Lithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway

doi:10.1016/j.brainres.2004.09.018

Brain Research

Volume 1029, Issue 1, 10 December 2004, Pages 48-55

https://doi.org/10.1016/j.brainres.2004.09.018 Get rights and content

Abstract

Lithium has been reported to inhibit opioid-induced properties. The present study examined the effect of acute and chronic administration of lithium chloride (LiCl) on morphine's biphasic modulation of susceptibility to pentylenetetrazole (PTZ)-induced clonic seizure in mice. We also examined the possible involvement of nitric oxide (NO) pathway in lithium effect. Both acute (0.1 and 1 mg/kg) and chronic (same doses, 21 consecutive days) administration of LiCl completely inhibited the anticonvulsant and proconvulsant effects of morphine (at doses 1 and 30 mg/kg, respectively). A very low and per se noneffective dose of LiCl (0.05 mg/kg) significantly inhibited both phases of morphine effect when administered concomitant with a noneffective low dose of naloxone (0.1 mg/kg). The NO synthase inhibitor N^G-nitro-l-arginine methyl ester (L-NAME) at a per se noneffective dose of 0.3 mg/kg potentiated the inhibitory effects of low doses of LiCl (0.01 and 0.05 mg/kg) on both phases of morphine effect. l-arginine, a NO synthase substrate, at a per se noneffective dose of 30 mg/kg reversed the inhibitory effects of lithium (1 mg/kg). Lithium is capable of antagonizing both modulatory effects of morphine on seizure susceptibility even at relatively low doses. These inhibitory effects of lithium may also involve NO synthesis.

Introduction

Lithium is the drug of choice for the treatment of mania and prophylaxis of bipolar affective disorders [47]. It is also known that lithium affects metabolism, neuronal communication and cell proliferation in a diverse array of organisms [43]. Although the mechanisms underlying lithium actions remain unclear, there is increasing evidence that lithium exerts its therapeutic effects by interfering with signal transduction through G-protein-coupled pathways [25] or direct inhibition of specific targets in signaling systems, which include inositol monophosphatase [4], [38] and glycogen synthase kinase-3 [29]. Recently, lithium has been reported to stimulate extracellular signal-regulated kinase (ERK) pathway as well [18].

There is evidence that lithium is capable of affecting the acute and chronic actions of morphine. For example, lithium has been reported to significantly reduce the self-stimulation facilitated by morphine [30] and decrease the amount of voluntary ingestion of morphine by addicted rats [52]. Moreover, acute and chronic administration of lithium to rodents may potentiate or attenuate opioid-induced antinociception [12], [35], [44], [45], [53], increase or decrease morphine-induced hyperactivity [9], increase sensitivity to naloxone [1] and significantly inhibit morphine withdrawal syndrome and development of physical dependence [13] as well as conditioned place preference (CPP) induced by morphine [56]. Lithium also abolished the resistance to stress in morphine-sensitized rats [22]. In fact, the reported interruption of opioid receptor function by lithium may imply potential benefits in certain clinical circumstances.

It is known that opioids exert both anticonvulsant and proconvulsant effects in different models of experimental seizure [24], [28]. Acute administration of morphine shows a biphasic pattern depending on the doses used. While low doses of morphine show an anticonvulsant effect against seizure models induced by GABA transmission blockers like picrotoxin, bicuculline and pentylenetetrazole (PTZ) [24], [28], [31], higher doses of this opioid-receptor agonist increase the susceptibility of animals to the same seizure models [21], [24], [28]. We used this biphasic model to investigate the possible interaction between lithium and opioid receptor function on regulation of seizure susceptibility. Although lithium, in combination with pilocarpine, exerts proconvulsant properties and is used as a model for slowly progressing limbic seizures [10], it does not have any effect of its own on acute PTZ-induced clonic seizures, and thus, this model is appropriate to examine lithium interactions with morphine on seizure threshold. Moreover, we had previously shown that even very low doses of lithium can effectively modulate opioid transmission [13], a finding that implies very specific mechanism of action for lithium. Thus, to assess if very low doses of lithium could also modulate the effects of opioids on seizure threshold, we further examined the effect of the combination of low doses of lithium and naloxone on two distinct phases of morphine effect.

