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Papers by mehdi ghasemi

Epilepsy Research, 2007

Although several studies have indicated that the opioid receptor agonist morphine exerts biphasic... more Although several studies have indicated that the opioid receptor agonist morphine exerts biphasic effects on clonic seizure threshold, as yet little is known of the underlying mechanisms in this effect. In the present study, using the specific ATP-sensitive K + (K ATP ) channel blocker glibenclamide and the specific K ATP channel opener cromakalim, the possible involvement of K ATP channels in the effects of morphine on pentylenetetrazole (PTZ)-induced seizure threshold in mice was investigated. Acute administration of lower doses of morphine (1, 3 and 7.5 mg/kg, i.p.) increased and higher doses of morphine (30 and 60 mg/kg, i.p.) decreased the PTZ-induced seizure threshold. Glibenclamide (2.5-5 mg/kg) increased the PTZ-induced seizure threshold. Non-effective dose of cromakalim (0.1 g/kg) inhibited anticonvulsant effect of glibenclamide (5 mg/kg). Acute administration of non-effective dose of glibenclamide (1 mg/kg) interestingly inhibited both anticonvulsant and proconvulsant effects of morphine and this effect was significantly reversed by cromakalim (0.1 g/kg). These results support the involvement of K ATP channels in the modulation of seizure threshold by morphine.

Journal of Gastroenterology and Hepatology, 2008

Background and Aim: Several studies have reported that endogenous opioid and cannabinoid systems... more Background and Aim: Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure.Methods: The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB1 receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined.Results: Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level.Conclusions: Both opioid and cannabinoid CB1 receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.

British Journal of Pharmacology, 2007

Background and purpose:Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) re... more Background and purpose:Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.Experimental approach:Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation.Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation.Key results:The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB1 antagonist) or capsazepine (vanilloid VR1 antagonist), but not AM630 (CB2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups.The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB1 antagonist) or capsazepine (vanilloid VR1 antagonist), but not AM630 (CB2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups.Conclusions and implications:Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB1 and vanilloid VR1 receptors.British Journal of Pharmacology (2007) 151, 591–601; doi:10.1038/sj.bjp.0707279Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB1 and vanilloid VR1 receptors.British Journal of Pharmacology (2007) 151, 591–601; doi:10.1038/sj.bjp.0707279

Journal of Psychopharmacology, 2010

Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the ac... more Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P < 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P < 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P < 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.

Nitric Oxide-biology and Chemistry, 2007

Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism... more Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism that has not yet been defined. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of rat isolated corpus cavernosum. The isolated rat corporeal strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation (EFS) was applied at different frequencies (2, 5, 10, and 15 Hz) to obtain NANC-mediated relaxation or relaxed by adding cumulative doses of acetylcholine (10nM-1mM) to obtain endothelium-dependent relaxation in the presence or absence of lithium (0.3, 0.5, 1, and 5mM). Also, effects of combining lithium (0.3mM) with 30 nM and 0.1 nM L-NAME (an NO synthase inhibitor) on NANC- and acetylcholine-mediated relaxation was investigated, respectively. Moreover, effects of combining lithium (1mM) with 0.1mM and 10 microM L-arginine (a precursor of NO) on NANC- and endothelium-mediated relaxation was assessed, respectively. Also, the effect of lithium (1mM) on relaxation to sodium nitroprusside (SNP; 1nM-1mM), an NO donor, was investigated. The NANC-mediated relaxation was significantly (P<0.001) reduced by 1 and 5mM, but not by 0.3 and 0.5mM lithium. Lithium significantly (P<0.001) attenuated the maximum response to acetylcholine in a concentration-dependent manner. Combination of lithium (0.3mM) with 30 and 0.1 nM L-NAME, which separately had a minimum effect on NANC- and endothelium-mediated relaxation, significantly (P<0.001) reduced the NANC- and endothelium-mediated relaxation, respectively. Although L-arginine at 10 microM and 0.1mM did not alter the relaxant responses to acetylcholine and EFS, it improved the inhibition by lithium (1mM) of relaxant responses to acetylcholine and EFS, respectively. Also, SNP produced similar concentration-dependent relaxations from both groups. Our experiments indicated that lithium likely by interfering with NO pathway in both endothelium and nitrergic nerve can result in impairment of both the endothelium- and NANC-mediated relaxation of rat corpus cavernosum.

European Journal of Pharmacology, 2006

The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide ... more The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide on the nonadrenergic noncholinergic (NANC) relaxant responses to electrical field stimulation in isolated rat corpus cavernosum. The corporal strips were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 μM) and atropine (1 μM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 μM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated relaxation. The expression of CB 1 , CB 2 and vanilloid receptor proteins within the rat corpus cavernosum was evaluated using western blot analysis. The results showed that the relaxant responses to electrical stimulation were significantly enhanced in the presence of anandamide at 1 and 3 μM. The potentiating effect of anandamide (1 μM) on relaxation responses was significantly attenuated by either the selective cannabinoid CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; 1 μM) or the vanilloid receptor antagonist capsazepine (3 μM), but not by the selective cannabinoid CB 2 receptor antagonist 6-iodo-2methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl (4-methoxyphenyl)methanone (AM630; 1 μM). Neither of these antagonists had influence on relaxation responses. Indomethacin (20 μM) had no effect on NANC-mediated relaxation in the presence or absence of anandamide (1 μM). Preincubation with N w -Nitro-L-Arginine Methyl Ester (L-NAME; 1 μM) significantly inhibited the relaxation responses in the presence or absence of 1 μM anandamide. Although at 30 nM, L-NAME did not cause a significant inhibition of relaxant responses individually, it significantly inhibited the potentiating effect of anandamide (1 μM) on relaxation responses. Anandamide (1 μM) had no influence on concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1 mM), a nitric oxide (NO) donor. The western blotting of corporal tissues demonstrated the existence of both vanilloid and CB 1 receptors in corporal strips. In conclusion, our results showed that anandamide has a potentiating effect on NANC-mediated relaxation of rat corpus cavernosum through both CB 1 and vanilloid receptors and the NO-mediated component of the NANC relaxant responses to electrical stimulation is involved in this enhancement.

European Journal of Pharmacology, 2008

Cannabinoids are psychoactive compounds with many pharmacological properties such as analgesia, s... more Cannabinoids are psychoactive compounds with many pharmacological properties such as analgesia, sedation and catalepsy most of which are mediated by cannabinoid CB 1 receptors. In the present study, we evaluated whether the ovarian sex hormones are involved in the cannabinoidinduced catalepsy and analgesia in ovariectomized female mice. Female NMRI mice (weighing 25-30 g) were divided into 3 main groups: unoperated, sham-operated and ovariectomized. Both the catalepsy and analgesia induced by different doses of the synthetic cannabinoid WIN 55,212-2 (2 and 4 mg/kg, i.p.) were examined in the groups in the presence or absence of the cannabinoid CB 1 antagonist AM251 (0.5 mg/kg). We also evaluated effects of estradiol valerate (10 mg/kg) and progesterone (25 mg/kg) on catalepsy and analgesia induced by WIN 55,212-2 in ovariectomized mice. The antinociceptive effect of WIN 55,212-2 was significantly (P b 0.01) enhanced in ovariectomized mice, which was prevented by pretreatment with estradiol but not by progesterone. There was no significant difference in the cannabinoid-induced catalepsy between control and ovariectomized mice. However, pretreatment with progesterone but not estradiol potentiated the cataleptic effect of low dose of WIN 55,212-2 (2 mg/kg) in ovariectomized mice (P b 0.01). The present data demonstrated for the first time that ovarian sex steroids could modulate both cannabinoid-induced catalepsy and analgesia in female ovariectomized mice.

