Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cannabinoid Receptor Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,513 records · Page 84Linked to original sources
PubMed2006

Cannabinoid signalling in TNF-alpha induced IL-8 release.

The molecular events mediating the immunomodulatory properties of cannabinoids have remained largely unresolved. We have therefore investigated the molecular mechanism(s) through which R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone (WIN55212-2) modulate production of interleukin-8 (IL-8) in HT-29 cells. Release of IL-8 induced by tumor necrosis factor-alpha (TNF-alpha) was determined by enzyme-linked immunosorbent assay (ELISA). Changes in expression of inhibitory kappa B (IkappaB) were monitored by Western blotting and activation of nuclear factor-kappa B (NF-kappaB) was determined in electrophoretic mobility shift assay (EMSAs). TNF-alpha induced release of IL-8 was inhibited by WIN55212-2 which also blocked the degradation of IkappaB-alpha and activation of NF-kappaB induced by TNF-alpha. These data provide strong evidence that WIN55212-2 may modulate IL-8 release by negatively regulating the signaling cascade leading to the activation of NF-kappaB. These findings highlight a potential mechanism for the immunomodulatory properties of cannabinoids and contribute towards acquiring a clear understanding of the role of cannabinoids in inflammation.

Benzoxazines↗
PubMed2005

Intracellular translocation of the decapeptide carboxyl terminal of Gi3 alpha induces the dual phosphorylation of p42/p44 MAP kinases.

The carboxyl terminal of heterotrimeric G protein alpha subunits binds both G protein-coupled receptors and mastoparan (MP), a tetradecapeptide allostere. Moreover, peptides corresponding to the carboxyl domains of G(i)3alpha and G(t) display intrinsic biological activities in cell-free systems. Thus, the purpose of this study was to develop a cell penetrant delivery system to further investigate the biological properties of a peptide mimetic of the G(i)3alpha carboxyl terminal (G(i)3alpha(346-355); H-KNNLKECGLY-NH2). Kinetic studies, using a CFDA-conjugated analogue of G(i)3alpha(346-355), confirmed the rapid and efficient intracellular translocation of TP10-G(i)3alpha(346-355) (t(0.5) = 3 min). Translocated G(i)3alpha(346-355), but not other bioactive cargoes derived from PKC and the CB1 cannabinoid receptor, promoted the dual phosphorylation of p42/p44 MAPK without adverse changes in cellular viability. The relative specificity of this novel biological activity was further confirmed by the observation that translocated G(i)3alpha(346-355) did not influence the exocytosis of beta-hexoseaminidase from RBL-2H3, a secretory event stimulated by other cell penetrant peptide cargoes and MP. We conclude that TP10-G(i)3alpha(346-355) is a valuable, non-toxic research tool with which to study and modulate signal transduction pathways mediated by heterotrimeric G proteins and MAPK.

Cell Line, Tumor↗
PubMed1997

Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant.

Traumatic brain injury triggers a cascade of events resulting in delayed edema, necrosis and impaired function. Harmful mediators are accumulating in the brain after injury and recently, the role of cytokines in the pathophysiology of brain injury has been suggested. We have developed an experimental model for closed head injury (CHI), in which edema, blood-brain-barrier disruption, motor and memory dysfunctions have been demonstrated. In this study, spatial and temporal induction of IL-1, IL-6 and TNF-alpha gene mRNA transcription and of TNF-alpha and IL-6 activity in rat brain after CHI are shown. Dexanabinol, HU-211, is a synthetic cannabinoid devoid of cannabimimetic effects; it exhibits pharmacological properties of N-methyl-D-aspartate (NMDA)-receptor antagonist and is an effective cerebroprotectant. We report here that HU-211 is a novel inhibitor of TNF-alpha production at a post-transcriptional stage. HU-211, pentoxyfilline and TNF-binding protein improved the outcome of CHI. We suggest that TNF-alpha is a primary mediator of neurotoxicity after CHI, as inhibition of TNF-alpha is associated with better clinical recovery. TNF-alpha modulating agents, if given within the early time window post-injury, may improve the final neurological outcome in victims of brain trauma.

Animals↗
PubMed2006

Gene transcription alterations associated with decrease of ethanol intake induced by naltrexone in the brain of Wistar rats.

