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PubMed1995

Effects of anandamide on hepatic fatty acid metabolism.

Incubation of rat hepatocytes with anandamide (arachidonoylethanolamide) inhibited acetyl-CoA carboxylase activity and fatty acid synthesis de novo without affecting fatty acid synthase. This was concomitant to a decrease in the intracellular levels of malonyl-CoA. Likewise, anandamide depressed both cholesterol synthesis de novo and the incorporation of exogenous palmitate into triacylglycerols and phospholipids. On the other hand, anandamide stimulated in parallel both carnitine palmitoyltransferase I activity and ketogenesis from palmitate, though ketogenesis from octanoate was unaffected. The effects of anandamide on hepatic fatty acid synthesis and oxidation were: (a) mimicked by arachidonic acid, a product of anandamide breakdown by anandamide amidase; (b) prevented by phenylmethylsulfonyl fluoride, an inhibitor of anandamide amidase; and (c) not affected by bisindolylmaleimide, a specific inhibitor of protein kinase C. Furthermore, delta 9-tetrahydrocannabinol had no effect on any of the parameters determined, ruling out the possibility that the effects of anandamide on hepatic fatty acid metabolism are mediated by the peripheral cannabinoid receptor. The results thus indicate that anandamide might function as a carrier of arachidonic acid in the modulation of hepatic fatty metabolism.

Acetyl-CoA Carboxylase↗

PubMed1997

Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons.

Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predominately located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent (K(1/2) = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (omega-conotoxin-GVIA-sensitive) and P/Q-type (omega-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.

Animals↗

PubMed2004

The gastrointestinal pharmacology of cannabinoids: an update.

Recent work in the field of gastrointestinal pharmacology of cannabinoids has focused on enteric endocannabinoid and endovanilloid systems and their modulation in pathophysiological conditions. CB(1) receptor immunoreactivity was detected on enteric cholinergic neurones and vasoactive intestinal peptide-containing submucosal ganglion cells, on discrete nuclei of the dorsovagal complex (involved in emesis) and on central and peripheral vagal terminals, thus controlling gastroesophageal reflux and gastrointestinal motility. CB(1) receptor activation by endocannabinoids inhibited induced fluid secretion and inflammation in animal models and reduced proliferation of cultured colorectal cancer cells. Endocannabinoids also activate cannabinoid CB(2) and vanilloid VR1 receptors in certain inflammatory states. Thus endocannabinoid metabolism could provide a useful therapeutic target for many gastrointestinal disorders.

Animals↗

PubMed2003

Increase of morphine withdrawal in mice lacking A2a receptors and no changes in CB1/A2a double knockout mice.

CB1 cannabinoid and A2a adenosine receptors are highly expressed in the central nervous system where they modulate numerous physiological processes including emotional behaviour and the responses of several drugs of abuse. To investigate the contribution of these receptors in emotional-like responses and opioid dependence we have generated CB1/A2a double deficient mice (CB1-/-/A2a-/-). The spontaneous locomotor activity was reduced in double knockout as compared to wild-type animals. Emotional-like responses of CB1-/-/A2a-/- mice were investigated using the elevated plus-maze and the lit-dark box. Mutant mice exhibited an increased level of anxiety in both behavioural models. The specific involvement of CB1 and A2a receptors in morphine dependence was evaluated by using A2a knockout mice and CB1/A2a double mutant mice. The severity of naloxone-precipitated morphine withdrawal syndrome was significantly increased in the absence of A2a adenosine receptors whereas no modifications were observed in the double knockout mice. These results suggest that both receptors participate in the control of emotional behaviour and seem to play an opposite role in the expression of opioid physical dependence.

Animals↗

PubMed1996

Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects.