Nitric Oxide-biology and Chemistry, 2009

In the present study, we evaluated the effect of lithium on the nitric oxide (NO)-mediated nonadr... more In the present study, we evaluated the effect of lithium on the nitric oxide (NO)-mediated nonadrenergic noncholinergic (NANC) relaxation of rat anococcygeus muscle. The isolated precontracted (phenylephrine, 7.5 lM) rat anococcygeus muscle were relaxed via electrical field stimulation (5 Hz) in the absence or presence of lithium (0.5, 1, and 5 mM) or in tissues excised from ex vivo lithium (600 mg/L in drinking water for 30 days)-treated animals. Effects of the NO synthase (NOS) inhibitor L-NAME (0.03 and 100 lM) or guanylyl cyclase inhibitor ODQ (1 lM) and NO precursor L-arginine (1 mM) on relaxations were investigated. Effect of either in vitro (1 and 5 mM) or ex vivo lithium treatment on relaxation to the NO donor sodium nitroprusside (SNP; 0.1-1000 lM) was also investigated on phenylephrine-contracted strips. The NANC relaxation was significantly reduced by in vitro (1 and 5 mM; up to P < 0.01) and ex vivo lithium treatment (P < 0.001). L-NAME (100 lM and 1 mM) and ODQ (1 and 10 lM) significantly inhibited NANC relaxations in either control or lithium-treated strips. Combination of lithium (0.5 mM) with L-NAME (0.03 lM) significantly (P < 0.001) reduced the NANC relaxation. Although 1 mM L-arginine had no effect on relaxations, it prevented their inhibition by both in vitro (1 and 5 mM) and ex vivo lithium of relaxations. SNP produced concentration-dependent relaxation in precontracted rat anococcygeus muscle which was not altered by lithium treatment. Reverse transcription polymerase chain reaction (RT-PCR) revealed a significant increase in the neuronal NOS expression in the anococcygeus muscle of ex vivo lithium-treated animals compared with controls. Our experiments suggested that both ex vivo and in vitro lithium administration attenuated the NO-mediated neurogenic relaxation of isolated rat anococcygeus muscle.

Journal of Hepatology, 2007

Background/Aims: The clinical relevance of QT prolongation, the most widely recognized cardiac el... more Background/Aims: The clinical relevance of QT prolongation, the most widely recognized cardiac electrophysiological abnormality of cirrhosis, is still undefined. The aim of this study is to examine the susceptibility of chronic (4-week) bile duct-ligated rats to epinephrine-induced arrhythmias. The roles of nitric oxide and endogenous opioids were also evaluated.

Behavioural Brain Research, 2007

Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we as... more Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we assessed the involvement of NO pathway in the estrous cycle-related changes of anxiety level in rat. By using elevated plus-maze test, we studied the changes of serum nitrate and nitrite (NO x ) levels in comparison to the estrous cycle-dependent changes of anxiety state. Then, we tested the effects of nitric oxide synthase (NOS) inhibitor, L-NAME (10, 60 mg/kg, i.p.), and the NO precursor, l-arginine (100 mg/kg, i.p.) on anxiety modulatory properties of exogenous ovarian hormones in ovariectomized (OVX) rats. Compared with other cycle phases and with OVX rats, cycling rats spent more time in open arms and had lower levels of serum NO x levels during metestrous while they spent less time in open arms and had lower levels of serum NO x levels during proestrous. In OVX rats, L-NAME (60 mg/kg, i.p.) exerted anxiolytic effect while l-arginine showed no effect. In comparison with corn oil-treated controls, estradiol benzoate (10 g/kg, subcutaneously (s.c.)) significantly increased the serum NO x level and exerted anxiogenic effect, which was dose-dependently inhibited by L-NAME but was not changed by l-arginine. In contrast, progesterone (25 mg/kg, s.c.) significantly decreased the serum NO x level and exerted anxiolytic effect, which was abolished by l-arginine but was not affected by L-NAME. These findings suggest that NO system might be involved in the estrous cycle-related changes of anxiety level, probably by mediating the effect of ovarian sex hormones. (H.R. Sadeghipour).

Bju International, 2007

OBJECTIVETo verify the effect of chronic lithium administration on the endothelium-dependent rela... more OBJECTIVETo verify the effect of chronic lithium administration on the endothelium-dependent relaxation of rat corpus cavernosum, as lithium is a major drug for treating bipolar disorder and some studies showed that lithium might cause erectile dysfunction in such patients, by a mechanism as yet unknown.To verify the effect of chronic lithium administration on the endothelium-dependent relaxation of rat corpus cavernosum, as lithium is a major drug for treating bipolar disorder and some studies showed that lithium might cause erectile dysfunction in such patients, by a mechanism as yet unknown.MATERIALS AND METHODSLiCl (600 mg/L) was dissolved in drinking water and Sprague–Dawley rats received the solution for 30 days; control rats received tap water. After 30 days corporeal strips were prepared from both groups, mounted under tension in oxygenated organ baths, and pre-contracted with phenylephrine (7.5 µm). After equilibration, the strips were relaxed by acetylcholine (10 nm to 1 mm) in the presence or absence of indomethacin (a cyclooxygenase inhibitor; 20 µm). Furthermore, the relaxant responses to sodium nitroprusside (1 nm to 1 mm), a nitric oxide (NO) donor, were investigated in both groups. NADPH-diaphorase histochemistry was used to identify NO synthase within cavernosal tissue strips of both groups.LiCl (600 mg/L) was dissolved in drinking water and Sprague–Dawley rats received the solution for 30 days; control rats received tap water. After 30 days corporeal strips were prepared from both groups, mounted under tension in oxygenated organ baths, and pre-contracted with phenylephrine (7.5 µm). After equilibration, the strips were relaxed by acetylcholine (10 nm to 1 mm) in the presence or absence of indomethacin (a cyclooxygenase inhibitor; 20 µm). Furthermore, the relaxant responses to sodium nitroprusside (1 nm to 1 mm), a nitric oxide (NO) donor, were investigated in both groups. NADPH-diaphorase histochemistry was used to identify NO synthase within cavernosal tissue strips of both groups.RESULTSThe acetylcholine-dependent relaxation was significantly lower in lithium-treated rats than in controls. Although indomethacin decreased significantly the relaxant responses to acetylcholine in controls, it increased the relaxant responses in lithium-treated rats. NADPH-diaphorase staining was greater in the chronic lithium-treated than in control preparations. Sodium nitroprusside produced similar relaxation in both groups.The acetylcholine-dependent relaxation was significantly lower in lithium-treated rats than in controls. Although indomethacin decreased significantly the relaxant responses to acetylcholine in controls, it increased the relaxant responses in lithium-treated rats. NADPH-diaphorase staining was greater in the chronic lithium-treated than in control preparations. Sodium nitroprusside produced similar relaxation in both groups.CONCLUSIONChronic lithium administration can impair the endothelium-dependent relaxation of rat corpus cavernosum; NO availability might decrease after lithium administration and the cyclooxygenase pathways might have a role in this effect.Chronic lithium administration can impair the endothelium-dependent relaxation of rat corpus cavernosum; NO availability might decrease after lithium administration and the cyclooxygenase pathways might have a role in this effect.

