anandamide and nimesulide

Ethanol (EtOH) self-administration is particularly sensitive to the modulation of CB. In order to further explore this hypothesis, we analyzed the alterations in operant EtOH self-administration induced by intra-NAc shell infusions of 2-AG itself, the CB. Surprisingly, self-administration of 10% EtOH was dose-dependently reduced by either intra-NAc shell SR141716A or 2-AG infusions. Similar effects were found by intra-NAc shell infusions of URB602, suggesting again a role for accumbal 2-AG on the modulation of EtOH intake. Intra-NAc shell anandamide did not alter EtOH self-administration, pointing to a specific role for 2-AG in the modulation of EtOH self-administration. Finally, the inhibitory effect of intra-NAc shell 2-AG on EtOH intake was significantly reversed by pretreatment with nimesulide, suggesting that oxidative metabolites of 2-AG might mediate these inhibitory effects on operant self-administration.. We propose that 2-AG signaling in the NAc exerts an inhibitory influence on EtOH consumption through a non-CB1 receptor mechanism involving the COX-2 pathway.

Topics: Alcohol Drinking; Animals; Arachidonic Acids; Biphenyl Compounds; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Endocannabinoids; Glycerides; Male; Nucleus Accumbens; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Self Administration; Sulfonamides

Endocannabinoids are protective in animal colitis models. As endocannabinoids also form novel prostaglandin ethanolamides (prostamides) via COX-2, we investigated the effects of prostamides and other COX-2 mediators on tissue damage in an ex vivo human mucosal explant colitis model. Healthy human colonic mucosae were incubated with pro-inflammatory cytokines TNF-α and IL-1β to elicit colitis-like tissue damage. The PGF-ethanolamide analogue, bimatoprost decreased colitis scores which were reversed by a prostamide-specific antagonist AGN 211334, but not the FP receptor antagonist AL-8810. PGF-ethanolamide and PGE-ethanolamide also reduced cytokine-evoked epithelial damage. Anandamide was protective in the explant colitis model; however COX-2 inhibition did not alter its effects, associated with a lack of COX-2 induction in explant mucosal tissue. These findings support an anti-inflammatory role for prostamides and endocannabinoids in the human colon.

Topics: Adult; Amides; Arachidonic Acids; Bimatoprost; Cloprostenol; Colitis; Colon, Sigmoid; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Endocannabinoids; Female; Humans; Immunohistochemistry; Interleukin-1beta; Male; Middle Aged; Oxazoles; Polyunsaturated Alkamides; Receptors, Prostaglandin; Sulfonamides; Tissue Culture Techniques; Tumor Necrosis Factor-alpha; Young Adult

Cyclooxygenase-2 (COX-2) mediates inflammation and contributes to neurodegeneration. Best known for its pathological up-regulation, COX-2 is also constitutively expressed within the brain and mediates synaptic transmission through prostaglandin synthesis. Along with arachidonic acid, COX-2 oxygenates the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol in vitro. Inhibition of COX-2 enhances retrograde signaling in the hippocampus, suggesting COX-2 mediates endocannabinoid tone in healthy brain. The degree to which COX-2 may regulate endocannabinoid metabolism in vivo is currently unclear. Therefore, we explored the effect of COX-2 inhibition on [(3)H]AEA metabolism in mouse brain. Although AEA is hydrolyzed primarily by fatty acid amide hydrolase (FAAH), ex vivo autoradiography revealed that COX-2 inhibition by nimesulide redirected [(3)H]AEA substrate from COX-2 to FAAH in the cortex, hippocampus, thalamus, and periaqueductal gray. These data indicate that COX-2 possesses the capacity to metabolize AEA in vivo and can compete with FAAH for AEA in several brain regions. Temporal fluctuations in COX-2 expression were observed in the brain, with an increase in COX-2 protein and mRNA in the hippocampus at midnight compared with noon. COX-2 immunolocalization was robust in the hippocampus and several cortical regions. Although most regions exhibited no temporal changes in COX-2 immunolocalization, increased numbers of immunoreactive cells were detected at midnight in layers II and III of the somatosensory and visual cortices. These temporal variations in COX-2 distribution reduced the enzyme's contribution toward [(3)H]AEA metabolism in the somatosensory cortex at midnight. Taken together, our findings establish COX-2 as a mediator of regional AEA metabolism in mouse brain.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Autoradiography; Biological Availability; Blotting, Western; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Endocannabinoids; Light; Mice; Mice, Inbred C57BL; Polyunsaturated Alkamides; Reverse Transcriptase Polymerase Chain Reaction; Somatosensory Cortex; Substrate Specificity; Sulfonamides; Visual Cortex

In hippocampal pyramidal cells, a rise in Ca(2+) releases endocannabinoids that activate the presynaptic cannabinoid receptor (CB1R) and transiently reduce GABAergic transmission-a process called depolarization-induced suppression of inhibition (DSI). The mechanism that limits the duration of endocannabinoid action in intact cells is unknown. Here we show that inhibition of cyclooxygenase-2 (COX-2), not fatty acid amide hydrolase (FAAH), prolongs DSI, suggesting that COX-2 limits endocannabinoid action.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Synergism; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hippocampus; In Vitro Techniques; Isoenzymes; Male; Meloxicam; Membrane Potentials; Neural Inhibition; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Prostaglandin-Endoperoxide Synthases; Pyramidal Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Thiazines; Thiazoles