Preclinical and clinical studies suggest that the administration of the opioid antagonist naltrexone decreases the intake of ethanol. However, the neuroplastic adaptations in the brain associated to reduction of ethanol consumption remains to be elucidated. The aim of the study was to identify gene transcription alterations underlying the attenuation of voluntary ethanol intake by administration of naltrexone in rats. Increasing doses of naltrexone (0.7 mg/kg, 4 days and 1.4 mg/kg/day, 4 days) to rats with acquired high preferring ethanol consumption (>3.5 g of ethanol/kg/day) decreased voluntary ethanol intake (50%). Voluntary ethanol consumption altered mu-opioid receptor function in the cingulate cortex, caudate-putamen (CPu), nucleus accumbens core (Acb C) and shell (Acb S), the expression of tyrosine hydroxylase (TH) in the ventral tegmental area and substantia nigra, proenkephalin (PENK) in the piriform cortex, olfactory tubercle, CPu, Acb C and Acb S, ventromedial nucleus (VMN) and paraventricular nucleus (PVN) of the hypothalamus, corticotropin releasing factor (CRF) in PVN, cannabinoid CB(1) receptor (CB1-R) in the CPu, hippocampus and VMN, and serotonin transporter (5-HTT) in the dorsal and median raphe nuclei. The reduction of ethanol intake induced by naltrexone was associated with a blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. These results point to a role for the mu-opioid receptor, TH, PENK, CRF, CB1-R, and 5-HTT genes in specific brain regions in the modulation of neuroadaptative mechanisms associated to the decrease of ethanol intake induced by naltrexone.

Alcohol Drinking↗
PubMed2006

PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons.

The oxygenation of endogenous cannabinoids (eCBs) 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide by cyclooxygenase-2 (COX-2) produces novel types of prostanoids: prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). However, the physiological function of COX-2 oxidative metabolites of eCBs is still unclear. Here we demonstrate that PGE2-G, a COX-2 oxidative metabolite of 2-AG, induced a concentration-dependent increase in the frequency ofminiature inhibitory postsynaptic currents (mIPSCs) in primary cultured hippocampal neurons, an effect opposite to that of 2-AG. This increase was not inhibited by SR141716, a CB1 receptor antagonist, but was attenuated by an IP3 or MAPK inhibitor. In addition, we also examined the effects of other prostanoids derived from COX-2 oxygenation of eCBs on mIPSCs. PGD2-G, PGF2alpha-G and PGD2-EA, but not PGE2-EA or PGF2alpha-EA, also increased the frequency of mIPSCs. The eCB-derived prostanoid-induced responses appeared to be different from those of corresponding arachidonic acid-derived prostanoids, implying that these effects are not mediated via known prostanoid receptors. We further discovered that the inhibition of COX-2 activity reduced inhibitory synaptic activity and augmented depolarization-induced suppression of inhibition (DSI), whereas the enhancement of COX-2 augmented the synaptic transmission and abolished DSI. Our results, which show that COX-2 oxidative metabolites of eCBs exert opposite effects to their parent molecules on inhibitory synaptic transmission, suggest that alterations in COX-2 activity will have significant impact on endocannabinoid signalling in hippocampal synaptic activity.

Animals↗
PubMed2007

Dopamine D3 receptor ligands for the treatment of tobacco dependence.

This review considers the potential use of the dopamine D(3) receptor (DRD3) as a novel therapeutic target for the treatment of tobacco dependence. Among the 5 dopamine receptors identified, the DRD3 is located in the nucleus accumbens, ventral tegmental area and amygdala: 3 brain structures that are implicated in the motivational control of drug-seeking behaviour and drug-conditioning processes. Although it has been proposed that modulating dopamine transmission would be effective in the treatment of drug dependence, no validation has been provided in humans so far. Several highly selective DRD3 ligands have recently been evaluated in preclinical models of drug dependence. These ligands act as DRD3 antagonists in vivo and are able to decrease the motivation to take various drugs of abuse and reduce the influence of associated drug-conditioned behaviour. Of note is that these effects have been found with nicotine-seeking behaviour and nicotine relapse in rodents, suggesting a potential use of these ligands for the treatment of tobacco smokers. In contrast to nicotine replacement therapy, varenicline and bupropion (which are currently used for the treatment of smokers), DRD3 antagonists do not seem to produce nicotine-like effects in experimental animals and, therefore, may not substitute for nicotine or alleviate nicotine withdrawal symptoms in human smokers. This behavioural profile, which was also reported recently with cannabinoid CB(1) receptor antagonists, may result from effects on specific brain pathways that express DRD3 receptors and are involved in relapse and conditioning processes. These preclinical studies suggest that the clinical evaluation of DRD3 ligands should be performed with clinical trials designed specifically to evaluate the relapse phenomena.

Animals↗
PubMed2003

Direct and indirect interactions between cannabinoid CB1 receptor and group II metabotropic glutamate receptor signalling in layer V pyramidal neurons from the rat prefrontal cortex.