Nitric oxide (NO) as a neuronal messenger or neurotransmitter in the central and peripheral nervous system [6], [17] is a known modulator of seizure susceptibility with either anticonvulsant [7], [50], [51] or proconvulsant [37], [40], [41] effects in different seizure paradigms and has been suggested to be involved in the biphasic effects of morphine on PTZ-induced seizure susceptibility [24]. Also, the existence of some interactions between lithium and nitric oxide signaling has been suggested in several studies [2], [3], [14], [15], [16], [24], [54]. Some authors have suggested that nitric oxide may mediate some of lithium-induced responses in the brain [23], [42] or other tissues [2], [15]. Notably, we have reported a dual modulation of NO-related endothelium-dependent relaxation by LiCl, which consists of an inhibitory effect at lower dose and a stimulating effect at higher dose [14]. Furthermore, according to another reported observation, while coadministration of lithium with N^G-nitro-l-arginine methyl ester (L-NAME) exerts a synergistic and potent inhibition of morphine withdrawal syndrome in mice, cotreatment with l-arginine (the NO precursor) decreases the inhibitory effect of lithium in the same model [16]. Moreover, the reversal of lithium-induced conditioned taste aversion (CTA) by administration of l-arginine supports the idea that NO may play a role in some effects of lithium [14]. In the two last experiments of the present study, we examined whether simultaneous administration of lithium with L-NAME or l-arginine has any effects on opioid-induced modulation of seizure.

The present study was undertaken to test the hypothesis that low doses of lithium may block the biphasic effects of opioids on seizure threshold and to examine the possible role of NO signaling in this interaction. Since lithium may induce long-term adaptations leading to altered responses to an opioid system [11], we also examined the effect of chronic treatment with lithium on regulation of seizure susceptibility.

Section snippets

Chemicals

The drugs used were pentylenetetrazole, lithium chloride, morphine sulfate, naloxone, L-NAME and l-arginine (all purchased from Sigma, Poole, UK). All drugs were dissolved in physiologic saline solution to such concentrations that requisite doses were administered in a volume of 10 ml/kg of the mice body weight. PTZ was prepared in saline as 1% solution. In all experiments, morphine sulfate was administered subcutaneously (s.c.), and lithium chloride, naloxone, L-NAME and l-arginine were

Effect of acute administration of lithium on anticonvulsant and proconvulsant effects of morphine

As previously reported [24], [28], morphine exerts a dose-dependent biphasic effect on seizure threshold with an anticonvulsant effect at 1 mg/kg and a proconvulsant effect at 30 mg/kg. As shown in Fig. 1, acute administration of relatively low doses of lithium dose-dependently blocked both the anticonvulsant and proconvulsant effects of morphine. Two-way ANOVA showed a significant effect for both lithium dose (F₁) and morphine treatment (F₂) as well as a lithium×morphine interaction (F_1*2) for

Discussion

The results of the present study show for the first time that lithium is capable of antagonizing both anticonvulsant and proconvulsant effects of morphine on the PTZ-induced clonic seizure, and this inhibition occurs at such a low dose as 0.1 mg/kg. Lithium produced an additive inhibition of morphine effects when combined with low dose opioids receptor antagonist. Moreover, the coadministration of low doses of L-NAME and lithium blocked both the anti- and proconvulsant phases of the morphine

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Cited by (38)

