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Purpose: Neuropathic pain involves injury or alteration of the normal sensory and modulatory nervous systems to produce a set of symptoms that are often difficult to treat. Previous study indicates that crocin has anti-inflammatory properties that may be mediated by the neurotransmitter system. In this study, we determine if there is an interaction between crocin and the cannabinoid system on chronic constriction injury (CCI)-induced neuropathic pain in male rats. Materials and Methods: In this experimental study, adult male Wistar rats (220– 250 g) were used. CCI was induced by setting four loose ligatures around the sciatic nerve. In part 1, after nerve lesion, vehicle, crocin (60 mg/kg) or Win 55-212-2 (0.1 mg/kg) as an agonist and AM 251 (0.1 mg/kg) as an antagonist of cannabinoid receptors were injected intraperitoneally daily in separate groups for 2 weeks. In part 2, two weeks after nerve lesion, vehicle (5 μL), crocin (6 μg/5 μL), Win 55-212-2 (0.1 μg/5 μL), AM 251 (0.1 μg/5 μL) were administered intracerebroventricularly (ICV) in separate groups. Mechanical allodynia and thermal hyperalgesia were measured using Von Frey filaments and plantar test device, respectively, at day 14. Data were analyzed by two-way ANOVA and Sidak's multiple comparisons post-test. Results: Results indicated that centrally administered crocin significantly decreased thermal hyperalgesia and mechanical allodynia. Also, peripheral injection of crocin significantly decreased mechanical allodynia but not thermal hyperalgesia. Central or peripheral administration of Win 55-212-2 or AM  251 modulates the analgesic effect of crocin significantly. Conclusion: Our findings showed that crocin has significant analgesic effects that are probably mediated by an endocannabinoid mechanism. [ABSTRACT FROM AUTHOR] more...

Background: Like emotional symptoms such as anxiety, modulations in working memory are among the frequently-reported but controversial psychiatric symptoms associated with nicotine (NC) administration. In the present study, repeated NC-induced modulations in working memory, along with concurrently-observed anxietyrelated behavioral alterations, were investigated in mice, and compared with the effects of a typical cognitionimpairing stressor, immobilization stress (IM). Furthermore, considering the structural and functional contributions of brain cannabinoid (CB) receptors in NC-induced psychiatric symptoms including emotional symptoms, the interactive effects of brain CB receptor ligands (CB ligands) and NC and/or IM on the working memory- and anxiety-related behaviors were examined. Results: Statistically significant working memory impairment-like behavioral alterations in the Y-maze test and anxiety-like behavioral alterations in the elevated plus-maze (EPM) test were observed in the groups of mice treated with 0.8 mg/kg NC (subcutaneous (s.c.) 0.8 mg/kg treatment, 4 days) and/or IM (10 min treatment, 4 days). In the group of mice treated with NC plus IM (NC-IM group), an enhancement of the behavioral alterations was observed. Among the CB type 1 (CB1) antagonist AM 251 (AM), the non-selective CB agonist CP 55,940 (CP), and the CB1 partial agonist/antagonist virodhamine (VD), significant recovering effects were provided by AM (0.2-2.5 mg/kg) and VD (5 mg/kg) against the working memory impairment-like behaviors, whereas significant anxiolytic-like effects (recoveries from both attenuated percentage of entries into open arms and attenuated percentage of time spent on open arms) were provided by VD (1-10 mg/kg) and CP (2 mg/kg) against the anxiety-like behaviors. Conclusions: Although working memory impairment- and anxiety-like behavioral alterations were commonly induced in the NC, IM, and NC-IM groups and the therapeutic involvement of CB receptors was shown, there were discrepancies in the types of effective CB ligands between the working memory- and anxiety-related behaviors. The differential involvements of CB receptor subtypes and indirectly activated neurotransmitter systems may contribute to these discrepancies. [ABSTRACT FROM AUTHOR] more...

Exposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxy phenylglycine (DHPG) induces epileptiform activity in the CA3 region of the hippocampus that persists following washout of DHPG. DHPG also can cause long-term depression of synaptic transmission, and at some synapses this may be mediated by endocannabinoids. We evaluated whether the selective cannabinoid type 1 (CB1) receptor antagonists SR 141716 or AM 251 could modify induction of epileptiform activity produced by DHPG exposure. The induction of epileptiform activity by DHPG exposure was significantly reduced by CB1 receptor antagonists, SR 141716 or AM 251. Minimal effects on epileptiform activity were noted once the activity had been induced. In control slices, exposure to DHPG for 30 min produced long-term depression (LTD) of synaptic transmission, on average about a 70% reduction in slope of the field excitatory postsynaptic potential (EPSP). When slices were exposed to both DHPG and SR 141716 (3 μm), LTD did not occur and the population EPSP remained at control values or greater. These results suggest that CB1 receptors mediate some of DHPG effects that result in persistent epileptiform activity, and antagonism of CB1 receptors has antiepileptogenic properties. Paradoxically DHPG also caused LTD of excitatory synaptic transmission in the CA3 region and CB1 receptor antagonism prevents the depression. We hypothesize that the ictal activity induced by DHPG requires depression of synaptic strength and CB1 receptor antagonism prevents this depression and the induction of ictal activity. [ABSTRACT FROM AUTHOR] more...

The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicle-injected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0·5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected. [ABSTRACT FROM PUBLISHER] more...

Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1–10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30–70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1–3 mg/kg) also significantly and dose-dependently inhibited (by 25–90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.Neuropsychopharmacology (2008) 33, 1735–1745; doi:10.1038/sj.npp.1301552; published online 29 August 2007 [ABSTRACT FROM AUTHOR] more...

Background and purpose:A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature.Experimental approach:VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum.Key results:VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca2+-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor.Conclusions and implications:VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses.British Journal of Pharmacology (2007) 152, 751–764; doi:10.1038/sj.bjp.0707470; published online 24 September 2007 [ABSTRACT FROM AUTHOR] more...

The cannabinoid 1 (CB(1)) receptor has been implicated in the regulation of food intake. Here, we examine the effect of the CB(1) receptor antagonist AM 251 on food intake and body weight over a prolonged period. Further, we examine whether AM 251 produces conditioned taste aversion (CTA) and if sustained antagonism at central receptors contributes to its anorectic effect. The effect of AM 251 of food intake and body weight was examined in daily (1 mg kg(-1)) and 5-day (5 mg kg(-1)) dosing schedules. Matching reductions in food intake and body weight were observed in both paradigms. A single administration of AM 251 (5 mg kg(-1)) significantly reduced food intake for 4 days. Tolerance to the anorectic effects of AM 251 did not develop in either dosing strategy. Active avoidance of AM 251 (3; 5 mg kg(-1), i.p.) was examined using a CTA assay. Rats showed no evidence of CTA associated with AM 251. We investigated the sustained effect of AM 251 (5 mg kg(-1), i.p.) on CB(1) receptors in the hypothalamus using Delta(9)-tetrahydrocannabinol (8 mg kg(-1), i.p.) induced hypothermia. AM 251 initially blocked hypothermia, but this effect was not seen 2 or 4 days later. The results demonstrate that smaller, or infrequent, administrations of AM 251 can produce sustained reductions in food intake and body weight in rat. Reductions in food intake were sustained longer than AM 251 antagonized the effects of a CB(1) receptor agonist in the hypothalamus, and occurred independently of CTA. [ABSTRACT FROM AUTHOR] more...