High hopes for CB2 receptors in neurogenesis

During life, new neurons are continually added to hippocampal circuitry, with evidence suggesting that these adult-born neurons are functionally linked to cognition and emotion. The mammalian brain contains actively dividing neural stem cells in discrete regions, including the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus. Once mature, these neurons integrate into neuronal networks, forming synaptic connections with interneurons, mossy cells and CA3 pyramidal cellsLinked ArticleThis article is a commentary on Avraham et al., pp. 468–479 of volume 171 issue 2. To view this paper visit http://dx.doi.org/10.1111/bph.12478     

The tail wags the dog: possible mechanism for reverse allosteric control of ligand-activated channels

In this issue of the British Journal of Pharmacology, a new article by Kozuska et al. discusses the multiple salt bridges in the intracellular domain of the 5HT_3A receptor. These interactions increase the overall rigidity of the receptor, stabilize its low conducting state and affect the ligand cooperativity. The authors suggest that the allosteric effects of these regions on the receptor may be involved in a possible ‘reverse’ allosteric modulation of 5HT₃ receptors.

Linked Article

This article is a Commentary on Kozuska et al., pp. 1617–1628 volume 171 issue 7. To view this paper visit http://dx.doi.org/10.1111/bph.12536     

Prostamide F2α receptor antagonism combined with inhibition of FAAH may block the pro-inflammatory mediators formed following selective FAAH inhibition

Background and PurposeProstamides are lipid mediators formed by COX-2-catalysed oxidation of the endocannabinoid anandamide and eliciting effects often opposed to those caused by anandamide. Prostamides may be formed when hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) is physiologically, pathologically or pharmacologically decreased. Thus, therapeutic benefits of FAAH inhibitors might be attenuated by concomitant production of prostamide F_2α. This loss of benefit might be minimized by compounds designed to selectively antagonize prostamide receptors and also inhibiting FAAH.Experimental ApproachInhibition of FAAH by a series of selective antagonists of prostamide receptors, including AGN 204396, AGN 211335 and AGN 211336, was assessed using rat, mouse and human FAAH in vitro, together with affinity for human recombinant CB₁ and CB₂ receptors. Effects in vivo were measured in a model of formalin-induced inflammatory pain in mice.Key ResultsThe prostamide F_2α receptor antagonists were active against mouse and rat FAAH in the low μM range and behaved as non-competitive and plasma membrane-permeant inhibitors. AGN 211335, the most potent inhibitor of rat FAAH (IC₅₀ = 1.2 μM), raised exogenous anandamide levels in intact cells and also bound to cannabinoid CB₁ receptors. Both AGN 211335 and AGN 211336 (0.25–1 mg·kg⁻¹, i.p.) inhibited the formalin-induced nociceptive response in mice.Conclusions and ImplicationsSynthetic compounds with indirect agonist activity at cannabinoid receptors and antagonist activity at prostamide receptors can be developed. Such compounds could be used as alternatives to selective FAAH inhibitors to prevent the possibility of prostamide F_2α-induced inflammation and pain.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

So what do we call GPR18 now?

The further characterization of the orphan GPCR GPR18 conducted by McHugh et al. in this issue of the British Journal of Pharmacology has generated a pharmacological profile that raises some interesting questions about the nomenclature of this receptor and may also prompt some questions about the pharmacological definition of the classical cannabinoid receptors, CB₁ and CB₂.

LINKED ARTICLES

This article is a commentary on McHugh et al., pp. 2414–2424 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view McHugh et al. visit http://dx.doi.org/10.1111/j.1476-5381.2011.01497.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

Class A1 scavenger receptors in cardiovascular diseases

Class A1 scavenger receptors (SR‐A1) are membrane glycoproteins that can form homotrimers. This receptor was originally defined by its ability to mediate the accumulation of lipids in macrophages. Subsequent studies reveal that SR‐A1 plays critical roles in innate immunity, cell apoptosis and proliferation. This review highlights recent advances in understanding the structure, receptor pathway and regulation of SR‐A1. Although its role in atherosclerosis is disputable, recent discoveries suggest that SR‐A1 function in anti‐inflammatory responses by promoting an M2 macrophage phenotype in cardiovascular diseases. Therefore, SR‐A1 may be a potential target for therapeutic intervention of cardiovascular diseases.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

acLDL

acetylated low‐density lipoprotein

ER

endoplasmic reticulum

I/R

ischaemia/reperfusion

LTA

lipoteichoic acid

MI

myocardial infarction

mLDL

modified low‐density lipoprotein

oxLDL

oxidized low‐density lipoprotein

PRR

pattern recognition receptor

RAGE

receptor for advanced glycated end‐products

SR‐A1

class A1 scavenger receptor

TLR4

Toll‐like receptor 4

TRAF6

TNF receptor‐associated factor 6

Tables of Links

Tubulin-targeting agent combination therapies: dosing schedule could matter

Tubulin-binding agents are potent cytotoxic drugs that are largely used to treat haematological malignancies and solid tumours. In this issue of British Journal of Pharmacology, doxorubicin was shown to decrease the activity of vincristine when administered simultaneously, unless cell cycle arrest mechanisms were disrupted. This observation emphasizes the need to better explore schedule-dependent antagonist effects in anticancer drug combination therapies.