Anticonvulsant Effects of Thalidomide on Pentylenetetrazole-Induced Seizure in Mice: A Role for Opioidergic and Nitrergic Transmissions
2020, Epilepsy Research
Although accumulating evidence indicates that the immunomodulatory medication thalidomide exerts anticonvulsant properties, the mechanisms underlying such effects of thalidomide are still unknown. Our previous preclinical study suggested that nitric oxide (NO) signaling may be involved in the anticonvulsant effects of thalidomide in a mouse model of clonic seizure. Additionally, several studies have shown a modulatory interaction between thalidomide and opioids in opioids intolerance, nociception and neuropathic pain. However, it is unclear whether opioidergic transmission or its interaction with NO signaling is involved in the anticonvulsant effects of thalidomide. Given the fact that both opioidergic and nitrergic transmissions have bimodal modulatory effects on seizure thresholds, in the present study we explored the involvement of these signaling pathways in the possible anticonvulsant effects of thalidomide on the pentylenetetrazole (PTZ)-induced clonic seizure in mice. Our data showed that acute administration of thalidomide (5-50 mg/kg, i.p., 30 min prior PTZ injection) dose-dependently elevated PTZ-induced clonic seizure thresholds. Acute administration of low doses (0.5-3 mg/kg, i.p., 60 min prior PTZ) of morphine exerted anticonvulsant effects (P < 0.001), whereas higher doses (15-60 mg/kg, 60 min prior PTZ) had proconvulsant effects (P < 0.01). Acute administration of a non-effective anticonvulsant dose of morphine (0.25 mg/kg) prior non-effective dose of thalidomide (5 mg/kg) exerted a robust (P < 0.01) anticonvulsant effect. Administration of a non-effective proconvulsant dose of morphine (7.5 mg/kg) prior thalidomide (5 mg/kg) didn’t affect clonic seizure thresholds. Acute administration of a non-effective dose of the opioid receptor antagonist naltrexone (1 mg/kg, i.p.) significantly prevented anticonvulsant effects of thalidomide (10 mg/kg, i.p.). Pretreatment with non-effective dose of the NO precursor L-arginine (60 mg/kg, i.p.) significantly (P < 0.01) reduced the anticonvulsant effects of combined low doses of morphine (0.25 mg/kg) and thalidomide (5 mg/kg). Conversely, pretreatment with non-effective doses of either non-selective (L-NAME, 5 mg/kg, i.p.) or selective neuronal (7-nitroindazole, 30 mg/kg, i.p.) NO synthase (NOS) inhibitors significantly augmented the anticonvulsant effects of combined low doses of thalidomide and morphine, whereas the inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) did not exert such effect. Our results indicate that opioidergic transmission and its interaction with neuronal NO signaling may contribute to the anti-seizure activity of thalidomide in the mice PTZ model of clonic seizure.
Nitric oxide and glutamate are contributors of anti-seizure activity of rubidium chloride: A comparison with lithium
2019, Neuroscience Letters
The neuro-protective effects of rubidium and lithium as alkali metals have been reported for different central nervous system dysfunctions including mania and depression. The aim of this study was evaluating as well as comparing the effects of rubidium chloride (RbCl) and lithium chloride (LiCl) on different seizures paradigms in mice and determining the involvement of NMDA receptors and nitrergic pathway.
To assess the seizures threshold, animals received intravenous pentylenetetrazole (PTZ, 0.5%; 1 mL/min). Male NMRI mice (6–8 weeks) received intraperitoneal (i.p.) injections of different doses of RbCl and LiCl. Doses greater than 10 mg/kg of RbCl showed a significant anticonvulsant activity 60 min after administration; the anticonvulsant effects of LiCl was observed at the doses more than 5 mg/kg and after 30 min in PTZ-induced seizure threshold. But, RbCl (10, 20 mg/kg, i.p) or LiCl (5, 10 mg/kg, i.p) injection did not induce protection against maximal electroshock (MES) or intraperitoneal injection of PTZ lethal dose (80 mg/kg)-induced seizure models.
Pre-treatment with L-NAME (non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg; i.p.) and 7-nitroindazole (selective neuronal NOS inhibitor, 30 mg/kg; i.p.) enhanced the anticonvulsive effects of both RbCl (5 mg/kg, i.p.) and LiCl (1 mg/kg, i.p.) in PTZ-induced seizure threshold model. Injection of MK-801 (NMDA receptor antagonist, 0.05 mg/kg; i.p.) before RbCl (5 mg/kg, i.p.; P < 0.001) and LiCl (1 mg/kg, i.p.; P < 0.001) administration increased the anti-seizure activity. But, treatment with L-arginine (precursor of nitric oxide, 100 mg/kg; i.p.) decreased the seizure threshold of both RbCl (20 mg/kg, i.p.; P < 0.001) and LiCl (10 mg/kg, i.p.; P < 0.001). Measurement of nitrite levels in hippocampus of animals revealed a remarkable reduction after treatment with RbCl (20 mg/kg, i.p; P < 0.05) and LiCl (10 mg/kg, i.p; P < 0.01).
