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PubMed2006

[Endocannabinoids as molecular instruments of health promotion].

UNLABELLED: Endocannabinoids may be a physiological model for our self-healin capacities, since they are part of a complex system of natural auto-regulatory processes. This system has been examined via neurobiology, where the experimental invertebrate model is useful. Endocannabinoids, as well as endogenous morphine, activate constitutive nitric oxide (NO) release, which exerts a variety of positive physiological effects. By doing so, we surmise endogenous stress reduction emerges. Therefore, in the context of endocannabinoid auto-regulation, it seems adequate to speak of "health promotion on a molecular level". The convergence of endogenous auto-regulation on NO pathways critically relies upon common or overlapping neurobiological molecular components, as they are represented by limbic reward and motivation mechanisms. To our knowledge, endogenous auto-regulation--involving deep limbic brain activities--plays a crucial role in successful modern strategies of applied and integrative health promotion. More research, however, is necessary before the different aspects of neurobiological science and clinical medicine in the field of prevention may be integrated extensively and with profound reason. CONCLUSIONS: Successful preventive programs, such as integrative medical stress management, include auto-regulative mechanisms on the physiological level. This leads to an interesting research potential, particularly when one considers the long-term effects of applied health promotion and its coupling to motivational neurobiological phenomena.

Amino Acid Sequence↗
PubMed1992

Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation.

Extensive behavioral and biochemical characterization of cannabinoid-mediated effects on the central nervous system has revealed at least three lines of evidence supporting the role of a putative guanine nucleotide-binding protein-coupled cannabinoid receptor for cannabimimetic effects, (i) stereoselectivity, (ii) inhibition of the adenylate cyclase/cAMP second messenger system, and (iii) radioligand-binding studies with the synthetic cannabinoid [3H]CP-55,940 indicating a high degree of specific binding to brain tissue preparations. Based on recent findings from our laboratory demonstrating that delta 9-tetrahydrocannabinol markedly inhibited forskolin-stimulated cAMP accumulation in mouse spleen cells, the presence of a guanine nucleotide-binding protein-coupled cannabinoid receptor associated with mouse spleen cells and its functional role in immune modulation were investigated. In the present studies, stereoselective immune modulation was observed with the synthetic bicyclic cannabinoid (-)-CP-55,940 versus (+) CP-56,667 and with 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl, (-)-HU-210 versus (+)-HU-211. In both cases, the (-)-enantiomer demonstrated greater immunoinhibitory potency than the (+)-isomer, as measured by the in vitro sheep red blood cell antibody-forming cell response. Radioligand binding studies produced a saturation isotherm exhibiting approximately 45-65% specific binding to mouse spleen cells. Scatchard analysis demonstrated a single binding site on spleen cells, possessing a Kd of 910 pM and a Bmax of approximately 1000 receptors/spleen cell. RNA polymerase chain reaction of isolated splenic RNA using specific primers for the cannabinoid receptor resulted in the amplification of a 854-kilobase predicted product that hybridized with cannabinoid receptor cDNA, demonstrating the presence of cannabinoid receptor mRNA in mouse spleen. Together, these findings strongly support the role of a cannabinoid receptor in immune modulation by cannabimimetic agents.

Animals↗
PubMed2006

Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.

The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/--derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.

Adrenocorticotropic Hormone↗
PubMed2003

Cannabinoid modulation of peripheral autonomic and sensory neurotransmission.

Cannabinoids are cell membrane-derived signalling molecules that are released from nerves, blood cells and endothelial cells, and have diverse biological effects. They act at two distinct types of G-protein-coupled receptors, cannabinoid CB(1) and CB(2) receptors. Cannabinoid CB(1) receptors are highly localised in the central nervous system and are also found in some peripheral tissues, and cannabinoid CB(2) receptors are found outside the central nervous system, in particular in association with immune tissues. Novel actions of cannabinoids at non-CB(1) non-CB(2) cannabinoid-like receptors and vanilloid VR1 receptors have also recently been described. There is growing evidence that, among other roles, cannabinoids can act at prejunctional sites to modulate peripheral autonomic and sensory neurotransmission, and the present article is aimed at providing an overview of this. Inhibitory cannabinoid CB(1) receptors are expressed on the peripheral terminals of autonomic and sensory nerves. The role of cannabinoid receptor ligands in modulation of sensory neurotransmission is complex, as certain of these (anandamide, an "endocannabinoid", and N-arachidonoyl-dopamine, an "endovanilloid") also activate vanilloid VR1 receptors (coexpressed with cannabinoid CB(1) receptors), which excites sensory nerves and causes a release of sensory neurotransmitter. The fact that the activities of anandamide and N-arachidonoyl-dopamine span two distinct receptor families raises important questions about cannabinoid/vanilloid nomenclature, and as both compounds are structurally related to the archetypal vanilloid capsaicin, all three are arguably members of the same family of signalling molecules. Anandamide is released from nerves, but unlike classical neurotransmitters, it is not stored in and released from nerve vesicles, but is released on demand from the nerve cell membrane. In the central nervous system, cannabinoids function as retrograde signalling molecules, inhibiting via presynaptic cannabinoid CB(1) receptors the release of classical transmitter following release from the postsynaptic cell. At the neuroeffector junction, it is more likely that cannabinoids are released from prejunctional sites, as the neuroeffector junction is wide in some peripheral tissues and cannabinoids are rapidly taken up and inactivated. Understanding the actions of cannabinoids as modulators of peripheral neurotransmission is relevant to a variety of biological systems and possibly their disorders.

Animals↗
PubMed2003

R+-methanandamide inhibits tracheal response to endogenously released acetylcholine via capsazepine-sensitive receptors.

The effects of cannabinoid drugs on the cholinergic response evoked by electrical field stimulation (0.2 ms pulse width, 20 V amplitude, 10 Hz, 7.5 s train duration) in guinea-pig tracheal preparations were investigated. The stable analogue of the endocannabinoid anandamide, R(+)-methanandamide (10(-7)-10(-4) M), produced a dose-dependent inhibition (up to 27+/-5% of control) of electrical field stimulation-mediated atropine-sensitive response. This effect was not blocked by the selective cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide hydrochloride (SR 141716A; 10(-6) M), and was not reproduced with the cannabinoid CB(1)/CB(2) receptor agonist R(+)-[2,3-dihydro-5-methyl-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate) (WIN 55,212-2; 10(-8)-10(-5) M) or the cannabinoid CB(2) receptor selective agonist 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015; 10(-8)-10(-5) M); it was, on the contrary, antagonized by the vanilloid antagonist 2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-2 benzazepine (capsazepine; 10(-6) M). At the postjunctional level, neither R(+)-methanandamide nor WIN 55,212-2 nor JWH-015 did affect tracheal contractions induced by exogenous acetylcholine (10(-6) M). An inhibitory vanilloid receptor-mediated effect on the cholinergic response evoked by electrical stimulation was confirmed with the vanilloid agonist capsaicin, at doses (3-6 x 10(-8) M) which poorly influenced the basal smooth muscle tone of trachea. In conclusion, our data indicate that in guinea-pig trachea (a) neither CB(1) nor CB(2) cannabinoid receptor-mediated modulation of acetylcholine release occurs; (b) vanilloid VR1-like receptors appear involved in R(+)-methanandamide inhibitory activity on the cholinergic response to electrical field stimulation.

Acetylcholine↗
PubMed2000

Stimulation of cannabinoid receptor agonist 2-arachidonylglycerol by chronic ethanol and its modulation by specific neuromodulators in cerebellar granule neurons.

In an earlier study, we reported that chronic ethanol (EtOH) stimulates the formation of anandamide in human SK-N-SH cells. In the present study, we investigated the effect of chronic EtOH on the formation of yet another cannabinoid receptor (CB1) agonist, 2-arachidonylglycerol (2-AG), in cerebellar granule neurons (CGNs). The formation of 2-[(3)H]AG without any stimulation was more pronounced in the older cultures than in younger cultures. Exposure of CGNs to EtOH led to a significant increase in the level of 2-[(3)H]AG (P<0.05). Incubation with the anandamidehydrolase inhibitor phenylmethylsulfonyl fluoride and EtOH did result in an additive increase in 2-[(3)H]AG, but did not with E-6-(bromomethylene)tetrahydro-3-(1-naphthelenyl)-2H-pyran-2-one. The formation of 2-[(3)H]AG was enhanced by ionomycin in both the control and EtOH-exposed CGNs, and the ionomycin-stimulated 2-[(3)H]AG synthesis was inhibited by the intracellular chelating agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Further, glutamate increased the formation of 2-[(3)H]AG only in control CGNs. MK-801 inhibited the EtOH-induced 2-[(3)H]AG synthesis, suggesting the participation of intracellular Ca(2+) in EtOH-induced 2-[(3)H]AG synthesis. The dopamine receptor (D2) agonist did not modify the 2-AG synthesis in either the control or EtOH-exposed CGNs. However, the D2 receptor antagonist inhibited the EtOH-induced formation of 2-[(3)H]AG. The EtOH-induced 2-[(3)H]AG formation was inhibited by SR141716A and pertussis toxin, suggesting the CB1 receptor- and Gi/o-protein-mediated regulation of 2-AG. The observed increase in 2-AG level in CGNs is possibly a mechanism for neuronal adaptation to the continuous presence of EtOH. These findings indicate that some of the pharmacological actions of EtOH may involve alterations in the endocannabinoid signaling system.

Animals↗
PubMed2001

Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes.

Lipopolysaccharide (LPS) increases the levels of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine, AEA) in rat macrophages, but the mechanism responsible for this effect has not been elucidated. Here we demonstrate that LPS enhances the levels of AEA (fourfold over controls) also in human lymphocytes. We show that in these cells LPS inhibits the activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH), by downregulating the gene expression at transcriptional level. Lymphocytes have also a specific AEA transporter and a functional CB1 cannabinoid receptor, which were not modulated by LPS. The effect of this endotoxin on FAAH was not mediated by AEA-induced activation of cannabinoid receptors. Conversely, the stimulatory action of LPS on AEA levels might be due to inhibition of FAAH, as suggested by the observation that an increase of AEA amounts was also induced by an irreversible FAAH inhibitor. These results suggest that lymphocytes take part in regulating the peripheral endocannabinoid system and endocannabinoid homeostasis.

Amidohydrolases↗
PubMed2005

The endocannabinoid system: a drug discovery perspective.

The endocannabinoids are lipid messengers that engage the same cell surface receptors targeted by delta9-tetrahydrocannabinol, the active component of marijuana. They are produced by cells in the brain and other tissues and combine with two subtypes of G protein-coupled cannabinoid receptors, CB1 and CB2. Their ability to modulate a variety of pathophysiological processes, including appetite, pain and mood, provides unique opportunities for drug discovery. Three such opportunities are discussed here: reduction of body weight through blockade of CB1 receptors, alleviation of pain through activation of extracerebral cannabinoid receptors, and modulation of pain and anxiety through inhibition of endocannabinoid degradation.

Animals↗
PubMed2006

In vivo neurochemical effects induced by changes in endocannabinoid neurotransmission.

Neurotropic effects of endo- and exo-cannabinoids are largely caused by their effects on classical neurotransmitter signaling. Pharmacological and molecular tools have been used to selectively target the endocannabinoid system. Endocannabinoids mostly act as retrograde messengers and, upon release from postsynaptic neurons, they modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Generally, increased and decreased endocannabinoid neurotransmission results in decreases and increases in neurotransmitter release, respectively. However, net effects are often pleiotropic, probably owing to the level of regional endogenous tone, transsynaptic mechanisms and cumulative actions. Changes in classical neurotransmitter function can, in turn, modulate endocannabinoid signaling. Importantly, the endocannabinoid system can be altered in response to physiological and pathogenic events and targeted for therapeutic intervention.

Animals↗
PubMed2006

Cannabinoid receptors in atherosclerosis.

PURPOSE OF REVIEW: Recent findings suggesting that cannabinoid receptors are potential targets for the treatment of atherosclerosis are reviewed. RECENT FINDINGS: Cannabinoids, such as Delta9-tetrahydrocannabinol, the major psychoactive compound of marijuana, their synthetic analogs and endogenous cannabinoid ligands, produce their biological effects by interacting with specific receptors. In the apolipoprotein E knockout mouse model of atherosclerosis, Delta9-tetrahydrocannabinol was shown to inhibit disease progression through pleiotropic effects on inflammatory cells. Blocking of cannabinoid receptor CB2, the main cannabinoid receptor expressed on immune cells, abolished the observed effects. The development of novel cannabinoid receptor ligands that selectively target CB2 receptors or pharmacological modulation of the endocannabinoid system might offer novel therapeutic strategies in the treatment of atherosclerosis. Several reports demonstrating an implication of the endocannabinoid system in different inflammatory conditions support this hypothesis. SUMMARY: The immunomodulatory capacity of cannabinoids is now well established and suggests a broad therapeutic potential of cannabinoids for a variety of conditions, including atherosclerosis. New strategies based on nonpsychotropic cannabinoid receptor ligands or compounds modulating endocannabinoid synthesis or stability might solve the problem of the unwanted side effects associated with cannabinoid administration.

Animals↗
PubMed2006

Modulation of paraoxon toxicity by the cannabinoid receptor agonist WIN 55,212-2.

Cannabinoids can reduce the pre-synaptic release of acetylcholine and other neurotransmitters in the mammalian brain through a retrograde signaling pathway. Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase and thereby increasing synaptic acetylcholine levels. Several studies suggest that some organophosphorus toxicants can potentially modify cannabinergic signaling by direct binding to cannabinoid receptors and inhibition of enzymes responsible for cannabinoid degradation (i.e., fatty acid amide hydrolase and monoacylglycerol lipase). We hypothesized that exposure to the cannabinoid receptor agonist WIN 55,212-2 (WIN) could alter the acute toxicity of the prototype anticholinesterase, paraoxon. In vitro, paraoxon inhibited hippocampal cholinesterase and fatty acid amide hydrolase activities, and displaced specific binding to the cannabinoid receptor ligand ([(3)H]CP 55,940) in a concentration-dependent manner. WIN (0.5, 1.5 or 5mg/kg/day) had a complex dose-related effect on locomotor activity when evaluated for 2h after either the first or last of seven daily exposures, and significantly decreased hippocampal CB1 binding following repeated dosing. Four hours after dosing, paraoxon (0.4 mg/kg, sc) elicited classical signs of cholinergic toxicity and significantly reduced hippocampal cholinesterase and fatty acid amide hydrolase activities as well as [(3)H]CP 55,940 binding. A single exposure to WIN (1.5 mg/kg) significantly reduced involuntary movements and SLUD signs following acute paraoxon exposure (0.4 and 0.6 mg/kg, sc). In contrast, when rats were challenged with paraoxon (0.4 mg/kg) after the seventh daily exposure to WIN (1.5mg/kg/day), involuntary movements were significantly increased at later timepoints, while SLUD signs were unaffected. These results suggest that acute and repeated exposure to cannabinoid agonists may differentially modify acute cholinergic toxicity, possibly through modulation of acetylcholine release and adaptation in cannabinergic signaling associated with repeated cannabinoid exposures.

Amidohydrolases↗
PubMedDate not supplied

Endocannabinoids in the immune system and cancer.

The present review focuses on the role of the endogenous cannabinoid system in the modulation of immune response and control of cancer cell proliferation. The involvement of cannabinoid receptors, endogenous ligands and enzymes for their biosynthesis and degradation, as well as of cannabinoid receptor-independent events is discussed. The picture arising from the recent literature appears very complex, indicating that the effects elicited by the stimulation of the endocannabinoid system are strictly dependent on the specific compounds and cell types considered. Both the endocannabinoid anandamide and its congener palmitoylethanolamide, exert a negative action in the onset of a variety of parameters of the immune response. However, 2-arachidonoylglycerol appears to be the true endogenous ligand for peripheral cannabinoid receptors, although its action as an immunomodulatory molecule requires further characterization. Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors, namely the VR1 class of vanilloid receptors. In conclusion, further investigations are needed to elucidate the function of endocannabinoids as immunosuppressant and antiproliferative/cytotoxic agents. The experimental evidence reviewed in this article argues in favor of the therapeutic potential of these compounds in immune disorders and cancer.

Animals↗
PubMedDate not supplied

Biphasic modulation of voltage-dependent currents of retinal cones by cannabinoid CB1 receptor agonist WIN 55212-2.

Endogenous cannabinoids modulate neurotransmitter action and release in the brain. The effects are exerted on membrane permeability to Ca2+ and K+ via protein kinase A (PKA). Cannabinoid CB1 receptors are present at the synaptic terminals of cones in goldfish retina. We investigated the effects of CB1 receptor agonist WIN 55212-2 on voltage-gated currents of goldfish cones. Whole-cell currents were recorded with conventional-patch-clamp methods in goldfish retinal slices. Depolarizing pulses elicited inward I(Ca) and I(outward) that contained several components: I(K), I(A), and I(Cl). WIN 55212-2 (< 1 microM) enhanced I(K), I(Cl), and I(Ca), while at > 1 microM, I(K), I(Cl), and I(Ca) were suppressed. The voltage-activation ranges of these currents were not affected. All effects of WIN 55212-2 were blocked by the CB1 receptor antagonist SR 141716A as well as the PKA inhibitor Wiptide. The enhancing effect of WIN 55212-2 was blocked selectively by 0.5 nM cholera toxin and the suppressive effect was blocked by pertussis toxin. The results obtained from long and short single cones and double cones were basically the same. Cannabinoids, via CB1 receptor and PKA, dose-dependently enhance I(K), I(Cl), and I(Ca) by a pertussis-toxin insensitive Gs and suppress these currents by a pertussis-toxin sensitive Gi/o in cones. This biphasic regulation may provide a mechanism to inhibit constitutively active CB1 receptors in the presence of a high concentration of ligand. Thus, neuronal excitability appears to be affected by cannabinoids at the first synapse of the visual pathway and could account for some of the visual effects of marijuana.

Animals↗
PubMed1987

Modulation of rat brain opioid receptors by cannabinoids.

The interaction of delta 9-tetrahydrocannabinol (delta 9-THC) and related cannabinoids with opioid receptors of neuronal membranes has been investigated. Treatment of membranes with delta 9-THC consistently decreased specific in vitro binding of [3H]dihydromorphine (mu opioid) in a dose-dependent fashion. Similar dose-dependent changes were elicited by cannabidiol and (+/-)-hexahydrocannabinol. Equilibrium binding studies in which brain membranes were titrated with [3H]dihydromorphine in the presence of delta 9-THC demonstrated that the decrease in [3H]dihydromorphine binding is due to a reduction in the number of binding sites, with no significant alteration in receptor affinity. This result suggests that the interaction of delta 9-THC with opioid receptors is a noncompetitive one. Delta 9-THC also inhibited the binding of the delta opioid [3H]D-Pen2, D-Pen5-enkephalin and the opioid antagonist [3H]naloxone (Ki = 16 and 19 microM, respectively) but failed to inhibit the binding of the kappa opioid [3H]ethylketocyclazocine (after suppression of mu and delta receptor binding), the phencyclidine analog [3H]N-(1-[2-theinyl]cyclohexyl)piperidine, the dopamine antagonist [3H]spiroperidol or the muscarinic antagonist [3H]quinuclidinyl benzilate. Moreover, delta 9-THC inhibited the binding of [3H]etorphine (potent opioid agonist) to solubilized, partially purified opioid receptors with a Ki value similar to that observed for the membrane-bound receptors. This finding indicates that the allosteric modulation of the opioid receptor by delta 9-THC is the result of a direct interaction with the receptor protein or with a specific protein-lipid complex and not merely the result of a perturbation of the lipid bilayer of the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Functions of cannabinoid receptors in the hippocampus.