Linked Article

This article is a commentary on the research paper by Ehrhardt et al., pp. 1558–1569 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12068     

A GPR18-based signalling system regulates IOP in murine eye

Background and Purpose

GPR18 is a recently deorphaned lipid receptor that is activated by the endogenous lipid N-arachidonoyl glycine (NAGly) as well the behaviourally inactive atypical cannabinoid, abnormal cannabidiol (Abn-CBD). The presence and/or function of any GPR18-based ocular signalling system remain essentially unstudied. The objectives of this research are: (i) to determine the disposition of GPR18 receptors and ligands in anterior murine eye, (ii) examine the effect of GPR18 activation on intraocular pressure (IOP) in a murine model, including knockout mice for CB₁, CB₂ and GPR55.

Experimental Approach

IOP was measured in mice following topical application of Abn-CBD, NAGly or the GPR55/GPR18 agonist O-1602, alone or with injection of the GPR18 antagonist, O-1918. GPR18 protein localization was assessed with immunohistochemistry. Endocannabinoids were measured using LC/MS-MS.

Key Results

GPR18 protein was expressed most prominently in the ciliary epithelium and the corneal epithelium and, interestingly, in the trabecular meshwork. The GPR18 ligand, NAGly, was also detected in mouse eye at a level comparable to that seen in the brain. Abn-CBD and NAGly, but not O-1602, significantly reduced IOP in all mice tested. The antagonist, O-1918, blocked the effects of Abn-CBD and NAGly.

Conclusions and Implications

We present evidence for a functional GPR18-based signalling system in the murine anterior eye, including receptors and ligands. GPR18 agonists, Abn-CBD and NAGly, reduce IOP independently of CB₁, CB₂ or GPR55. These findings suggest that GPR18 may serve as a desirable target for the development of novel ocular hypotensive medications.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8     

Pharmacological modulation of the endocannabinoid signalling alters binge-type eating behaviour in female rats

Background and Purpose

Binge eating disorder (BED) is characterized by excessive food intake during short periods of time. Recent evidence suggests that alterations in the endocannabinoid signalling could be involved in the pathophysiology of BED. In this study, we investigated whether pharmacological manipulation of endocannabinoid transmission may be effective in modulating the aberrant eating behaviour present in a validated rat model of BED.

Experimental Approach

Binge-type eating was induced in female rats by providing limited access to an optional source of dietary fat (margarine). Rats were divided into three groups, all with ad libitum access to chow and water: control (C), with no access to margarine; low restriction (LR), with 2 h margarine access 7 days a week; high restriction (HR), with 2 h margarine access 3 days a week.

Key Results

Compared with the LR group, the HR group consumed more margarine and this was accompanied by an increase in body weight. The cannabinoid CB₁/CB₂ receptor agonist Δ⁹-tetrahydrocannabinol significantly increased margarine intake selectively in LR rats, while the fatty acid amide hydrolase inhibitor URB597 showed no effect. The CB₁ receptor inverse agonist/antagonist rimonabant dose-dependently reduced margarine intake in HR rats. Notably, in HR rats, chronic treatment with a low dose of rimonabant induced a selective long-lasting reduction in margarine intake that did not develop tolerance, and a significant and persistent reduction in body weight.

Conclusions and Implications

Chronic pharmacological blockade of CB₁ receptors reduces binge eating behaviour in female rats and may prove effective in treating BED, with an associated significant reduction in body weight.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8     

Towards a better cannabis drug

This commentary discusses the importance of a new study entitled ‘Cannabidiol attenuates deficits of visuo-spatial associative memory induced by Δ⁹-tetrahydrocannabinol’ by Wright et al. from the Scripps Institute in La Jolla, California. The results in this study show that the non-psychoactive cannabis constituent cannabidiol opposes some, but not all, forms of behavioural and memory disruption caused by Δ⁹-tetrahydrocannabinol in male rhesus monkeys.