To conclude, rubidium may protect central nervous system against seizures in PTZ-induced seizures threshold model through NMDA/nitrergic pathways with a similarity to lithium effects in mice.
Lithium attenuated the behavioral despair induced by acute neurogenic stress through blockade of opioid receptors in mice
2016, Biomedicine and Pharmacotherapy
Major depressive disorder is disease with high rate of morbidity and mortality. Stressful events lead to depression and they can be used as a model of depression in rodents. In this study we aimed to investigate whether lithium modifies the stressed-induced depression through blockade of opioid receptors in mice. We used foot shock stress as stressor and forced swimming test (FST), tail suspension test (TST) and open field test (OFT) to evaluation the behavioral responses in mice. We also used naltrexone hydrochloride (as opioid receptor antagonist), and morphine (as opioid receptor agonist). Our results displayed that foot-shock stress significantly increased the immobility time in TST and FST but it could not change the locomotor behavior in OFT. When we combined the low concentrations of lithium and naltrexone a significant reduction in immobility time was seen in the FST and TST in comparison with control foot-shock stressed group administered saline only. Despite the fact that our data showed low concentrations of lithium, when administered independently did not significantly affect the immobility time. Also our data indicated that concurrent administration of lithium and naltrexone had no effect on open field test. Further we demonstrated that simultaneous administration of morphine and lithium reverses the antidepressant like effect of active doses of lithium. Our data acclaimed that we lithium can augment stressed-induced depression and opioid pathways are involved in this action.
A role for ATP-sensitive potassium channels in the anticonvulsant effects of triamterene in mice
2016, Epilepsy Research
There are reports indicating that diuretics including chlorothiazide, furosemide, ethacrynic acid, amiloride and bumetanide can have anticonvulsant properties. Intracellular acidification appears to be a mechanism for the anticonvulsant action of some diuretics. This study was conducted to investigate whether or not triamterene, a K⁺-sparing diuretic, can generate protection against seizures induced by intravenous or intraperitoneal pentylenetetrazole (PTZ) models. And to see if, triamterene can withstand maximal electroshock seizure (MES) in mice. We also investigated to see if there is any connection between triamterene's anti-seizure effect and ATP-sensitive K⁺ (K_ATP) channels. Five days triamterene oral administration (10, 20 and 40 mg/kg), significantly increased clonic seizure threshold which was induced by intravenous pentylenetetrazole. Triamterene (10, 20 and 40 mg/kg) treatment also increased the latency of clonic seizure and decreased its frequency in intraperitoneal PTZ model. Administration of triamterene (20 mg/kg) also decreased the incidence of tonic seizure in MES-induced seizure. Co-administration of a K_ATP sensitive channel blocker, glibenclamide, in the 6th day, 60 min before intravenous PTZ blocked triamterene's anticonvulsant effect. A K_ATP sensitive channel opener, diazoxide, enhanced triamterene's anti-seizure effect in both intravenous PTZ or MES seizure models. At the end, triamterene exerts anticonvulsant effect in 3 seizure models of mice including intravenous PTZ, intraperitoneal PTZ and MES. The anti-seizure effect of triamterene probably is induced through K_ATP channels.
Effects of D-penicillamine on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide/NMDA pathways
2014, Epilepsy and Behavior
Citation Excerpt :
Our evidence suggested that the anti- and proconvulsant activities of d-pen may be mediated through a NO-dependent mechanism given that l-NAME and 7-NI blocked both aforementioned phases of d-pen. Nitric oxide is a known modulator of seizure susceptibility with either anticonvulsant [41–44] or proconvulsant [20,44,45] effects in different seizure paradigms. Increasing evidence suggests that both neuronal and inducible isoforms of NOS participate in several important brain processes [46].