Bju International, 2007

OBJECTIVETo investigate the ability of acute administration of the endogenous cannabinoid, ananda... more OBJECTIVETo investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35–75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED.To investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35–75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED.MATERIALS AND METHODSDiabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured.Diabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured.RESULTSThe neurogenic relaxation of phenylephrine (7.5 µm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 µm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB1 receptor antagonist AM251 (1 µm) and the selective vanilloid receptor antagonist capsazepine (3 µm). Concurrent administration of partially effective doses of l-arginine (10 µm) and anandamide (0.3 µm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups.The neurogenic relaxation of phenylephrine (7.5 µm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 µm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB1 receptor antagonist AM251 (1 µm) and the selective vanilloid receptor antagonist capsazepine (3 µm). Concurrent administration of partially effective doses of l-arginine (10 µm) and anandamide (0.3 µm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups.CONCLUSIONFor the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l-arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB1 and vanilloid VR1 receptors within the CC.For the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l-arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB1 and vanilloid VR1 receptors within the CC.

European Journal of Pharmacology, 2008

In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiova... more In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiovascular actions. Recently, they have been suggested to protect the myocardium against ischemia/reperfusion injury. The aim of this study is to examine the contribution of endogenous cannabinoids to cardioprotection afforded by remote ischemic preconditioning. Three groups of remote preconditioned (15 min of mesenteric artery occlusion followed by 15 min of reperfusion) and three groups of sham-operated rats were included in the study. Animals were pretreated intravenously by vehicle, cannabinoid CB 1 (AM251, 1 mg/kg) or CB 2 (AM630, 1 mg/kg) receptor antagonist 15 min prior to remote preconditioning or sham operation. Myocardial injury was induced by 30 min of coronary artery occlusion followed by 2 h of reperfusion. The resultant arterial hypotension, ventricular arrhythmias, and infarct size were compared among the groups. Remote preconditioning exerted potent cardioprotection manifested as significant reductions in infarct size (P b 0.001) as well as number and duration of arrhythmias (P b 0.01, 0.01 and 0.05 for premature ventricular contractions, ventricular tachycardias and fibrillations; respectively). The cannabinoid CB 1 receptor antagonist pretreatment had no significant effect on ischemia-induced hypotension, arrhythmias or infarct size. On the other hand, the cannabinoid CB 2 receptor antagonist pretreatment abolished the protective effects of remote preconditioning on infarct size (P b 0.01) and arrhythmias (P b 0.01), without any significant effect on ischemia-induced hypotension. The results of this study suggest that endogenous cannabinoids, through acting on cannabinoid CB 2 receptors, are involved in the cardioprotective phenomenon of remote ischemic preconditioning, induced by mesenteric artery occlusion and reperfusion.

Neuropharmacology, 2007

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have i... more Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G i/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. However, regarding the seizure modulating properties of both classes of receptors this study investigated whether ultra-low dose cannabinoid antagonist AM251 influences cannabinoid anticonvulsant effects. The clonic seizure threshold (CST) was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the cannabinoid CB 1 antagonist AM251 and a combination of ACEA and AM251 doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic administration of ultra-low doses of AM251 (10 fg/kge100 ng/kg) significantly potentiated the anticonvulsant effect of ACEA at 0.5 and 1 mg/kg. Moreover, inhibition of cannabinoid induced excitatory signaling by AM251 (100 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (100 ng/kge100 mg/kg), suggesting that a presumed inhibitory component of cannabinoid receptor signaling can exert strong seizureprotective effects even at very low levels of cannabinoid receptor activation. A similar potentiation by AM251 (100 pg/kg and 1 ng/kg) of anticonvulsant effects of non-effective dose of ACEA (0.5 and 1 mg/kg) was also observed in the generalized toniceclonic model of seizure. The present data suggest that ultra-low doses of cannabinoid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of cannabinoids.

Behavioural Brain Research, 2009

In the present study we evaluated the involvement of nitric oxide (NO) system in the antidepressa... more In the present study we evaluated the involvement of nitric oxide (NO) system in the antidepressantlike effects of chronic lithium administration in the mouse forced swimming test (FST). Administration of lithium chloride (300 mg/L in drinking water for 21 days) had no effect on the immobility of mice in the FST, whereas 600 mg/L lithium caused a significant (P < 0.001) decrease in the immobility time compared with control animals. Administration of the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, daily for a week, i.p.) had no significant effect on the immobility time of either control or lithium (300 mg/L)-treated mice, whereas acute administration of non-effective dose of L-NAME (30 mg/kg, i.p.) caused a robust decrease (P < 0.01) in the immobility time of lithium (300 mg/L)-treated animals in the FST. Moreover, chronic administration of low dose of the NO precursor L-arginine (200 mg/kg, daily for a week, i.p.) prevented (P < 0.001) the antidepressant-like effects of lithium treatment (600 mg/L) in the FST. Acute treatment with L-arginine (200 mg/kg, i.p.) increased (P < 0.05) the immobility time of lithium (600 mg/L)-treated mice in the FST. Chronic lithium treatment (600 mg/L but not 300 mg/L) caused a significant (P < 0.05) decrease in the serum NO X levels in mice compared with controls. Our data suggested that the NO system could be involved in the antidepressant-like effect of chronic lithium treatment in the FST.

Seizure-european Journal of Epilepsy, 2010

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptami... more There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.

