Search

Neuropathic pain consequent to peripheral nerve injury has been associated with local inflammation. Following noxious stimulation afferent fibres release substance P (SP) and calcitonin-gene related peptide (CGRP), which are closely related to oedema formation and plasma leakage. The effect of the anandamide transport blocker AM404 has been studied on plasma extravasation after chronic constriction injury (CCI) which consists in a unilateral loose ligation of the rat sciatic nerve (Bennett and Xie, 1988). AM404 (1-3-10 mg kg(-1)) reduced plasma extravasation in the legated paw, measured as mug of Evans Blue per gram of fresh tissue. A strong effect on vascular permeability was also produced by the synthetic cannabinoid agonist WIN 55,212-2 (0.1-0.3-1 mg kg(-1)). Using specific antagonists or enzyme inhibitors, we demonstrate that cannabinoids act at several levels: data on the 3rd day suggest a strong involvement of substance P (SP) and calcitonin gene-related peptide (CGRP) in the control of vascular tone, whereas at the 7th and 14th days the major role seems to be played by prostaglandins (PGs) and nitric oxide (NO). Capsaicin injection in ligated paws of AM404- or WIN 55,212-2-treated rats resulted in an increase of Evans Blue extravasation, suggesting the involvement of the cannabinergic system in the protective effect of C fibres of ligated paws. Taken together, these data demonstrate the efficacy of cannabinoids in controlling pain behaviour through the modulation of several pain mediators and markers of vascular reactivity, such as SP, CGRP, PGs and NO.

The ability of CB(1) receptors to regulate the release of glutamate in the striatum, together with the finding that, in experimental models of Huntington disease (HD), both endocannabinoid levels and CB(1) receptor densities are reduced, has prompted the investigation on the neuroprotective role of the cannabinoids in HD. Quinolinic acid (QA) is an excitotoxin that, when injected in the rat striatum reproduces many features of HD and that acts by stimulating glutamate outflow. The aim of the present study was to test the ability of the cannabinoid receptor agonist WIN 55,212-2 to prevent the effects induced by QA in the rat striatum. In microdialysis experiments, probe perfusion with WIN 55,212-2 significantly and dose-dependently prevented the increase in extracellular glutamate induced by QA. In electrophysiological recordings in corticostriatal slices, the application of WIN 55,212-2 prevented QA-induced reduction of the field potential amplitude. Both effects of WIN 55,212-2 were prevented by the CB(1) receptor antagonist AM 251. In in vivo experiments, intrastriatal WIN 55,212-2 significantly attenuated the striatal damage induced by QA, although no significant effects were observed on a behavioural ground. These data demonstrate that the stimulation of CB(1) receptors might lead to neuroprotective effects against excitotoxic striatal toxicity.

Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs. We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain. Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia. Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation. Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cannabinoid pharmacology has been intensely studied because of cannabis' pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB 1 ) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s). Allosteric receptor modulators hold potential to develop subtype-specific and pathway-specific therapeutics. Here we briefly discuss the first-generation of allosteric modulators of CB 1 receptor, their structure-activity relationships, signaling pathways and the allosteric binding site(s) on the CB 1 receptor. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology"., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The objective of this review is to point out some important facts that we don't know about endogenous cannabinoids - lipid-derived signaling molecules that activate CB1 cannabinoid receptors and play key roles in motivation, emotion and energy balance. The first endocannabinoid substance to be discovered, anandamide, was isolated from brain tissue in 1992. Research has shown that this molecule is a bona fide brain neurotransmitter involved in the regulation of stress responses and pain, but the molecular mechanisms that govern its formation and the neural pathways in which it is employed are still unknown. There is a general consensus that enzyme-mediated cleavage, catalyzed by fatty acid amide hydrolase (FAAH), terminates the biological actions of anandamide, but there are many reasons to believe that other as-yet-unidentified proteins are also involved in this process. We have made significant headway in understanding the second arrived in the endocannabinoid family, 2-arachidonoyl-sn-glycerol (2-AG), which was discovered three years after anandamide. Researchers have established some of the key molecular players involved in 2-AG formation and deactivation, localized them to specific synaptic components, and showed that their assembly into a multi-molecular protein complex (termed the '2-AG signalosome') allows 2-AG to act as a retrograde messenger at excitatory synapses of the brain. Basic questions that remain to be answered pertain to the exact molecular composition of the 2-AG signalosome, its regulation by neural activity and its potential role in the actions of drugs of abuse such as Δ(9)-THC and cocaine. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.