Besides the clinical applications of penicillamine, some reports show that use of d-penicillamine (d-pen) has been associated with adverse effects such as seizures. So, the purpose of this study was to evaluate the effects of d-pen on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice. It also examined whether N-methyl-d-aspartate (NMDA) receptor/nitrergic system blockage was able to alter the probable effects of d-pen.
Different doses of d-pen (0.1, 0.5, 1, 10, 100, 150, and 250 mg/kg) were administered intraperitoneally (i.p.) 90 min prior to induction of seizures. d-Penicillamine at a low dose (0.5 mg/kg, i.p.) had anticonvulsant effects, whereas at a high dose (250 mg/kg, i.p.), it was proconvulsant. Both anti- and proconvulsant effects of d-pen were blocked by a single dose of a nonspecific inhibitor of nitric oxide synthase (NOS), l-NAME (10 mg/kg, i.p.), and a single dose of a specific inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (30 mg/kg, i.p.). A selective inhibitor of iNOS, aminoguanidine (100 mg/kg, i.p.), had no effect on these activities. An NMDA receptor antagonist, MK-801 (0.05 mg/kg, i.p.), alters the anti- and proconvulsant effects of d-pen.
The results of the present study showed that the nitric oxide system and NMDA receptors may contribute to the biphasic effects of d-pen, which remain to be clarified further.
Proconvulsant effects of tramadol and morphine on pentylenetetrazol-induced seizures in adult rats using different routes of administration
2014, Epilepsy and Behavior
Citation Excerpt :
Continued activation of pharmacological opioid receptors has been proven to precipitate seizures via GABA inhibitory pathways [56,57]. Observations of the present work were also in line with those of the previous findings that indicated that morphine and tramadol could modulate seizure susceptibility [21,40,41,58,59] and show proconvulsant effects in higher doses [24,39,60]. Proconvulsant effects of μ-opioid system activation have been reported in various seizure models induced by PTZ [24,61,62], bicuculline [63,64], NMDA [65], and pilocarpine [66], suggesting a more general modulatory influence on other seizure models.
Tramadol is frequently used as a pain reliever. However, it has been sometimes noted to have the potential to cause seizures. Because of its dual mechanism of action (both opioid and nonopioid), the adverse effect profile of tramadol can be different in comparison with single-mechanism opioid analgesics, such as morphine. In the present study, the facilitatory effects of tramadol and morphine on pentylenetetrazol-induced seizures using different routes of administration were compared in rats. Adult female rats were divided into six groups and continuously received saline, morphine, or tramadol on a daily basis for 15 days [gavage (PO) or intraperitoneal (IP)]. An increasing dose of morphine and tramadol was used to prevent resistance to repetitive dose (20–125 mg/kg). Following one week of withdrawal period and 30 min before the seizure induction (PTZ = 80 mg/kg, IP), each group of rats was further divided into subgroups that received saline, morphine, or tramadol for the second time on the 22nd day of the experiment. Results showed that, while morphine, tramadol, and their administration had different effects on seizure behaviors, both acute and chronic administrations of morphine and tramadol potentiated PTZ-induced seizures. However, there was no significant difference between morphine and tramadol in terms of seizure severity. Effects of morphine and tramadol on PTZ-induced seizures were also stable following one week of withdrawal. In conclusion, this study indicated similar severity in the proconvulsant effect of morphine and tramadol on PTZ-induced seizures, which might depend on their similar effects on GABAergic pathways.

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Research reportLithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway

Abstract

Introduction

Section snippets

Chemicals

Effect of acute administration of lithium on anticonvulsant and proconvulsant effects of morphine

Discussion

Neuropharmacology

Psychoneuroendocrinology

Eur. J. Pharmacol.

Gen. Pharmacol.

Lancet

Neuroscience

Neurosci. Lett.

Gen. Pharmacol.

Neuropharmacology

Gen. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Epilepsy Res.

Biochem. Pharmacol.

J. Biol. Chem.

Neuropharmacology

Epilepsy Res.

Life Sci.

Trends Pharmac. Sci.

Brain Res.

Exp. Neurol.

Eur. J. Pharmacol.

Gen. Pharmacol.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Neurosci. Res.

Inositol phosphates and cell signaling

Nature

Research report
Lithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway