Sina Tavakoli

The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice

Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB(1) receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5-2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5-2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB(1) receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific kappa-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5-1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic-clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.

Role of ATP-sensitive potassium channels in the biphasic effects of morphine on pentylenetetrazole-induced seizure threshold in mice.

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 microg/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 pro-convulsant effects of morphine and this effect was significantly reversed by cromakalim (0.1 microg/kg). These results support the involvement of K(ATP) channels in the modulation of seizure threshold by morphine.

Role of the nitric oxide pathway and the endocannabinoid system in neurogenic relaxation of corpus cavernosum from biliary cirrhotic rats

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.

Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to β‐adrenergic stimulation in cirrhotic rats

It is well known that chronotropic and inotropic responses to β‐adrenergic stimulation are impaired in cirrhosis, but the exact reason is not clear. Considering the inhibitory effect of endogenous opioid peptides and nitric oxide (NO) on β‐adrenergic pathway, we examined their roles in hyporesponsiveness of isolated atria and papillary muscles to isoproterenol stimulation in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation. Four weeks after ligation or sham operation, the responses of the isolated atria and papillary muscles to isoproterenol stimulation were evaluated in the absence and presence of naltrexone HCl (10−6 m), N(ω)‐nitro‐l‐arginine methyl ester (l‐NAME, 10−4 m), and naltrexone plus l‐NAME in the organ bath. Considering the role of inducible NOS (iNOS) in hemodynamic abnormalities of cirrhotic rats, the chronotropic and inotropic responses of cirrhotic rats to isoproterenol stimulation were also assessed in the presence of aminoguanidine (a selective inhibitor of iNOS, 3 × 10−4 m). Sham operation had no significant effect on basal atrial beating rate, contractile force, and maximal time derivatives for the development and the dissipation of papillary muscle tension. The basal atrial beating rate of cirrhotic rats did not show any significant difference compared with the sham‐operated ones; however, the basal contractile parameters were significantly decreased in cirrhosis. Although the maximum effects of isoproterenol on chronotropic and inotropic responses were significantly reduced in cirrhotic rats, there was no difference in half‐maximal effective concentrations of isoproterenol in these concentration–response curves. The basal abnormalities and the attenuated chronotropic and inotropic responses to isoproterenol were completely corrected by the administration of naltrexone, l‐NAME and aminoguanidine. Concurrent administration of naltrexone and l‐NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to β‐adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO‐induced hyporesponsiveness to β‐adrenergic stimulation in cirrhosis.

The nonadrenergic noncholinergic-mediated relaxation of corpus cavernosum was impaired in chronic lithium-treated rats: Improvement with l-arginine

One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms of which are not yet known. In this study we investigated the effect of chronic lithium (LiCl, 600 mg/l for 30 days) administration on the neurogenic relaxation of isolated rat corpus cavernosum. The corporal strips were precontracted with phenylephrine and electrical field stimulation (EFS) was applied to obtain relaxation. Relaxation to EFS was significantly (P<0.001) impaired in LiCl-treated rats. The nitric oxide (NO) synthase inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME; 100 microM) inhibited the relaxation to EFS in both LiCl-treated and control rats. The NO precursor l-arginine, at per se noneffective concentration (0.1 mM), significantly (P<0.001) enhanced the EFS-induced relaxation of LiCl-treated corporal strips. The relaxation responses to the NO donor sodium nitroprusside were similar between two groups. These data demonstrate that chronic lithium treatment could impair the NO-mediated neurogenic relaxation of rat corpus cavernosum which could be prevented by l-arginine.

Pentoxifylline improves reoxygenation-induced contractile recovery through a nitric oxide-dependent mechanism in rat papillary muscles.

In this study, the protective effect of pentoxifylline against hypoxia-reoxygenation injury and the possible involvement of nitric oxide (NO)-mediated pathways in this protection were investigated in isolated rat papillary muscles. Papillary muscles were excised and isolated in Krebs–Henseleit solution aerated with 95% O2 and 5% CO2. Hypoxia was simulated by substituting O2 with argon. Three sets of experiments, testing 30, 60, and 90 min of hypoxia, were performed. The effects of different pentoxifylline concentrations on papillary muscle contractile parameters and responsiveness to isoproterenol were assessed. To investigate the role of NO, N(ω)-nitro-L-arginine methyl ester was added before pentoxifylline treatment. Pentoxifylline did not show any inotropic effect on papillary muscles. Hypoxia caused a profound depression of contractile parameters, which was not affected by pentoxifylline treatment. Reoxygenation resulted in significant partial recovery of contractile parameters after 30 and 60 but not 90 min of hypoxia. In experiments with 30 and 60 min of hypoxia, reoxygenation-induced contractile recovery and responsiveness to isoproterenol were improved by pentoxifylline in a concentration-dependent fashion. These functional improvements were completely blocked by N(ω)-nitro-L-arginine methyl ester pretreatment. No improvement was observed in 90-min hypoxia experiment. In conclusion, pentoxifylline improved contractile recovery during reoxygenation and postreoxygenation responsiveness to β-adrenergic stimulation through the NO-dependent mechanism.