Research reportLithium inhibits the modulatory effects of morphine on susceptibility to pentylenetetrazole-induced clonic seizure in mice: involvement of a nitric oxide pathway
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 NG-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 (F1*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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2014, Epilepsy and BehaviorCitation 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.