European Neuropsychopharmacology, 2008

In the present study we evaluated the involvement of L-arginine/nitric oxide (NO)/cGMP pathway in... more In the present study we evaluated the involvement of L-arginine/nitric oxide (NO)/cGMP pathway in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test (FST). Lithium, at 30 and 100 mg/kg, significantly reduced the immobility times of mice in the FST, whereas at lower doses (0.5, 5 and 10 mg/kg) had no effect on the immobility time. The NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME), at 10 and 30 mg/kg, and the selective neuronal NOS inhibitor N ω -propyl-L-arginine (L-NPA), at 5 and 15 mg/kg, had no significant effects on the FST, whereas they significantly decreased the immobility time at 100 and 30 mg/kg, respectively. Combination of non-effective dose of lithium (10 mg/kg) with low doses of L-NAME (30 mg/kg) or L-NPA (15 mg/kg) significantly reduced the immobility times in the FST. Moreover, the guanylyl cyclase inhibitor ODQ at 50 mg/kg significantly decreased the immobility time of mice, whereas it had not significant effects on the FST at 2, 10 and 20 mg/kg. Combination of lithium (10 mg/kg) with 20 mg/kg ODQ significantly decreased the immobility times in the FST. Non-effective doses of L-arginine (750 mg/kg) or sildenafil (5 mg/kg) significantly reversed the antidepressant-like effect of 30 mg/kg lithium in the FST. Neither of the drugs had effect on the locomotor activity. These data indicate the involvement of Larginine/NO/cGMP pathway in the antidepressant-like effect of lithium in the mouse FSTand also might suggest the concurrent administration of NOS inhibitors and lithium as an appropriate strategy for treatment of depression.

Epilepsy Research, 2008

Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, ... more Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G i/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoidinduced antinociception. Thus, concerning the seizure modulating properties of both classes of receptors this study investigated whether the ultra-low dose opioid antagonist naltrexone influences cannabinoid anticonvulsant effects. The clonic seizure threshold was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the opioid receptor antagonist naltrexone and a combination of ACEA and naltrexone doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic injection of ultra-low doses of naltrexone (1 pg/kg to 1 ng/kg, i.p.) significantly potentiated the anticonvulsant effect of ACEA (1 mg/kg, i.p.). Moreover, the very low dose of naltrexone (500 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (10 and 100 g/kg). A similar potentiation by naltrexone (500 pg/kg) of anticonvulsant effects of non-effective dose of ACEA (1 mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data indicate that the interaction between opioid and cannabinoid systems extends to ultra-low dose levels and ultra-low doses of opioid receptor antagonist in conjunction with very low doses of cannabinoids may provide a potent strategy to modulate seizure susceptibility.

Epilepsy & Behavior, 2008

Nasal obstruction and consequent mouth breathing have been shown to change the acid-base balance,... more Nasal obstruction and consequent mouth breathing have been shown to change the acid-base balance, producing respiratory acidosis. Additionally, there exists a large body of evidence maintaining that acidosis affects the activity of ATP-sensitive potassium (K ATP ) channels, which play a crucial role in the function of the central nervous system (CNS), for example, in modulating seizure threshold. Thus, in the study described here, we examined whether mouth breathing, induced by surgical ligation of nostrils, could affect the seizure threshold induced by pentylenetetrazole in male NMRI mice. Using the selective K ATP channel opener (diazoxide) and blocker (glibenclamide), we also evaluated the possible role of K ATP channels in this process. Our data revealed that seizure threshold was increased 6 to 72 hours after nasal obstruction, reaching a peak 48 hours afterward, compared with either control or sham-operated mice (P < 0.01). There was a significant decrease in pH of arterial blood samples and increase in CO 2 partial pressure (PCO 2 ) during this time. Systemic injection of glibenclamide (1 and 2 mg/kg, ip, daily) significantly prevented the increase in seizure threshold in 48-hour bilaterally nasally obstructed mice, whereas it had no effect on seizure threshold in sham-operated mice. Systemic injection of diazoxide (25 mg/kg, ip, daily) had no effect on seizure threshold in all groups, whereas higher doses (50 and 100 mg/kg, ip, daily) significantly increased seizure threshold in both 48-hour-obstructed and shamoperated mice. The decrease in seizure threshold induced by glibenclamide (2 mg/kg, ip, daily) was prevented by diazoxide (25 mg/kg, ip, daily). These results demonstrate for the first time that mouth breathing, which could result in respiratory acidosis, increases seizure threshold in mice and K ATP channels may play a role in this effect.

Nitric Oxide-biology and Chemistry, 2007

Lithium has largely met its initial promise as the first drug to be discovered in the modern era ... more Lithium has largely met its initial promise as the first drug to be discovered in the modern era of psychopharmacology. However, the mechanism for its action remains an enigma. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)-mediated relaxation of rat isolated gastric fundus and to evaluate the role of nitric oxide pathway in this manner. The isolated rat gastric fundus strips were precontracted with 0.5 microM serotonin and electrical field stimulation (EFS) was applied at 5 Hz frequency to obtain NANC-mediated relaxation in the presence or absence of lithium (0.1, 0.5, 1 and 5 mM). Also, effects of combining lithium (0.1 mM) with the NO synthase (NOS) inhibitor L-NAME (0.03 microM) or the guanylyl cyclase inhibitor ODQ (1 microM) on relaxant responses to EFS was investigated. Moreover, effects of combining lithium (1 mM) with 0.1 mM L-arginine (a precursor of NO) on neurogenic relaxation were assessed. Also, the effect of lithium (1 mM) on relaxation to sodium nitroprusside (SNP; 1 nM-0.1 mM) and glyceryltrinitrate (GTN; 0.1-10 microM) was investigated. The NANC-mediated relaxation was significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) reduced by lithium in a dose- and time-dependent manner. Combination of lithium (0.1 mM) with L-NAME (0.03 microM), which separately had partial inhibitory effect on relaxations, significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) reduced the NANC-mediated relaxation of gastric fundus. ODQ (1 microM) significantly inhibited the neurogenic relaxations in the presence or absence of lithium (0.1 and 1 mM). Although L-arginine at 0.1 mM had no effect on relaxation to EFS, it prevented the inhibition by lithium (1 mM) of relaxant responses to EFS. Also, SNP and GTN produced concentration-dependent relaxation in precontracted rat gastric fundus which was not altered by lithium incubation (1 mM). Our experiments indicated that lithium likely by interfering with L-arginine/NO pathway in nitrergic nerve can result in impairment of NANC-mediated relaxation of rat gastric fundus.

Epilepsy Research, 2007

Although several studies have indicated that the opioid receptor agonist morphine exerts biphasic... more Although several studies have indicated that the opioid receptor agonist morphine exerts biphasic effects on clonic seizure threshold, as yet little is known of the underlying mechanisms in this effect. In the present study, using the specific ATP-sensitive K + (K ATP ) channel blocker glibenclamide and the specific K ATP channel opener cromakalim, the possible involvement of K ATP channels in the effects of morphine on pentylenetetrazole (PTZ)-induced seizure threshold in mice was investigated. Acute administration of lower doses of morphine (1, 3 and 7.5 mg/kg, i.p.) increased and higher doses of morphine (30 and 60 mg/kg, i.p.) decreased the PTZ-induced seizure threshold. Glibenclamide (2.5-5 mg/kg) increased the PTZ-induced seizure threshold. Non-effective dose of cromakalim (0.1 g/kg) inhibited anticonvulsant effect of glibenclamide (5 mg/kg). Acute administration of non-effective dose of glibenclamide (1 mg/kg) interestingly inhibited both anticonvulsant and proconvulsant effects of morphine and this effect was significantly reversed by cromakalim (0.1 g/kg). These results support the involvement of K ATP channels in the modulation of seizure threshold by morphine.

Journal of Gastroenterology and Hepatology, 2008

Background and Aim: Several studies have reported that endogenous opioid and cannabinoid systems... more Background and Aim: Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure.Methods: The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB1 receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined.Results: Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level.Conclusions: Both opioid and cannabinoid CB1 receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.

British Journal of Pharmacology, 2007

Background and purpose:Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) re... more Background and purpose:Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.Relaxation of corpus cavernosum, which is mediated by nitric oxide (NO) released from non-adrenergic non-cholinergic (NANC) neurotransmission, is critical for inducing penile erection and can be affected by many pathophysiological conditions. However, the peripheral effect of liver cirrhosis on erectile function is as yet unknown. The aim of the present study was to investigate the effect of biliary cirrhosis on NANC-mediated relaxation of rat corpus cavernosum and the possible roles of endocannabinoid and nitric oxide systems in this model.Experimental approach:Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation.Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, strips of corpus cavernosum were mounted in a standard organ bath and NANC-mediated relaxations were obtained by applying electrical field stimulation.Key results:The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB1 antagonist) or capsazepine (vanilloid VR1 antagonist), but not AM630 (CB2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups.The NANC-mediated relaxation was enhanced in corporal strips from cirrhotic animals. Anandamide potentiated the relaxations in both groups. Either AM251 (CB1 antagonist) or capsazepine (vanilloid VR1 antagonist), but not AM630 (CB2 antagonist), prevented the enhanced relaxations of cirrhotic strips. Either the non-selective NOS inhibitor L-NAME or the selective neuronal NOS inhibitor L-NPA inhibited relaxations in both groups, but cirrhotic groups were more resistant to the inhibitory effects of these agents. Relaxations to sodium nitroprusside (NO donor) were similar in tissues from the two groups.Conclusions and implications:Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB1 and vanilloid VR1 receptors.British Journal of Pharmacology (2007) 151, 591–601; doi:10.1038/sj.bjp.0707279Cirrhosis potentiates the neurogenic relaxation of rat corpus cavernosum probably via the NO pathway and involving cannabinoid CB1 and vanilloid VR1 receptors.British Journal of Pharmacology (2007) 151, 591–601; doi:10.1038/sj.bjp.0707279

Journal of Psychopharmacology, 2010

Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the ac... more Although there is evidence of the involvement of N-methyl-D-aspartate receptors (NMDAR) in the action of lithium, its role in the antidepressant effects of lithium in a behavioural model remains unclear. In this study, we evaluated the effects of NMDAR antagonists on the antidepressant-like effects of lithium in the mouse forced swimming test. Lithium (30 and 100 mg/kg, i.p.) significantly (P &lt; 0.01) reduced the immobility times of mice, whereas at lower doses (5 and 10 mg/kg) had no effect. NMDA antagonists ketamine (2 and 5 mg/kg, i.p.), MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) significantly (P &lt; 0.05) decreased the immobility time. Lower doses of ketamine (0.5 and 1 mg/kg), MK-801 (0.01 and 0.05 mg/kg) and ifenprodil (0.1 and 0.5 mg/kg) had no effect. Combined treatment of subeffective doses of lithium (10 mg/kg) and ketamine (1 mg/kg), MK-801 (0.05 mg/kg) or ifenprodil (0.5 mg/kg) robustly (P &lt; 0.001) exerted an antidepressant-like effect. The noneffective dose of a NMDA agonist (NMDA, 75 mg/kg, i.p.) prevented the antidepressant-like effect of lithium (30 mg/kg). None of the drugs at subactive doses or in combination with lithium had significant effect on the locomotor activity in the open field test. We for the first time suggested a role for NMDAR signalling in the antidepressant-like effects of lithium, providing a new approach for treatment of depression.

Nitric Oxide-biology and Chemistry, 2007

Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism... more Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism that has not yet been defined. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of rat isolated corpus cavernosum. The isolated rat corporeal strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation (EFS) was applied at different frequencies (2, 5, 10, and 15 Hz) to obtain NANC-mediated relaxation or relaxed by adding cumulative doses of acetylcholine (10nM-1mM) to obtain endothelium-dependent relaxation in the presence or absence of lithium (0.3, 0.5, 1, and 5mM). Also, effects of combining lithium (0.3mM) with 30 nM and 0.1 nM L-NAME (an NO synthase inhibitor) on NANC- and acetylcholine-mediated relaxation was investigated, respectively. Moreover, effects of combining lithium (1mM) with 0.1mM and 10 microM L-arginine (a precursor of NO) on NANC- and endothelium-mediated relaxation was assessed, respectively. Also, the effect of lithium (1mM) on relaxation to sodium nitroprusside (SNP; 1nM-1mM), an NO donor, was investigated. The NANC-mediated relaxation was significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) reduced by 1 and 5mM, but not by 0.3 and 0.5mM lithium. Lithium significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) attenuated the maximum response to acetylcholine in a concentration-dependent manner. Combination of lithium (0.3mM) with 30 and 0.1 nM L-NAME, which separately had a minimum effect on NANC- and endothelium-mediated relaxation, significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) reduced the NANC- and endothelium-mediated relaxation, respectively. Although L-arginine at 10 microM and 0.1mM did not alter the relaxant responses to acetylcholine and EFS, it improved the inhibition by lithium (1mM) of relaxant responses to acetylcholine and EFS, respectively. Also, SNP produced similar concentration-dependent relaxations from both groups. Our experiments indicated that lithium likely by interfering with NO pathway in both endothelium and nitrergic nerve can result in impairment of both the endothelium- and NANC-mediated relaxation of rat corpus cavernosum.

European Journal of Pharmacology, 2006

The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide ... more The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide on the nonadrenergic noncholinergic (NANC) relaxant responses to electrical field stimulation in isolated rat corpus cavernosum. The corporal strips were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 μM) and atropine (1 μM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 μM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated relaxation. The expression of CB 1 , CB 2 and vanilloid receptor proteins within the rat corpus cavernosum was evaluated using western blot analysis. The results showed that the relaxant responses to electrical stimulation were significantly enhanced in the presence of anandamide at 1 and 3 μM. The potentiating effect of anandamide (1 μM) on relaxation responses was significantly attenuated by either the selective cannabinoid CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; 1 μM) or the vanilloid receptor antagonist capsazepine (3 μM), but not by the selective cannabinoid CB 2 receptor antagonist 6-iodo-2methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl (4-methoxyphenyl)methanone (AM630; 1 μM). Neither of these antagonists had influence on relaxation responses. Indomethacin (20 μM) had no effect on NANC-mediated relaxation in the presence or absence of anandamide (1 μM). Preincubation with N w -Nitro-L-Arginine Methyl Ester (L-NAME; 1 μM) significantly inhibited the relaxation responses in the presence or absence of 1 μM anandamide. Although at 30 nM, L-NAME did not cause a significant inhibition of relaxant responses individually, it significantly inhibited the potentiating effect of anandamide (1 μM) on relaxation responses. Anandamide (1 μM) had no influence on concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1 mM), a nitric oxide (NO) donor. The western blotting of corporal tissues demonstrated the existence of both vanilloid and CB 1 receptors in corporal strips. In conclusion, our results showed that anandamide has a potentiating effect on NANC-mediated relaxation of rat corpus cavernosum through both CB 1 and vanilloid receptors and the NO-mediated component of the NANC relaxant responses to electrical stimulation is involved in this enhancement.

European Journal of Pharmacology, 2008

Cannabinoids are psychoactive compounds with many pharmacological properties such as analgesia, s... more Cannabinoids are psychoactive compounds with many pharmacological properties such as analgesia, sedation and catalepsy most of which are mediated by cannabinoid CB 1 receptors. In the present study, we evaluated whether the ovarian sex hormones are involved in the cannabinoidinduced catalepsy and analgesia in ovariectomized female mice. Female NMRI mice (weighing 25-30 g) were divided into 3 main groups: unoperated, sham-operated and ovariectomized. Both the catalepsy and analgesia induced by different doses of the synthetic cannabinoid WIN 55,212-2 (2 and 4 mg/kg, i.p.) were examined in the groups in the presence or absence of the cannabinoid CB 1 antagonist AM251 (0.5 mg/kg). We also evaluated effects of estradiol valerate (10 mg/kg) and progesterone (25 mg/kg) on catalepsy and analgesia induced by WIN 55,212-2 in ovariectomized mice. The antinociceptive effect of WIN 55,212-2 was significantly (P b 0.01) enhanced in ovariectomized mice, which was prevented by pretreatment with estradiol but not by progesterone. There was no significant difference in the cannabinoid-induced catalepsy between control and ovariectomized mice. However, pretreatment with progesterone but not estradiol potentiated the cataleptic effect of low dose of WIN 55,212-2 (2 mg/kg) in ovariectomized mice (P b 0.01). The present data demonstrated for the first time that ovarian sex steroids could modulate both cannabinoid-induced catalepsy and analgesia in female ovariectomized mice.

Nitric Oxide-biology and Chemistry, 2009

In the present study, we evaluated the effect of lithium on the nitric oxide (NO)-mediated nonadr... more In the present study, we evaluated the effect of lithium on the nitric oxide (NO)-mediated nonadrenergic noncholinergic (NANC) relaxation of rat anococcygeus muscle. The isolated precontracted (phenylephrine, 7.5 lM) rat anococcygeus muscle were relaxed via electrical field stimulation (5 Hz) in the absence or presence of lithium (0.5, 1, and 5 mM) or in tissues excised from ex vivo lithium (600 mg/L in drinking water for 30 days)-treated animals. Effects of the NO synthase (NOS) inhibitor L-NAME (0.03 and 100 lM) or guanylyl cyclase inhibitor ODQ (1 lM) and NO precursor L-arginine (1 mM) on relaxations were investigated. Effect of either in vitro (1 and 5 mM) or ex vivo lithium treatment on relaxation to the NO donor sodium nitroprusside (SNP; 0.1-1000 lM) was also investigated on phenylephrine-contracted strips. The NANC relaxation was significantly reduced by in vitro (1 and 5 mM; up to P < 0.01) and ex vivo lithium treatment (P < 0.001). L-NAME (100 lM and 1 mM) and ODQ (1 and 10 lM) significantly inhibited NANC relaxations in either control or lithium-treated strips. Combination of lithium (0.5 mM) with L-NAME (0.03 lM) significantly (P < 0.001) reduced the NANC relaxation. Although 1 mM L-arginine had no effect on relaxations, it prevented their inhibition by both in vitro (1 and 5 mM) and ex vivo lithium of relaxations. SNP produced concentration-dependent relaxation in precontracted rat anococcygeus muscle which was not altered by lithium treatment. Reverse transcription polymerase chain reaction (RT-PCR) revealed a significant increase in the neuronal NOS expression in the anococcygeus muscle of ex vivo lithium-treated animals compared with controls. Our experiments suggested that both ex vivo and in vitro lithium administration attenuated the NO-mediated neurogenic relaxation of isolated rat anococcygeus muscle.

Journal of Hepatology, 2007

Background/Aims: The clinical relevance of QT prolongation, the most widely recognized cardiac el... more Background/Aims: The clinical relevance of QT prolongation, the most widely recognized cardiac electrophysiological abnormality of cirrhosis, is still undefined. The aim of this study is to examine the susceptibility of chronic (4-week) bile duct-ligated rats to epinephrine-induced arrhythmias. The roles of nitric oxide and endogenous opioids were also evaluated.

Behavioural Brain Research, 2007

Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we as... more Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we assessed the involvement of NO pathway in the estrous cycle-related changes of anxiety level in rat. By using elevated plus-maze test, we studied the changes of serum nitrate and nitrite (NO x ) levels in comparison to the estrous cycle-dependent changes of anxiety state. Then, we tested the effects of nitric oxide synthase (NOS) inhibitor, L-NAME (10, 60 mg/kg, i.p.), and the NO precursor, l-arginine (100 mg/kg, i.p.) on anxiety modulatory properties of exogenous ovarian hormones in ovariectomized (OVX) rats. Compared with other cycle phases and with OVX rats, cycling rats spent more time in open arms and had lower levels of serum NO x levels during metestrous while they spent less time in open arms and had lower levels of serum NO x levels during proestrous. In OVX rats, L-NAME (60 mg/kg, i.p.) exerted anxiolytic effect while l-arginine showed no effect. In comparison with corn oil-treated controls, estradiol benzoate (10 g/kg, subcutaneously (s.c.)) significantly increased the serum NO x level and exerted anxiogenic effect, which was dose-dependently inhibited by L-NAME but was not changed by l-arginine. In contrast, progesterone (25 mg/kg, s.c.) significantly decreased the serum NO x level and exerted anxiolytic effect, which was abolished by l-arginine but was not affected by L-NAME. These findings suggest that NO system might be involved in the estrous cycle-related changes of anxiety level, probably by mediating the effect of ovarian sex hormones. (H.R. Sadeghipour).