At proximal synapses from layer V pyramidal neurons from the rat prefrontal cortex, activation of group II metabotropic glutamate receptors (group II mGlu) by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCG IV) induced a long-lasting depression of excitatory postsynaptic currents. Paired-pulse experiments suggested that the depression was expressed presynaptically. Activation of type 1 cannabinoid receptors (CB1) by WIN 55,212-2 occluded the DCG IV-induced depression in a mutually occlusive manner. At the postsynaptic level, WIN 55,212-2 and DCG IV were also occlusive for the activation of extracellular signal-regulated kinase. The postsynaptic localization of active extracellular signal-regulated kinase was confirmed by immunocytochemistry after activation of CB1 receptors. However, phosphorylation of extracellular signal-regulated kinase in layer V pyramidal neurons was dependent on the activation of N-methyl-d-aspartate receptors, consequently to a release of glutamate in the local network. Group II mGlu were also shown to be involved in long-term changes in synaptic plasticity induced by high frequency stimulations. The group II mGlu antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE) favoured long-term depression. However, no interaction was found between MSOPPE, WIN 55,212-2 and the CB1 receptor antagonist SR 141716A on the modulation of long-term depression or long-term potentiation and the effects of these drugs were rather additive. We suggest that CB1 receptor and group II mGlu signalling may interact through a presynaptic mechanism in the induction of a DCG IV-induced depression. Postsynaptically, an indirect interaction occurs for activation of extracellular signal-regulated kinase. However, none of these interactions seem to play a role in synaptic plasticities induced with high frequency stimulations.

Animals↗
PubMed1998

Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat.

1. It has been suggested that the dose of delta9-tetrahydrocannabinol (delta9-THC) that induces hypothermia in the rat increases the release of brain 5-hydroxytryptamine (5-HT). In light of this, we investigated the hypothermia produced by delta4-THC, and the effect the selective serotonin reuptake inhibitor fluoxetine has on this response. 2. A significant dose-dependent decrease in body temperature occurred after i.v. administration of 0.5 to 5 mg kg(-1) delta9-THC; maximum decreases being 0.8+/-0.2 degrees C to 2.9+/-0.3 degrees C. This hypothermic response was attenuated by the cannabinoid CB1 receptor antagonist SR 141716. 3. Fluoxetine (10 mg kg(-1) i.p.) alone caused a decrease in body temperature of 0.6+/-0.1 degrees C (n=32, P < 0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg(-1) i.p.) 40 min before delta9-THC significantly reduced the delta9-THC-induced hypothermia (n=7-8, P < 0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after delta9-THC significantly potentiated the delta9-THC-induced hypothermia, producing a maximum decrease of 3.2+/-0.3 degrees C. 4. It is suggested that the effect of fluoxetine on the delta9-THC-induced hypothermic response is dependent on the time of its administration relative to that of delta9-THC. Pretreatment with fluoxetine increases extracellular 5-HT due to reuptake inhibition. Increased extracellular 5-HT can activate autoreceptors which may decrease serotonergic activity, thereby reducing the delta9-THC-induced hypothermia. Conversely, when fluoxetine is administered after delta9-THC, the reuptake block is thought to potentiate the already activated serotonergic system, hence potentiating the delta9-THC-induced hypothermia.

Animals↗
PubMed2006

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice.

RATIONALE: Acute behavioural effects and motivational responses induced by nicotine can be modulated by the endocannabinoid system supporting the existence of a physiological interaction between these two systems. OBJECTIVES: The present study was designed to examine the possible involvement of the cannabinoid system in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. METHODS: Animals were only exposed once to nicotine. The acute administration of low (0.05) or high (0.8 mg/kg, s.c.) doses of nicotine produced opposite effects in the elevated plus-maze, i.e. anxiolytic- and anxiogenic-like responses, respectively. The effects of the pretreatment with the CB1 cannabinoid receptor antagonist, rimonabant (0.25, 0.5 and 1 mg/kg, i.p.), and the cannabinoid agonist, delta9-tetrahydrocannabinol (delta9-THC, 0.1 mg/kg, ip), were evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. RESULTS: Rimonabant completely abolished nicotine-induced anxiolytic-like effects and increased the anxiogenic-like responses of nicotine, suggesting an involvement of CB1 receptors in these behavioural responses. On the other hand, delta9-THC failed to modify nicotine anxiolytic-like responses but attenuated its anxiogenic-like effects. In addition, the association of non-effective doses of delta9-THC and nicotine produced clear anxiolytic-like responses. CONCLUSIONS: These results demonstrate that the endogenous cannabinoid system is involved in the regulation of nicotine anxiety-like behaviour in mice and provide new findings to support the use of cannabinoid antagonists in the treatment of tobacco addiction.