Marijuana smoking is recognised to impair human cognition and learning, but the mechanisms by which this occurs are not well characterised. This article focuses exclusively on the hippocampus to review the effects of cannabinoids on hippocampal function and evaluate the evidence that hippocampal cannabinoid receptors play a role in learning and formation of memory. Activation of cannabinoid receptors inhibits release of a variety of neurotransmitters, and modulates a number of intrinsic membrane conductances. Suppression of inhibitory GABAergic synaptic transmission has been repeatedly described, but whether there is also control of excitatory glutamatergic transmission is more controversial. The recognition that the commonly used WIN55,212-2 also acts via non-cannabinoid receptors may help resolve this issue. The involvement of endocannabinoids in depolarisation induced suppression of inhibition (DSI) and the demonstration that activation of metabotropic glutamate receptors can stimulate endocannabinoid release have provided the first insights into the physiological roles of the cannabinoids. Cannabinoids have consistently been reported to inhibit high frequency stimulation induced synaptic long-term potentiation but the experimental design of most behavioural experiments have meant it is not possible to categorically demonstrate a role for hippocampal cannabinoid receptors in learning and memory.

Animals↗
PubMed2006

Adenosine A2a blockade prevents synergy between mu-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats.

Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of mu-opiate receptors (MORs) and CB1 receptors in primary NAc/striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP/PKA signaling in NAc/striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.

Adenosine A2 Receptor Antagonists↗
PubMed2002

Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity.

The anticonvulsant effect of cannabinoids has been shown to be mediated through activation of the cannabinoid CB(1) receptor. This study was initiated to evaluate the effects of endogenously occurring cannabinoids (endocannabinoids) on seizure severity and threshold. The anticonvulsant effect of the endocannabinoid, arachidonylethanolamine (anandamide), was evaluated in the maximal electroshock seizure model using male CF-1 mice and was found to be a fully efficacious anticonvulsant (ED(50)=50 mg/kg i.p.). The metabolically stable analog of anandamide, (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1'-hydroxy-2'-propylamine (O-1812), was also determined to be a potent anticonvulsant in the maximal electroshock model (ED(50)=1.5 mg/kg i.p.). Furthermore, pretreatment with the cannabinoid CB(1) receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) completely abolished the anticonvulsant effect of anandamide as well as O-1812 (P< or =0.01, Fisher exact test), indicating a cannabinoid CB(1) receptor-mediated anticonvulsant mechanism for both endocannabinoid compounds. Additionally, the influence of cannabinoid CB(1) receptor endogenous tone on maximal seizure threshold was assessed using SR141716A alone. Our data show that SR141716A (10 mg/kg i.p.) significantly reduced maximal seizure threshold (CC(50)=14.27 mA) compared to vehicle-treated animals (CC(50)=17.57 mA) (potency ratio=1.23, lower confidence limit=1.06, upper confidence limit=1.43), indicating the presence of an endogenous cannabinoid tone that modulates seizure activity. These data demonstrate that anandamide and its analog, O-1812, are anticonvulsant in a whole animal model and further implicate the cannabinoid CB(1) receptor as a major endogenous site of seizure modulation.

Animals↗