The CNS contains a putative cannabinergic neurotransmitter and an abundance of G-protein-coupled cannabinoid receptors. However, little is known about the function of this novel neurochemical system. Cannabinold agonists produce antinociception in behavioral tests, suggesting the possibility that this system serves in part to modulate pain sensitivity. To explore this possibility, the effects of the cannabinoid agonist WIN 55,212-2 on nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus were examined in urethane-anesthetized rats. After identification of a nociresponsive neuron, a computer-controlled device delivered graded pressure stimuli to the contralateral hindpaw. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, i.v.) suppressed noxious stimulus-evoked activity of VPL neurons in a dose-dependent and reversible manner. Noxious stimulus-evoked firing was affected more than spontaneous firing. These effects were apparently mediated by cannabinoid receptors, because the cannabinoid receptor-inactive enantiomer of the drug (WIN 55,212-3, 0.25 mg/kg) failed to alter the activity of this population of cells. Administration of morphine (0.5 mg/kg, i.v.) produced effects that were very similar to those produced by the cannabinoid. WIN 55,212-2 (0.25 mg/kg, i.v.) failed to alter the responses of non-nociceptive low-threshold mechanosensitive neurons in the VPL WIN 55,212-2 produced antinociceptive effects with a potency and time course similar to that observed in the electrophysiological experiments, despite the differences in the anesthetic states of the animals used in these experiments. The antinociceptive and electrophysiological effects on VPL neurons outlasted the motor effects of the drug. Furthermore, the changes in nociceptive responding could not be attributed to changes in skin temperature. Taken together, these findings suggest that cannabinoids decrease nociceptive neurotransmission at the level of the thalamus and that one function of endogenous cannabinoids may be to modulate pain sensitivity.

Analgesics↗

PubMed2004

Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide.

The CB1 cannabinoid receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant; SR141716A), and oleoylethanolamide (OEA) are known to reduce food consumption, by, at least partially, a peripheral regulation of feeding. The effects of systemic SR141716A or OEA (5 mg/kg) administrations on food consumption in 24 h food-deprived and fed rats were investigated. In fasted rats, SR141716A and OEA produced an inhibition in food intake measurable the first 20 min following injection. The increase in ghrelin levels observed in the vehicle-injected rats was abolished in animals receiving OEA and significantly reduced with SR141716A. Neither OEA nor SR141716A modified glucagon-like peptide-1 (7-36) amide portal levels 20 min after the administration. In fed rats, plasma ghrelin levels of SR141716A- and OEA-treated rats were 35% lower as compared with those of the vehicle-injected rats. These results show an influence of cannabinoid agents on circulating ghrelin levels and suggest that their short-term action on appetite seems to be in accordance with the control of secretion of gastrointestinal orexigenic peptides, mainly expressed in the upper part of the gastrointestinal tract.

Animals↗

PubMed2000

The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt.

Cannabinoids exert most of their effects in the central nervous system through the CB(1) cannabinoid receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylate cyclase, modulation of ion channels and activation of extracellular-signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB(1) receptor cDNA we show here that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of protein kinase B/Akt (PKB). This effect of THC was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoids CP-55940 and HU-210, and was prevented by the selective CB(1) antagonist SR141716. Pertussis toxin and wortmannin blocked the CB(1) receptor-evoked activation of PKB, pointing to the sequential involvement of a G(i)/G(o) protein and phosphoinositide 3'-kinase. The functionality of the cannabinoid-induced stimulation of PKB was proved by the increased phosphorylation of glycogen synthase kinase-3 serine 21 observed in cannabinoid-treated cells and its prevention by SR141716 and wortmannin. Cannabinoids activated PKB in the human astrocytoma cell line U373 MG, which expresses the CB(1) receptor, but not in the human promyelocytic cell line HL-60, which expresses the CB(2) receptor. Data indicate that activation of PKB may be responsible for some of the effects of cannabinoids in cells expressing the CB(1) receptor.

Adenylate Cyclase Toxin↗

PubMed2003

The cannabinoid receptor antagonist SR 141716 attenuates overfeeding induced by systemic or intracranial morphine.