Animals↗
PubMed2004

Differential effects of CB1 and opioid agonists on two populations of adult rat dorsal root ganglion neurons.

Inhibition of primary afferent neurons contributes to the antihyperalgesic effects of opioid and CB1 receptor agonists. Two bioassays were used to compare the effects of the CB1 receptor agonist CP 55,940 and morphine on dissociated adult rat DRG neurons. Both agonists inhibited the increase in free intracellular Ca2+ concentration evoked by depolarization; however, effects of CP 55,940 occurred primarily in large neurons (cell area, >800 microm2), whereas morphine inhibited the response in smaller neurons. Cotreatment with selective blockers of L-, N-, and P/Q-type voltage-dependent Ca2+ channels indicated that CB1 receptors on DRG neurons couple solely with N-type channels but opioid receptors couple with multiple subtypes. Experiments with selective agonists and antagonists of opioid receptors indicated that mu and delta, but not kappa, receptors contributed to the inhibitory effect of morphine on voltage-dependent Ca2+ influx. Because Ca2+ channels underlie release of transmitters from neurons, the effects of opioid agonists and CP 55,940 on depolarization-evoked release of calcitonin gene-related peptide (CGRP) were compared. Morphine inhibited release through delta receptors but CP 55,940 had no effect. Colocalization of CGRP with delta-opioid but not mu-opioid or CB1 receptor immunoreactivity in superficial laminae of the dorsal horn of the spinal cord was consistent with the data for agonist inhibition of peptide release. Therefore, CB1 and opioid agonists couple with different voltage-dependent Ca2+ channels in different populations of DRG neurons. Furthermore, differences occur in the distribution of receptors between the cell body and terminals of DRG neurons. The complementary action of CB1 and opioid receptor agonists on populations of DRG neurons provides a rationale for their combined use in modulation of somatosensory input to the spinal cord.

Animals↗
PubMed2003

Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats.

Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.

Animals↗
PubMed2004

[Cannabinoids and the immune system. Of men, mice and cells].

The medical use of cannabis or cannabinoid compounds is controversial. Cannabinoids like the Delta(9)-THC (tetrahydrocannabinol) or the synthetic derivative Nabilone are available against cancer- and HIV-associated cachexia, nausea and vomiting. Over the last 20 years, the cannabinoid receptors CB(1) and CB(2) and their endogenous ligands have been found. The involvement of this endogenous cannabinoid signalling system in feeding, appetite, pain perception and immunomodulation could be demonstrated using animal and in vitro studies. Thus, the concern about immunosuppressive effects in humans using medical cannabinoid preparations grew. However, up to now most human studies have failed to demonstrate a well-defined and reproducible immunosuppressive cannabinoid-effect. Only the smoking of marijuana showed a significant local immunosuppression of the bactericidal activity of human alveolar macrophages. In animal studies, cannabinoids were identified as potent modulators of cytokine production, causing a shift from Th1 to Th2 cytokines. In consequence, a compromised cellular immunity was observed in these animals, resulting in enhanced tumor growth and reduced immunity to viral infections. In vitro, immunosuppressive effects were shown in all immune cells, but only at high micromolar cannabinoid concentrations not reached under normal clinical conditions. In conclusion, there is no evidence that cannabinoids induce a serious, relevant immunosuppression in humans, with the exception of marijuana-smoking which may affect local broncho-alveolar immunity.

Animals↗
PubMed1991

Marijuana's interaction with brain reward systems: update 1991.

The most pervasive commonality amongst noncannabinoid drugs of abuse is that they enhance electrical brain stimulation reward and act as direct or indirect dopamine agonists in the reward relevant dopaminergic projections of the medial forebrain bundle (MFB). These dopaminergic projections constitute a crucial drug sensitive link in the brain's reward circuitry, and abused drugs derive significant abuse liability from enhancing these circuits. Marijuana and other cannabinoids were long considered "anomalous" drugs of abuse, lacking pharmacological interaction with these brain reward substrates. It is now clear, however, that delta 9-tetrahydrocannabinol (delta 9-THC), marijuana's principal psychoactive constituent, acts on these brain reward substrates in strikingly similar fashion to noncannabinoid drugs of abuse. Specifically, delta 9-THC enhances MFB electrical brain stimulation reward, and enhances both basal and stimulated dopamine release in reward relevant MFB projection loci. Furthermore, delta 9-THC's actions on these mechanisms is naloxone blockable, and delta 9-THC modulates brain mu and delta opioid receptors. This paper reviews these data, suggests that marijuana's interaction with brain reward systems is fundamentally similar to that of other abused drugs, and proposes a specific neural model of that interaction.