LINKED ARTICLE

This article is a commentary on the research paper by Wright et al., pp 1365–1373 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12199     

Changes in CB1 and CB2 receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias

Background and PurposeSpinocerebellar ataxias (SCAs) are a family of chronic progressive neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to degeneration of the cerebellum and its afferent and efferent connections. Unlike other motor disorders, the possible role of changes in the endocannabinoid system in the pathogenesis of SCAs has not been investigated.Experimental ApproachThe status of cannabinoid receptor type 1 (CB₁) and cannabinoid receptor type 2 (CB₂) receptors in the post-mortem cerebellum of SCA patients and controls was investigated using immunohistochemical procedures.Key ResultsImmunoreactivity for the CB₁ receptor, and also for the CB₂ receptor, was found in the granular layer, Purkinje cells, neurons of the dentate nucleus and areas of white matter in the cerebellum of SCA patients at levels notably higher than controls. Double-labelling procedures demonstrated co-localization of CB₁ and, in particular, CB₂ receptors with calbindin, supporting the presence of these receptors in Purkinje neurons. Both receptors also co-localized with Iba-1 and glial fibrillary acidic protein in the granular layer and white matter areas, indicating that they are present in microglia and astrocytes respectively.Conclusions and ImplicationsOur results demonstrate that CB₁ and CB₂ receptor levels are significantly altered in the cerebellum of SCA patients. Their identification in Purkinje neurons, which are the main cells affected in SCAs, as well as the changes they experienced, suggest that alterations in endocannabinoid receptors may be related to the pathogenesis of SCAs. Therefore, the endocannabinoid system could provide potential therapeutic targets for the treatment of SCAs and its progression.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

Long-term consequences of perinatal fatty acid amino hydrolase inhibition

Background and PurposeFatty acid amide hydrolase inhibitors show promise as a treatment for anxiety, depression and pain. Here we investigated whether perinatal exposure to URB597, a fatty acid amide hydrolase inhibitor, alters brain development and affects behaviour in adult mice.Experimental ApproachMouse dams were treated daily from gestational day 10.5 to 16.5 with 1, 3 or 10 mg kg⁻¹ URB597. MS was used to measure a panel of endocannabinoids and related lipid compounds and brain development was assessed at embryonic day 16.5. Separate cohorts of mouse dams were treated with 10 mg kg⁻¹ URB597, from gestational day 10.5 to postnatal day 7, and the adult offspring were assessed with a battery of behavioural tests.Key ResultsPerinatal URB597 exposure elevated anandamide and related N-acyl amides. URB597 did not induce signs of toxicity or affect dam weight gain, neurogenesis or axonal development at embryonic day 16.5. It did lead to subtle behavioural deficits in adult offspring, manifested by reduced cocaine-conditioned preference, increased depressive behaviours and impaired working memory. Anxiety levels, motor function and sensory-motor gating were not significantly altered.Conclusions and ImplicationsTaken together, the present results highlight how exposure to elevated levels of anandamide and related N-acyl amides during brain development can lead to subtle alterations in behaviour in adulthood.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects

Background and Purpose

The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects.

Experimental Approach

Three new fluorophosphonate compounds O-7458, O-7459 and O-7460 were synthesized and characterized in various enzymatic assays. The effects of O-7460 on high-fat diet intake were tested in mice.

Key Results

Of the new compounds, O-7460 exhibited the highest potency (IC₅₀ = 690 nM) against the human recombinant DAGLα, and selectivity (IC₅₀ > 10 μM) towards COS-7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity-based protein profiling confirmed that O-7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off-target’, that is, the serine hydrolase KIAA1363. O-7460 did not exhibit measurable affinity for human recombinant CB₁ or CB₂ cannabinoid receptors (K_i > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 μM) reduced 2-AG levels. When administered to mice, O-7460 dose-dependently (0–12 mg·kg⁻¹, i.p.) inhibited the intake of a high-fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.

Conclusions and Implications

O-7460 might be considered a useful pharmacological tool to investigate further the role played by 2-AG both in vitro and in vivo under physiological as well as pathological conditions.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8     

The dynamic nature of type 1 cannabinoid receptor (CB1) gene transcription

The type 1 cannabinoid receptor (CB₁) is an integral component of the endocannabinoid system that modulates several functions in the CNS and periphery. The majority of our knowledge of the endocannabinoid system involves ligand–receptor binding, mechanisms of signal transduction, and protein–protein interactions. In contrast, comparatively little is known about regulation of CB₁ gene expression. The levels and anatomical distribution of CB₁ mRNA and protein are developmental stage-specific and are dysregulated in several pathological conditions. Moreover, exposure to a variety of drugs, including cannabinoids themselves, alters CB₁ gene expression and mRNA levels. As such, alterations in CB₁ gene expression are likely to affect the optimal response to cannabinoid-based therapies, which are being developed to treat a growing number of conditions. Here, we will examine the regulation of CB₁ mRNA levels and the therapeutic potential inherent in manipulating expression of this gene.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8     