RATIONALE: Considerable interplay exists between the brain's opioid and cannabinoid systems. These systems are both involved in the control of appetite and research supports the notion that the opioid system modulates the role of the cannabinoid system on appetite. However, the ability of the cannabinoid system to modulate the opioid system's control over appetite has not been well studied. OBJECTIVES: The present study examined the role of cannabinoid CB(1) receptors in the control of opioid-induced feeding, and sought to identify specific brain regions underlying this role. METHODS: After being habituated to the test environment and injection procedure, sated rats were injected with the cannabinoid CB(1) receptor antagonist SR 141716 (0.03-3.0 mg/kg, IP). Thirty minutes later, morphine or its vehicle were administered systemically (2.5 mg/kg SC, experiments 1 and 2) or intracranially into the nucleus accumbens (nAcc, experiment 3) or paraventricular nucleus of the hypothalamus (PVN, experiment 4). Food intake and locomotor activity was then recorded for 120 min. RESULTS: A significant increase in food intake was observed following systemic and intracranial (10 nmol) application of morphine in all experiments. SR 141716 suppressed systemic and intra-PVN morphine induced feeding (experiments 2 and 4), but did not attenuate food intake induced by intra-nAcc application of morphine (experiment 3). CONCLUSIONS: Because SR 141716 had no effect on intra-nAcc morphine-stimulated feeding, it would appear that cannabinoid receptors do not modify opioid-mediated hedonic responses to food. Rather, we conclude that cannabinoid CB(1) receptor blockade may suppress opioid-induced feeding by stimulating the release of satiety-related peptides within the hypothalamus. Further, because SR 141716 did not block morphine induced locomotor activity, the observed effects on feeding do not appear to be due to a non-specific reduction in motivated behaviour.

Animals↗

PubMed2001

Modulation of CB1 mRNA upon activation of murine splenocytes.

There is significant evidence that cannabinoids have the ability to exert immunomodulatory effects. The identification of cannabinoid receptors in immune tissues has therefore led to questions about whether these immunomodulatory effects occur via these cannabinoid receptors. The cannabinoid receptor 1 (CB 1), although expressed primarily in the brain, is also expressed in lower amounts in peripheral tissues. Of interest to us is the fact that CB1 is expressed in immune tissues such as spleen, albeit at lower levels than the peripheral cannabinoid receptor, CB2. To examine the function of CBI in immune cells, activation experiments were performed using different stimuli e.g., anti-CD3, phorbol 12-myristate 13-acetate (PMA)/Ionomycin (Io), and PMA/Io + IL-2. Whole spleen cells were cultured in the presence of different stimuli for 0, 2, 4, and 24 hours, harvested at each time point, RNA isolated, and RT-PCR performed. FACS analysis was also performed using CD69 (an early activation marker) to determine whether cells were actually being activated. Results from anti-CD3 stimulation indicated a decrease in CB1 mRNA expression following activation. CB1 mRNA expression in murine splenocytes that were stimulated with PMA/Io in the presence or absence of IL-2 was also modulated. Expression of the message was enhanced upon stimulation with PMA/Io and PMA/Io + IL-2, however, stimulation with PMA/Io + IL-2 led to a stronger increase within 2 to 4 hours with CB1 returning to at or below baseline levels by 24 hours. Expression of CD69 was detected in all stimulated samples thereby indicating that the splenocytes were becoming activated. In summary, anti-CD3 stimulation appeared to decrease CB1 mRNA expression while PMA/Io + IL-2 stimulation significantly increased CB1 mRNA expression. These results demonstrate that the expression of CB1 mRNA is modulated upon cellular activation and that this modulation is dependent on the stimulus that is used.

Animals↗

PubMed1996

N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation.

Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides ('ALIAmides') represent novel therapeutic agents useful in the management of inflammatory disease conditions.

Amides↗

PubMed2002

Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum.

Cross-talk between cannabinoid CB1 and serotonin 5-HT receptors in rat cerebellar membranes was investigated using radioligand binding. In competition against the CB1 antagonist, [3 H]SR141716A, the agonist, WIN 55,212-2 yielded a biphasic isotherm. The majority of binding was to a high-affinity state that was significantly reduced by the GTP analogue, Gpp(NH)p. Interestingly, 5-HT enhanced the high-affinity binding constant of WIN 55,212-2 while attenuating the proportion of high-affinity binding. 5-HT also significantly reduced the proportion of high-affinity binding of the cannabinoid agonist, HU 210, but had no effect on the agonist, CP 55,940. The effect of 5-HT on WIN 55,212-2 binding was inhibited by the 5-HT2 receptor antagonist ritanserin as well as Gpp(NH)p, suggesting a dependence on the 5-HT2 receptor and on G protein-receptor interactions, respectively. Subsequent [3 H]WIN 55,212-2 dissociation kinetic experiments revealed that 5-HT promoted a slower-dissociating species of radiolabelled agonist-receptor complex. Our findings support a membrane-delimited cross-talk between two G protein-coupled receptors that are co-localized in certain cells of the central nervous system. Intriguingly, the cannabinoid agonist dependence of the 5-HT modulatory effect suggests that agonist-specific conformations of the CB1 receptor may also be important in determining the extent of this cross-talk.

