Evaluation of the role of the arachidonic acid cascade in anandamide's in vivo effects in mice

Wiley, Jenny L.; Razdan, Raj K.; Martin, Billy R.

doi:10.1016/j.lfs.2006.08.017

Cited by 28 publications

(41 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is likely that these high doses are necessary to overcome the rapid and massive inactivation of anandamide by FAAH so that brain anandamide concentrations can reach levels sufficient to activate brain CB 1 receptors. Administration of these high doses of anandamide may be accompanied by rapid and massive formation of anandamide metabolites that may be responsible for depression of responding through non-CB 1 receptor mechanisms (Wiley et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The Endogenous Cannabinoid Anandamide Produces δ-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

Solinas¹,

Tanda²,

Justinová³

et al. 2007

J Pharmacol Exp Ther

104

130

View full text Add to dashboard Cite

Anandamide is an endogenous ligand for brain cannabinoid CB 1 receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of ␦-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3Ј-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB 1 receptor antagonist rimonabant, but not the vanilloid VR 1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl) 8,11, and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.The endogenous cannabinoid (CB) system, which is targeted by the psychoactive ingredient in cannabis, ␦-9-tetrahydrocannabinol (THC), comprises receptors termed CB 1 and CB 2 (and others not yet identified) endogenous compounds that activate these receptors and enzymes involved in the synthesis and degradation of these endogenous cannabinoids

show abstract

Section: Discussionmentioning

confidence: 99%

The Endogenous Cannabinoid Anandamide Produces δ-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

Solinas¹,

Tanda²,

Justinová³

et al. 2007

J Pharmacol Exp Ther

104

130

View full text Add to dashboard Cite

show abstract

“…FAAH ( − / − ) mice were employed in all experiments examining the in vivo actions of exogenously administered AEA to prevent its rapid hydrolysis to arachidonic acid, which is known to produce CB1 receptor-independent effects (Wiley et al, 2006). Although constitutively elevated levels of AEA and other lipids in FAAH ( − / − ) mice might complicate interpretation, it should be noted that these mice display normal CB1 receptor expression and function (Cravatt et al, 2001;Lichtman et al, 2002;Falenski et al, 2010).…”

Section: Animalsmentioning

confidence: 99%

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Ignatowska‐Jankowska

Baillie

Kinsey

et al. 2015

Neuropsychopharmacol

137

180

View full text Add to dashboard Cite

The CB 1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ 9 -tetrahydrocannabinol and other CB 1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB 1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB 1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB 1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [ 3 H]CP55,940 to the CB 1 receptor as well as enhancing AEA-stimulated [35 S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB 1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB 1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB 1 PAM and provide the first proof of principle that CB 1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.

show abstract

“…In previous drug discrimination studies, anandamide did not always substitute for Δ 9 -THC in rats and rhesus monkeys (Wiley et al 1995, 1997; Burkey and Nation 1997; Järbe et al 2001), suggesting that anandamide and Δ 9 -THC differ in their mechanism of action. These differences might result from metabolism of anandamide to metabolites (i.e., ethanolamine and arachidonic acid; Deutsch and Chin 1993) that act at non-CB 1 receptors to produce behavioral effects (Wiley et al 2006). Strategies available for decreasing the metabolism of anandamide include modification of its chemical structure and combination of anandamide with inhibitors of its enzymatic degradation, and both were reported to increase Δ 9 -THC-like behavioral effects.…”

Section: Introductionmentioning

confidence: 99%

Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Δ9-tetrahydrocannabinol

McMahon

2008

Psychopharmacology

View full text Add to dashboard Cite

Rationale Anandamide and Δ9-tetrahydrocannabinol (Δ9-THC) sometimes produce different discriminative stimulus effects and, therefore, appear to differ in their mechanism of action. In order to understand the widespread use of cannabis and the therapeutic potential of cannabinoids, mechanisms responsible for behavioral effects need to be identified. Objective Drug discrimination was used to compare the mechanism of action of Δ9-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys. Materials and methods Monkeys discriminated Δ9-THC (0.1 mg/kg i.v.) from vehicle. Δ9-THC, anandamide, methanandamide, and arachidonylcyclopropylamide (ACPA) were administered i.v. alone and in combination with at least one dose of rimonabant. Schild analysis and single-dose apparent affinity estimates were used to estimate the potency of rimonabant as an antagonist of each cannabinoid; these values were compared to examine whether the same receptors mediated discriminative stimulus effects. Results Δ9-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Δ9-THC lever. The ED50 values were 0.024 mg/kg for Δ9-THC, 0.14 mg/kg for ACPA, 0.28 mg/kg for methanandamide, and 1.7 mg/kg for anandamide. The duration of action of Δ9-THC was 4–6 h and longer than the duration of action ACPA, methanandamide, and anandamide (i.e., each less than 50 min). Rimonabant surmountably antagonized the discriminative stimulus effects of each agonist, and the apparent affinity estimates (pA2 and pKB values) were 6.24–6.83. Conclusions Rimonabant can produce surmountable antagonism of the behavioral effects of not only Δ9-THC but also anandamide, methanandamide, and ACPA, and the interactions appear simple, competitive, and reversible. These cannabinoid agonists act at the same receptors to produce discriminative stimulus effects.

show abstract

Evaluation of the role of the arachidonic acid cascade in anandamide's in vivo effects in mice

Cited by 28 publications

References 37 publications

The Endogenous Cannabinoid Anandamide Produces δ-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

The Endogenous Cannabinoid Anandamide Produces δ-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Δ9-tetrahydrocannabinol

Contact Info

Product

Resources

About