Efficacy and ligand bias at the μ-opioid receptor

In order to describe drug action at a GPCR, a full understanding of the pharmacological terms affinity, efficacy and potency is necessary. This is true whether comparing the ability of different agonists to produce a measurable response in a cell or tissue, or determining the relative ability of an agonist to activate a single receptor subtype and produce multiple responses. There is a great deal of interest in the μ-opioid receptor (MOP receptor) and the ligands that act at this GPCR not only because of the clinically important analgesic effects produced by MOP agonists but also because of their liability to induce adverse effects such as respiratory depression and dependence. Our understanding of the mechanisms underlying these effects, as well as the ability to develop new, more effective MOP receptor drugs, depends upon the accurate determination of the efficacy with which these ligands induce coupling of MOP receptors to downstream signalling events. In this review, which is written with the minimum of mathematical content, the basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacology, and in particular in relation to biased agonism at this important GPCR.

Linked Articles

Recent reviews on aspects of efficacy can be found at:Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476-5381.2012.02223.xRoche D, Gil D and Giraldo J (2013). Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models. British Journal of Pharmacology 169: 1189–1202. doi: 10.1111/bph.12231     

The influence of cannabinoids on generic traits of neurodegeneration

In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer''s disease, Parkinson''s disease and Huntington''s disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB₁ and CB₂ receptors are known to be involved in the regulation of Ca²⁺ homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARγ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

The Concise Guide to PHARMACOLOGY 2015/16: Other ion channels

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13351/full. Other ion channels are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.

Conflict of interest

The authors state that there are no conflicts of interest to declare.

Family structure

5943 Aquaporins 5944 Chloride channels 5944 ClC family 5947 CFTR 5948 Calcium activated chloride channel 5949 Maxi chloride channel 5950 Volume regulated chloride channels 5952 Connexins and Pannexins 5954 Sodium leak channel, non‐selective     

The FAAH inhibitor URB597 efficiently reduces tyrosine hydroxylase expression through CB1- and FAAH-independent mechanisms

Background

Anandamide and 2-arachidonoylglycerol are neuromodulatory lipids interacting with cannabinoid receptors, whose availability is regulated by the balance between ‘on demand’ generation and enzymatic degradation [by fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase]. Given the reported effects of anandamide on dopamine transmission, we investigated the influence of endocannabinoids and URB597, a well-known FAAH inhibitor, on the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis.

Experimental Approach

We investigated TH expression in N1E115 neuroblastoma using a reporter gene assay, as well as mRNA and protein quantifications. FAAH inhibition was confirmed by measuring radiolabelled substrate hydrolysis and endogenous endocannabinoids.

Key Results

Anandamide decreased TH promoter activity in N1E115 cells through CB₁ receptor activation. Unexpectedly, URB597 reduced TH expression (pEC₅₀ = 8.7 ± 0.2) through FAAH-independent mechanisms. Indeed, four structurally unrelated inhibitors of FAAH had no influence on TH expression, although all the inhibitors increased endocannabinoid levels. At variance with the endocannabinoid responses, the use of selective antagonists indicated that the URB597-mediated decrease in TH expression was not directed by the CB₁ receptor, but rather by abnormal-cannabidiol-sensitive receptors and PPARs. Further supporting the physiological relevance of these in vitro data, URB597 administration resulted in reduced TH mRNA levels in mice brain.

Conclusions

While confirming the implication of endocannabinoids on the modulation of TH, we provide strong evidence for additional physiologically relevant off-target effects of URB597. In light of the numerous preclinical studies involving URB597, particularly in anxiety and depression, the existence of non-CB₁ and non-FAAH mediated influences of URB597 on key enzymes of the catecholaminergic transmission system should be taken into account when interpreting the data.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8     

In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects

Background and PurposeSince monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate).Experimental ApproachIn the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac-induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.Key ResultsKML29 attenuated carrageenan-induced paw oedema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by cannabinoid receptor 1 (CB₁) receptor desensitization. Acute or repeated KML29 administration increased 2-AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac-induced gastric haemorrhages. CB₁ and CB₂ receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ⁹-tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose-dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (−/−) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC-like subjective effects.Conclusions and ImplicationsThese results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6