Animals↗

PubMed1993

delta 9-Tetrahydrocannabinol affects mesolimbic dopaminergic activity in the female rat brain: interactions with estrogens.

In this work, we studied the possible estrogenic modulation of the effects of delta 9-tetrahydrocannabinol (THC) on mesolimbic dopaminergic activity, by examining the effects of an acute dose of this cannabinoid: (i) during the estrous cycle; (ii) after ovariectomy, chronic estrogen-replacement and tamoxifen (TMX)-induced blockade of estrogenic receptors; and (iii) combined with a single and physiological injection of estradiol to ovariectomized rats. THC significantly decreased the density of D 1 dopaminergic receptors and non-significantly increased the L-3,4-dihydroxyphenylacetic acid (DOPAC) content in the limbic forebrain of ovariectomized rats chronically replaced with estrogens. The decrease in D 1 receptors was also produced by TMX, whereas the coadministration of both THC and TMX did not lead to a major decrease. In addition to the trend of THC increasing DOPAC content, this cannabinoid was also able to increase the ratio between DOPAC and dopamine, although this last effect only occurred after coadministration of THC and TMX, which had been ineffective administered individually. All these effects were not seen when THC was administered to normal cycling rats during each phase of estrous cycle and to ovariectomized rats without chronic estrogen replacement or only submitted to a single and acute dose of estradiol. This observation might be related to the fact that the density of limbic cannabinoid receptors increased in chronic estrogen-replaced ovariectomized rats versus normal cycling, ovariectomized or acutely estrogen-treated ovariectomized rats. Interestingly, THC administration in ovariectomized rats was followed by a slight, although significant, increase in tyrosine hydroxylase activity, which was also observed after coadministration of THC with a short-time and acute dose of estradiol. In summary, THC stimulated the presynaptic activity of mesolimbic dopaminergic neurons, but accompanied by a decrease in their postsynaptic sensitivity. These effects did not appear in normal cycling rats being only evident after ovariectomy and chronic estrogen replacement, which might be related to changes in binding characteristics of cannabinoid receptors in this area. Moreover, some of them appeared after TMX-induced blockade of estrogenic cytosolic receptors, which likely suggests the existence of a certain estrogenic modulation of the actions of THC on mesolimbic neurons. On the contrary, coadministration of THC with a single and shortly tested dose of estradiol was always ineffective in modifying THC effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells.

Human leukocytes express cannabinoid (CB) receptors, suggesting a role for both endogenous ligands and Delta 9-tetrahydrocannabinol (THC) as immune modulators. To evaluate this, human T cells were stimulated with allogeneic dendritic cells (DC) in the presence or absence of THC (0.625-5 microg/ml). THC suppressed T cell proliferation, inhibited the production of interferon-gamma and shifted the balance of T helper 1 (Th1)/T helper 2 (Th2) cytokines. Intracellular cytokine staining demonstrated that THC reduced both the percentage and mean fluorescence intensity of activated T cells capable of producing interferon-gamma, with variable effects on the number of T cells capable of producing interleukin-4. Exposure to THC also decreased steady-state levels of mRNA encoding for Th1 cytokines, while increasing mRNA levels for Th2 cytokines. The CB2 receptor antagonist, SR144528, abrogated the majority of these effects. We conclude that cannabinoids have the potential to regulate the activation and balance of human Th1/Th2 cells by a CB2 receptor-dependent pathway.

Cannabinoids↗

PubMed1999

Involvement of the carboxyl terminus of the third intracellular loop of the cannabinoid CB1 receptor in constitutive activation of Gs.

The human cannabinoid receptor CB1 functionally couples primarily to Gi-, but also to Gs-mediated pathways to modulate intracellular cyclic AMP (cAMP) levels. To probe the features of the receptor that may be involved in promoting interactions with one G protein type over another, we generated the L341A/A342L mutant CB1 receptor. The double mutation involved the swap in position of two adjacent residues in the carboxyl-terminal segment of the third intracellular loop of CB1. This resulted in partial constitutive activation of the receptor and an agonist-independent enhancement in cAMP levels. Characterization following treatment with either pertussis or cholera toxin indicated that the constitutive activity is selective for a Gs- and not a Gi-mediated pathway. Treatment with the CB1-specific inverse agonist SR141716A inhibited the basal accumulation of cAMP in the presence of pertussis toxin, establishing that the effect is CB1 mediated. The binding of the agonist CP-55,940 to the L341A/A342L receptor was not markedly different from that for the wild-type receptor despite the constitutive Gs activity. This may reflect a preference of this ligand for an activated receptor state associated with the Gi coupling form and underscores the potential for developing therapeutics that selectively activate one pathway over another.