Bju International, 2007

OBJECTIVETo verify the effect of chronic lithium administration on the endothelium-dependent rela... more OBJECTIVETo verify the effect of chronic lithium administration on the endothelium-dependent relaxation of rat corpus cavernosum, as lithium is a major drug for treating bipolar disorder and some studies showed that lithium might cause erectile dysfunction in such patients, by a mechanism as yet unknown.To verify the effect of chronic lithium administration on the endothelium-dependent relaxation of rat corpus cavernosum, as lithium is a major drug for treating bipolar disorder and some studies showed that lithium might cause erectile dysfunction in such patients, by a mechanism as yet unknown.MATERIALS AND METHODSLiCl (600 mg/L) was dissolved in drinking water and Sprague–Dawley rats received the solution for 30 days; control rats received tap water. After 30 days corporeal strips were prepared from both groups, mounted under tension in oxygenated organ baths, and pre-contracted with phenylephrine (7.5 µm). After equilibration, the strips were relaxed by acetylcholine (10 nm to 1 mm) in the presence or absence of indomethacin (a cyclooxygenase inhibitor; 20 µm). Furthermore, the relaxant responses to sodium nitroprusside (1 nm to 1 mm), a nitric oxide (NO) donor, were investigated in both groups. NADPH-diaphorase histochemistry was used to identify NO synthase within cavernosal tissue strips of both groups.LiCl (600 mg/L) was dissolved in drinking water and Sprague–Dawley rats received the solution for 30 days; control rats received tap water. After 30 days corporeal strips were prepared from both groups, mounted under tension in oxygenated organ baths, and pre-contracted with phenylephrine (7.5 µm). After equilibration, the strips were relaxed by acetylcholine (10 nm to 1 mm) in the presence or absence of indomethacin (a cyclooxygenase inhibitor; 20 µm). Furthermore, the relaxant responses to sodium nitroprusside (1 nm to 1 mm), a nitric oxide (NO) donor, were investigated in both groups. NADPH-diaphorase histochemistry was used to identify NO synthase within cavernosal tissue strips of both groups.RESULTSThe acetylcholine-dependent relaxation was significantly lower in lithium-treated rats than in controls. Although indomethacin decreased significantly the relaxant responses to acetylcholine in controls, it increased the relaxant responses in lithium-treated rats. NADPH-diaphorase staining was greater in the chronic lithium-treated than in control preparations. Sodium nitroprusside produced similar relaxation in both groups.The acetylcholine-dependent relaxation was significantly lower in lithium-treated rats than in controls. Although indomethacin decreased significantly the relaxant responses to acetylcholine in controls, it increased the relaxant responses in lithium-treated rats. NADPH-diaphorase staining was greater in the chronic lithium-treated than in control preparations. Sodium nitroprusside produced similar relaxation in both groups.CONCLUSIONChronic lithium administration can impair the endothelium-dependent relaxation of rat corpus cavernosum; NO availability might decrease after lithium administration and the cyclooxygenase pathways might have a role in this effect.Chronic lithium administration can impair the endothelium-dependent relaxation of rat corpus cavernosum; NO availability might decrease after lithium administration and the cyclooxygenase pathways might have a role in this effect.

Bju International, 2007

OBJECTIVETo investigate the ability of acute administration of the endogenous cannabinoid, ananda... more OBJECTIVETo investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35–75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED.To investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35–75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED.MATERIALS AND METHODSDiabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured.Diabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured.RESULTSThe neurogenic relaxation of phenylephrine (7.5 µm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 µm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB1 receptor antagonist AM251 (1 µm) and the selective vanilloid receptor antagonist capsazepine (3 µm). Concurrent administration of partially effective doses of l-arginine (10 µm) and anandamide (0.3 µm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups.The neurogenic relaxation of phenylephrine (7.5 µm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 µm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB1 receptor antagonist AM251 (1 µm) and the selective vanilloid receptor antagonist capsazepine (3 µm). Concurrent administration of partially effective doses of l-arginine (10 µm) and anandamide (0.3 µm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups.CONCLUSIONFor the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l-arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB1 and vanilloid VR1 receptors within the CC.For the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l-arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB1 and vanilloid VR1 receptors within the CC.

European Journal of Pharmacology, 2008

In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiova... more In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiovascular actions. Recently, they have been suggested to protect the myocardium against ischemia/reperfusion injury. The aim of this study is to examine the contribution of endogenous cannabinoids to cardioprotection afforded by remote ischemic preconditioning. Three groups of remote preconditioned (15 min of mesenteric artery occlusion followed by 15 min of reperfusion) and three groups of sham-operated rats were included in the study. Animals were pretreated intravenously by vehicle, cannabinoid CB 1 (AM251, 1 mg/kg) or CB 2 (AM630, 1 mg/kg) receptor antagonist 15 min prior to remote preconditioning or sham operation. Myocardial injury was induced by 30 min of coronary artery occlusion followed by 2 h of reperfusion. The resultant arterial hypotension, ventricular arrhythmias, and infarct size were compared among the groups. Remote preconditioning exerted potent cardioprotection manifested as significant reductions in infarct size (P b 0.001) as well as number and duration of arrhythmias (P b 0.01, 0.01 and 0.05 for premature ventricular contractions, ventricular tachycardias and fibrillations; respectively). The cannabinoid CB 1 receptor antagonist pretreatment had no significant effect on ischemia-induced hypotension, arrhythmias or infarct size. On the other hand, the cannabinoid CB 2 receptor antagonist pretreatment abolished the protective effects of remote preconditioning on infarct size (P b 0.01) and arrhythmias (P b 0.01), without any significant effect on ischemia-induced hypotension. The results of this study suggest that endogenous cannabinoids, through acting on cannabinoid CB 2 receptors, are involved in the cardioprotective phenomenon of remote ischemic preconditioning, induced by mesenteric artery occlusion and reperfusion.

Neuropharmacology, 2007

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have i... more Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G i/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. However, regarding the seizure modulating properties of both classes of receptors this study investigated whether ultra-low dose cannabinoid antagonist AM251 influences cannabinoid anticonvulsant effects. The clonic seizure threshold (CST) was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the cannabinoid CB 1 antagonist AM251 and a combination of ACEA and AM251 doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic administration of ultra-low doses of AM251 (10 fg/kge100 ng/kg) significantly potentiated the anticonvulsant effect of ACEA at 0.5 and 1 mg/kg. Moreover, inhibition of cannabinoid induced excitatory signaling by AM251 (100 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (100 ng/kge100 mg/kg), suggesting that a presumed inhibitory component of cannabinoid receptor signaling can exert strong seizureprotective effects even at very low levels of cannabinoid receptor activation. A similar potentiation by AM251 (100 pg/kg and 1 ng/kg) of anticonvulsant effects of non-effective dose of ACEA (0.5 and 1 mg/kg) was also observed in the generalized toniceclonic model of seizure. The present data suggest that ultra-low doses of cannabinoid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of cannabinoids.

Behavioural Brain Research, 2009

In the present study we evaluated the involvement of nitric oxide (NO) system in the antidepressa... more In the present study we evaluated the involvement of nitric oxide (NO) system in the antidepressantlike effects of chronic lithium administration in the mouse forced swimming test (FST). Administration of lithium chloride (300 mg/L in drinking water for 21 days) had no effect on the immobility of mice in the FST, whereas 600 mg/L lithium caused a significant (P < 0.001) decrease in the immobility time compared with control animals. Administration of the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, daily for a week, i.p.) had no significant effect on the immobility time of either control or lithium (300 mg/L)-treated mice, whereas acute administration of non-effective dose of L-NAME (30 mg/kg, i.p.) caused a robust decrease (P < 0.01) in the immobility time of lithium (300 mg/L)-treated animals in the FST. Moreover, chronic administration of low dose of the NO precursor L-arginine (200 mg/kg, daily for a week, i.p.) prevented (P < 0.001) the antidepressant-like effects of lithium treatment (600 mg/L) in the FST. Acute treatment with L-arginine (200 mg/kg, i.p.) increased (P < 0.05) the immobility time of lithium (600 mg/L)-treated mice in the FST. Chronic lithium treatment (600 mg/L but not 300 mg/L) caused a significant (P < 0.05) decrease in the serum NO X levels in mice compared with controls. Our data suggested that the NO system could be involved in the antidepressant-like effect of chronic lithium treatment in the FST.

