low doses of anandamide.

Aggression↗
PubMed2001

Ceramide: a new second messenger of cannabinoid action.

Cannabinoids, the active components of Cannabis sativa (marijuana), and their endogenous counterparts exert their effects by binding to specific G(i/o)-protein-coupled receptors that modulate adenylyl cyclase, ion channels and extracellular signal-regulated kinases. Recent research has shown that the CB(1) cannabinoid receptor is coupled to the generation of the lipid second messenger ceramide via two different pathways: sphingomyelin hydrolysis, and ceramide synthesis de novo. Ceramide in turn mediates cannabinoid-induced apoptosis, as shown by in vitro and in vivo studies. These findings provide a new perspective on how cannabinoids act, and raise exciting physiological and therapeutic questions.

Animals↗
PubMed2002

Endocannabinoid degradation, endotoxic shock and inflammation.

Endocannabinoids are an emerging class of lipid mediators, which include amides and esters of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors. Endotoxic shock is a potentially lethal failure of multiple organs that can be initiated by the inflammatory agent lipopolysaccharide (LPS), present in the outer membrane of gram-negative bacteria. LPS has been recently shown to stimulate the production of AEA in rat macrophages, and of 2-AG in rat platelets. The mechanism responsible for this effect has not been elucidated. On the other hand, mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play an essential role in inflammation. As yet, little is known about endogenous modulators and mechanisms of mast cell activation. Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH). We also report the ability of the HMC-1 human mast cells to degrade AEA through a nitric oxide-sensitive AMT and a FAAH. The role of endocannabinoids in HMC-1 degranulation is discussed as well. Taken together, it can be suggested that human lymphocytes and mast cells take part in regulating the peripheral endocannabinoid system, which can affect some activities of these cells.

Animals↗
PubMed2006

Cannabinoid modulation of electrically evoked pH and oxygen transients in the nucleus accumbens of awake rats.

Cannabinoid receptors have been implicated in the regulation of blood flow in the cerebral vasculature. Because the nucleus accumbens (NAc) shows high levels of central cannabinoid receptor 1 (CB1) expression we examined the effects of cannabinoids on the local transient alkaline shifts and increases in extracellular oxygen induced by electrical stimulation of the medial forebrain bundle (MFB) in conscious animals. These changes result from increases in cerebral blood flow (CBF) and metabolism in the NAc that are evoked by the stimulation. Oxygen and pH changes were monitored using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in the NAc of freely moving rats. Administration of the cannabinoid receptor agonist WIN55,212-2 potently inhibited extracellular oxygen and pH changes, an effect that was reversed and prevented by pre-treatment with the CB1 receptor antagonists SR141716A and AM251. The effects on pH following WIN55,212-2 were similar to those following nimodipine, a recognized vasodilator. When AM251 was injected alone, the amplitude of electrically evoked pH shifts was unaffected. Administration of AM404 and VDM11, endocannabinoid transport inhibitors, partially inhibited pH transients in a CB1 receptor-dependent manner. The present findings suggest that CB1 receptor activation modulates changes in two well-established indices of local blood flow and metabolism resulting from electrically evoked activation of ascending fibers. Although endogenous cannabinoid tone alone is not sufficient to modify these responses, uptake blockade demonstrates that the system has the potential to exert CB1-specific effects similar to those of full agonists.

Animals↗