Animals↗

PubMed2006

Estrogen differentially modulates the cannabinoid- induced presynaptic inhibition of amino acid neurotransmission in proopiomelanocortin neurons of the arcuate nucleus.

The present study sought to determine whether cannabinoids inhibit glutamatergic and GABAergic synaptic input onto neurons of the hypothalamic arcuate nucleus (ARC), and whether estrogen modulates this process. Whole-cell patch clamp recordings were performed in hypothalamic slices prepared from ovariectomized female guinea pigs. CB1 receptor activation reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation that were sensitive to ionotropic glutamate receptor antagonists. The CB1 receptor antagonist AM251 increased evoked EPSC (eEPSC) amplitude, and reversed the agonist-induced decrease. CB1 receptor activation similarly decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). The cannabinoid-induced reduction in eEPSC and eIPSC amplitude correlated with a decrease in the frequency of miniature EPSCs (mEPSCs) and IPSCs (mIPSCs) that were abolished by ionotropic glutamate and GABA(A) receptor antagonists, respectively. AM251 increased mEPSC frequency, and antagonized the agonist-induced decrease. Compared to neurons obtained from vehicle-treated controls, estradiol benzoate (25 mug; s.c.) given 24 h prior to experimentation increased mEPSC frequency, and markedly decreased the potency of CB1 receptor agonists to decrease mEPSC frequency. Conversely, the steroid potentiated the cannabinoid-induced decrease in mIPSC frequency. These effects were observed in neurons subsequently identified as proopiomelanocortin (POMC) neurons. These data reveal that ARC neurons, including POMC neurons, receive glutamatergic and GABAergic synaptic inputs that are presynaptically inhibited by cannabinoids, and differentially modulated by estrogen. These opposing effects of estrogen on the cannabinoid regulation of amino acid neurotransmission excite POMC neurons, and lend additional insight into the mechanisms underlying estrogen-induced anorexia and negative feedback of the reproductive axis.

Animals↗

PubMed2002

Effect of cannabinoids on neural transmission in rat gastric fundus.

The purpose of this study was to examine the possible role of cannabinoids on the neuromuscular function of rat gastric fundus. In addition to possible direct effects on smooth muscle, the influence of cannabinoids on contractile (cholinergic) and relaxant (non-adrenergic, non-cholinergic (NANC)) neural innervation of the rat gastric fundus was investigated in vitro. Neither anandamide (an endogenous cannabinoid receptor agonist) nor Win 55,212-2 and methanandamide (synthetic cannabinoid receptor agonists) nor AM 630 (a cannabinoid receptor antagonist) showed any effect on smooth muscle activity at baseline or after precontraction with 5-hydroxytryptamine (5-HT; 10(-7) M). Electrical field stimulation (EFS) of the smooth muscle preparation (40 V; 5 Hz) caused cholinergically mediated twitch contractions that were abolished by atropine (10(-6) M) or tetrodotoxin (TTX; 10(-6) M). Anandamide and Win 55,212-2 reduced these twitch contractions in a concentration-dependent manner, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When NANC relaxant neural responses (presence of atropine (10(-6) M) and guanethidine (10(-6) M)) were induced by EFS, the cannabinoid receptor agonists anandamide and Win 55,212-2 reduced the relaxant response, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When given alone AM 630 caused an increase in the EFS-induced relaxant response. The presence of CB1 and CB2 cannabinoid receptor mRNA within the rat stomach was demonstrated by reverse transcription polymerase chain reaction (RT-PCR). The results of this study indicate that cannabinoids modulate excitatory cholinergic and inhibitory NANC neurotransmission in the rat gastric fundus. Endogenous cannabinoids may play a physiological role only in NANC inhibitory transmission, as AM 630 did not modify the electrically induced cholinergic contraction. The involved cannabinoid receptors are most likely located on neuronal structures. The present study also provides evidence that more than one receptor type is involved.

Animals↗

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↗