Animals↗
PubMed2006

Expanding role of AMPK in endocrinology.

Adenosine 5' monophosphate-activated protein kinase (AMPK) is a regulator of cellular and systemic energy homeostasis. It mediates some of the effects of peripheral hormones such as leptin, ghrelin and adiponectin, and it is involved in the insulin-sensitizing role of the antidiabetic drug metformin. There is increasing evidence that AMPK has a central role in mediating the appetite-modulating and metabolic effects of many other hormones and substances, including the cannabinoids. Recent studies have illustrated the interaction between hormones and AMPK, and highlighted AMPK as a potential target for the development of tissue-specific AMPK modulators in the treatment of obesity and the metabolic syndrome.

AMP-Activated Protein Kinases↗
PubMed2001

Modulation of dopamine release in the guinea-pig retina by G(i)- but not by G(s)- or G(q)-protein-coupled receptors.

The modulation of dopamine release from the guinea-pig retina was studied using maximally effective concentrations of 10 agonists acting on G(i)-, G(s)- or G(q)-protein-coupled receptors (PCRs). Retinal discs were preincubated with [(3)H]noradrenaline and superfused; tritium overflow was evoked electrically. The following compounds acting on G(i)-PCRs reduced the tritium overflow, which represents quasi-physiological dopamine release under the experimental conditions of our study: the dopamine and alpha(2)-adrenoceptor agonist B-HT 920 by 95%, the muscarinic agonist oxotremorine by 96%, melatonin by 94%, the cannabinoid agonist WIN 55,212-2 by 71% and histamine by 66%. Tritium overflow was not affected by serotonin or by agonists acting on G(s)-PCRs (ACTH1-24 and the beta-adrenoceptor agonist procaterol) and G(q)-PCRs (angiotensin II and bradykinin). The effects of B-HT 920, oxotremorine and melatonin were studied in more detail using appropriate antagonists. The inhibitory effect of a submaximally active concentration of B-HT 920 was counteracted by the dopamine D(2/3) antagonist haloperidol but not affected by the alpha(2)-adrenoceptor antagonist phentolamine. The muscarinic antagonist atropine shifted to the right the concentration-response curve of oxotremorine (pA(2) 8.7) and the melatonin MT(2) antagonist 4-P-PDOT produced a rightward shift of the concentration-response curve of melatonin (pA(2) 10.6). Melatonin was also studied in superfused brain slices (from the guinea-pig) preincubated with [(3)H]noradrenaline. The electrically evoked tritium overflow in cerebrocortical, hippocampal and hypothalamic slices (representing quasi-physiological noradrenaline release) and in striatal slices (representing quasi-physiological dopamine release) was not affected by melatonin at a concentration that causes the maximum effect in retinal discs. In conclusion, dopamine release in the guinea-pig retina is inhibited via G(i)-PCRs including dopamine (D(2/3)), muscarinic and melatonin (MT(2)) receptors but not affected via any of the G(s)- or G(q)-PCRs under study. Unlike in the retina, melatonin fails to inhibit monoamine release in four brain regions of the guinea-pig.

Animals↗
PubMed2006

Investigational therapies in the treatment of obesity.

Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.

Animals↗
PubMed2006

CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms.

In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)-AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)-AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5-L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2-mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up-regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)-AM1241 dose dependently (EC50 of 3.6 and 4.5 nM, respectively) reduced capsaicin-induced calcitonin gene-related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)-AM1241 and L768242, respectively) of the dose-response curve. Experiments on capsaicin-induced CGRP release in tissue from CB1-/- mice ruled out a CB1-mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.

Analgesics↗
PubMed1998

An analgesia circuit activated by cannabinoids.

Although many anecdotal reports indicate that marijuana and its active constituent, delta-9-tetrahydrocannabinol (delta-9-THC), may reduce pain sensation, studies of humans have produced inconsistent results. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs are confounded by motor deficits. Here we show that a brainstem circuit that contributes to the pain-suppressing effects of morphine is also required for the analgesic effects of cannabinoids. Inactivation of the rostral ventromedial medulla (RVM) prevents the analgesia but not the motor deficits produced by systemically administered cannabinoids. Furthermore, cannabinoids produce analgesia by modulating RVM neuronal activity in a manner similar to, but pharmacologically dissociable from, that of morphine. We also show that endogenous cannabinoids tonically regulate pain thresholds in part through the modulation of RVM neuronal activity. These results show that analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.

Analgesia↗