Converging evidence suggests that the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). Anandamide (0.03-3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamide's metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50-300 microg/kg, intravenous) produced dose-related conditioned place aversions. When anxiety-related effects of anandamide and URB597 were evaluated in a light/dark box, both a low anandamide dose (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. A higher dose of anandamide (3 mg/kg) produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Finally, anxiogenic effects of anandamide plus URB597 and development of place aversions with URB597 plus anandamide were prevented by the CB1-receptor antagonist AM251 (3 mg/kg intraperitoneal). Thus, additive interactions between the effects of anandamide on brain reward processes and on anxiety may account for its aversive effects when intravenously administered during FAAH inhibition with URB597.

Recent work in our laboratories has demonstrated that an opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous cannabinoids [Hohmann et al., 2005. Nature 435, 1108]. Non-opioid SIA, induced by a 3-min continuous foot shock, is characterized by the mobilization of two endocannabinoid lipids--2-arachidonoylglycerol (2-AG) and anandamide--in the midbrain periaqueductal gray (PAG). The present studies were conducted to examine the contributions of spinal endocannabinoids to nonopioid SIA. Time-dependent increases in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats. Notably, 2-AG accumulation was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock. 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), whereas anandamide is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH). This metabolic segregation enabled us to manipulate endocannabinoid tone at the spinal level to further evaluate the roles of 2-AG and anandamide in nonopioid SIA. Intrathecal administration of the competitive CB1 antagonist SR141716A (rimonabant) failed to suppress nonopioid SIA, suggesting that supraspinal rather than spinal CB1 receptor activation plays a pivotal role in endocannabinoid-mediated SIA. By contrast, spinal inhibition of MGL using URB602, which selectively inhibits 2-AG hydrolysis in the PAG, enhanced SIA through a CB1-selective mechanism. Spinal inhibition of FAAH, with either URB597 or arachidonoyl serotonin (AA-5-HT), also enhanced SIA through a CB1-mediated mechanism, presumably by increasing accumulation of tonically released anandamide. Our results suggest that endocannabinoids in the spinal cord regulate, but do not mediate, nonopioid SIA.

The fatty-acid ethanolamide, oleoylethanolamide (OEA), is a naturally occurring lipid that regulates feeding and body weight [Rodriguez de Fonseca, F., Navarro, M., Gomez, R., Escuredo, L., Nava, F., Fu, J., Murillo-Rodriguez, E., Giuffrida, A., LoVerme, J., Gaetani, S., Kathuria, S., Gall, C., Piomelli, D., 2001. An anorexic lipid mediator regulated by feeding. Nature 414, 209-212], and serves as an endogenous agonist of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) [Fu, J., Gaetani, S., Oveisi, F., Lo Verme, J., Serrano, A., Rodriguez De Fonseca, F., Rosengarth., A., Luecke, H., Di Giacomo, B., Tarzia, G., Piomelli, D., 2003. Oleoylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425, 90-93], a ligand-activated transcription factor that regulates several aspects of lipid metabolism [. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20, 649-688]). OEA reduces food intake in wild-type mice, but not in mice deficient in PPAR-alpha (PPAR-alpha(-/-)), an effect that is also observed with the PPAR-alpha agonists Wy-14643 and GW7647 [Brown, P.J., Chapman, J.M., Oplinger, J.A., Stuart, L.W., Willson, T.M. and Wu, Z., 2000. Chemical compounds as selective activators of PPAR-alpha. PCT Int. Appl., 32; . The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527-550]. By contrast, specific agonists of PPAR-delta/beta (GW501516) or PPAR-gamma (ciglitazone) have no such effect. In obese Zucker rats, which lack functional leptin receptors, OEA reduces food intake and lowers body-weight gain along with plasma lipid levels. Similar effects are seen in diet-induced obese rats and mice. In the present study, we report that subchronic OEA treatment (5mgkg(-1), intraperitoneally, i.p., once daily for two weeks) in Zucker rats initiates transcription of PPAR-alpha and other PPAR-alpha target genes, including fatty-acid translocase (FAT/CD36), liver fatty-acid binding protein (L-FABP), and uncoupling protein-2 (UCP-2). Moreover, OEA decreases neutral lipid content in hepatocytes, as assessed by Oil red O staining, as well as serum cholesterol and triglyceride levels. The results suggest that OEA regulates lipid metabolism and that this effect may contribute to its anti-obesity properties.

The active principle of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), exerts its pharmacological effects by binding to selective receptors present on the membranes of neurons and other cells. These cannabinoid receptors are normally engaged by a family of lipid mediators, called endocannabinoids, which are thought to participate in the regulation of a diversity of brain functions, including pain, mood, appetite and memory. Marijuana use may lead to adaptive changes in endocannabinoid signaling, and these changes might contribute to effects of marijuana as well as to the establishment of marijuana dependence. In the present article, I outline current views on how endocannabinoid substances are produced, released, and deactivated in the brain. In addition, I review recent progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of marijuana dependence and other aspects of drug abuse.