Seizure-european Journal of Epilepsy, 2010

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptami... more There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.

European Neuropsychopharmacology, 2008

In the present study we evaluated the involvement of L-arginine/nitric oxide (NO)/cGMP pathway in... more In the present study we evaluated the involvement of L-arginine/nitric oxide (NO)/cGMP pathway in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test (FST). Lithium, at 30 and 100 mg/kg, significantly reduced the immobility times of mice in the FST, whereas at lower doses (0.5, 5 and 10 mg/kg) had no effect on the immobility time. The NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME), at 10 and 30 mg/kg, and the selective neuronal NOS inhibitor N ω -propyl-L-arginine (L-NPA), at 5 and 15 mg/kg, had no significant effects on the FST, whereas they significantly decreased the immobility time at 100 and 30 mg/kg, respectively. Combination of non-effective dose of lithium (10 mg/kg) with low doses of L-NAME (30 mg/kg) or L-NPA (15 mg/kg) significantly reduced the immobility times in the FST. Moreover, the guanylyl cyclase inhibitor ODQ at 50 mg/kg significantly decreased the immobility time of mice, whereas it had not significant effects on the FST at 2, 10 and 20 mg/kg. Combination of lithium (10 mg/kg) with 20 mg/kg ODQ significantly decreased the immobility times in the FST. Non-effective doses of L-arginine (750 mg/kg) or sildenafil (5 mg/kg) significantly reversed the antidepressant-like effect of 30 mg/kg lithium in the FST. Neither of the drugs had effect on the locomotor activity. These data indicate the involvement of Larginine/NO/cGMP pathway in the antidepressant-like effect of lithium in the mouse FSTand also might suggest the concurrent administration of NOS inhibitors and lithium as an appropriate strategy for treatment of depression.

Epilepsy Research, 2008

Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, ... more Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G i/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoidinduced antinociception. Thus, concerning the seizure modulating properties of both classes of receptors this study investigated whether the ultra-low dose opioid antagonist naltrexone influences cannabinoid anticonvulsant effects. The clonic seizure threshold was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the opioid receptor antagonist naltrexone and a combination of ACEA and naltrexone doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic injection of ultra-low doses of naltrexone (1 pg/kg to 1 ng/kg, i.p.) significantly potentiated the anticonvulsant effect of ACEA (1 mg/kg, i.p.). Moreover, the very low dose of naltrexone (500 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (10 and 100 g/kg). A similar potentiation by naltrexone (500 pg/kg) of anticonvulsant effects of non-effective dose of ACEA (1 mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data indicate that the interaction between opioid and cannabinoid systems extends to ultra-low dose levels and ultra-low doses of opioid receptor antagonist in conjunction with very low doses of cannabinoids may provide a potent strategy to modulate seizure susceptibility.

Epilepsy & Behavior, 2008

Nasal obstruction and consequent mouth breathing have been shown to change the acid-base balance,... more Nasal obstruction and consequent mouth breathing have been shown to change the acid-base balance, producing respiratory acidosis. Additionally, there exists a large body of evidence maintaining that acidosis affects the activity of ATP-sensitive potassium (K ATP ) channels, which play a crucial role in the function of the central nervous system (CNS), for example, in modulating seizure threshold. Thus, in the study described here, we examined whether mouth breathing, induced by surgical ligation of nostrils, could affect the seizure threshold induced by pentylenetetrazole in male NMRI mice. Using the selective K ATP channel opener (diazoxide) and blocker (glibenclamide), we also evaluated the possible role of K ATP channels in this process. Our data revealed that seizure threshold was increased 6 to 72 hours after nasal obstruction, reaching a peak 48 hours afterward, compared with either control or sham-operated mice (P < 0.01). There was a significant decrease in pH of arterial blood samples and increase in CO 2 partial pressure (PCO 2 ) during this time. Systemic injection of glibenclamide (1 and 2 mg/kg, ip, daily) significantly prevented the increase in seizure threshold in 48-hour bilaterally nasally obstructed mice, whereas it had no effect on seizure threshold in sham-operated mice. Systemic injection of diazoxide (25 mg/kg, ip, daily) had no effect on seizure threshold in all groups, whereas higher doses (50 and 100 mg/kg, ip, daily) significantly increased seizure threshold in both 48-hour-obstructed and shamoperated mice. The decrease in seizure threshold induced by glibenclamide (2 mg/kg, ip, daily) was prevented by diazoxide (25 mg/kg, ip, daily). These results demonstrate for the first time that mouth breathing, which could result in respiratory acidosis, increases seizure threshold in mice and K ATP channels may play a role in this effect.

Nitric Oxide-biology and Chemistry, 2007

Lithium has largely met its initial promise as the first drug to be discovered in the modern era ... more Lithium has largely met its initial promise as the first drug to be discovered in the modern era of psychopharmacology. However, the mechanism for its action remains an enigma. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)-mediated relaxation of rat isolated gastric fundus and to evaluate the role of nitric oxide pathway in this manner. The isolated rat gastric fundus strips were precontracted with 0.5 microM serotonin and electrical field stimulation (EFS) was applied at 5 Hz frequency to obtain NANC-mediated relaxation in the presence or absence of lithium (0.1, 0.5, 1 and 5 mM). Also, effects of combining lithium (0.1 mM) with the NO synthase (NOS) inhibitor L-NAME (0.03 microM) or the guanylyl cyclase inhibitor ODQ (1 microM) on relaxant responses to EFS was investigated. Moreover, effects of combining lithium (1 mM) with 0.1 mM L-arginine (a precursor of NO) on neurogenic relaxation were assessed. Also, the effect of lithium (1 mM) on relaxation to sodium nitroprusside (SNP; 1 nM-0.1 mM) and glyceryltrinitrate (GTN; 0.1-10 microM) was investigated. The NANC-mediated relaxation was significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) reduced by lithium in a dose- and time-dependent manner. Combination of lithium (0.1 mM) with L-NAME (0.03 microM), which separately had partial inhibitory effect on relaxations, significantly (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) reduced the NANC-mediated relaxation of gastric fundus. ODQ (1 microM) significantly inhibited the neurogenic relaxations in the presence or absence of lithium (0.1 and 1 mM). Although L-arginine at 0.1 mM had no effect on relaxation to EFS, it prevented the inhibition by lithium (1 mM) of relaxant responses to EFS. Also, SNP and GTN produced concentration-dependent relaxation in precontracted rat gastric fundus which was not altered by lithium incubation (1 mM). Our experiments indicated that lithium likely by interfering with L-arginine/NO pathway in nitrergic nerve can result in impairment of NANC-mediated relaxation of rat gastric fundus.