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The Role of Opioid and Nitrergic Systems in Dual Modulation of Date Published Online: 31/08/2020; Seizure Susceptibility www.als-journal.com/ ISSN 2310-5380/ August 2020 Review Article Advancements in Life Sciences – International Quarterly Journal of Biological Sciences ARTICLE INFO Open Access Date Received: 16/05/2020; Date Revised: 23/08/2020; The role of opioid and nitrergic systems in dual modulation of Date Published Online: 31/08/2020; seizure susceptibility Authors’ Affiliation: 1,3 2,3 1 4 5 1. Department Muhammad Imran Khan , Farid Ullah Shah , Abdul Wahab , Vahid Nikoui *, Ahmad Reza Dehpour * of Pharmacy, Kohat University of Science and Technology, Abstract 26000 Kohat – Pakistan pilepsy is a chronic disorder presented by recurrent episodes of seizures and affect worldwide 2. Department of Biochemistry, Bannu individuals. The underlying mechanism of seizure is still elusive. Hence, there is still a need to determine Medical College, the contribution of various systems in neurobiology and treatment of seizure. Evidence shows that opioid 28100 Bannu, KPK - and nitrergic systems within the brain interact to modulate various physiological and pathological Pakistan E 3. Drug Detoxification conditions including memory, pain, reward, addiction, depression, and seizure. Various studies revealed that Health Welfare Research Center, diverse dose of opioids such as morphine has dual modulation in seizure susceptibility. For instance, it is Bannu, KPK - reported that morphine at lower doses (0.5, 1, and 3 mg/kg) exerts an anticonvulsant effect in experimental Pakistan 4. Razi Drug seizure models, whereas at higher doses (15, 30, and 60 mg/kg) it could exacerbate the seizure. Similarly, Research Center, Iran nitrergic system has also been observed to possess dual effects in modulating the seizure threshold. Therefore, University of Medical Sciences, Tehran - understanding of opioidergic and nitrergic systems interaction in seizure seems important to achieve the Iran successful goal of seizure management. This review aimed to clarify and provide insight into how opioidergic 5. Department of Pharmacology, School and nitrergic systems interact in brain and mediate seizure behavior. of Medicine, Tehran University of Medical Sciences, Tehran - Iran *Corresponding Authors: Ahmad Reza Dehpour Email: [email protected] Vahid Nikoui Email: [email protected] How to Cite: Khan MI, Shah FU, Wahab A, Nikoui V, Dehpour AR (2020). The role of opioid and nitrergic systems in dual modulation of seizure susceptibility. Adv. Life Sci. 7(4): 193-201. Keywords: Opioids; Nitric oxide; Seizures; Morphine als Advancements in Life Sciences | www.als-journal.com | August 2020 | Volume 7 | Issue 4 193 You’re reading The role of opioid and nitrergic systems in dual modulation of seizure susceptibility morphine diminishes the electrographic seizure, while Introduction exacerbates seizure activity in high concentrations [20]. Opioid system is a complex system involved in a diverse In addition, in some early studies, it was found that range of homeostatic functions. It is highly expressed opioids inhibit the inhibitory interneurons, which thereby throughout the brain, spinal cord, peripheral nervous exacerbate the epileptic seizure rather than inhibiting it. systems, and in various other tissues. Interaction of DOR exerts suppressive epileptic activities in cortical various agents with endogenous opioids could cause regions trough inhibiting sodium channels. Interestingly, both beneficial and adverse effects. Currently, its researchers have reported that if DOR is down-regulated physiological and pharmacological effects are attributed and sodium channels are up-regulated, then it will by the activity of its three distinct receptors, mu, delta, exacerbate epilepsy [21,22]. It is also stated that α2- and kappa. All are G protein-coupled receptors and are adrenoceptors play a dramatic role in modulating the expressed both in presynaptic and postsynaptic anticonvulsant effects of morphine. In addition, agmatine neurons. Endogenous opioid peptides such as that is considered to be used as an adjunct therapy for dynorphins, endorphins, enkephalins and the exogenous seizure, enhances the anticonvulsant effect of morphine alkaloids such as morphine can activate these receptors. through α2-adrenoceptors [23]. Lipopolysaccharide has Recent research has reported new information on opioid been found to facilitate seizure susceptibility in colonic receptor-mediated activities and their underlying seizure model of mice. This activity was facilitated by phenomena with reference to seizure threshold. Opioid opioid system along with other molecules such as system involved in seizure modulation is extremely prostaglandins and NO [24]. complex as both proconvulsant and anticonvulsant actions have been reported. Our previous experiments Morphine and endogenous opioids possess have revealed the involvement of specific opioid anticonvulsant effects receptors in the proconvulsant and anticonvulsant Morphine is the main psychoactive chemical agent effects, which are linked to interaction of opioids with in opium used in certain clinical conditions. Since its nitric oxide (NO) system [1-10]. Therefore, information discovery dates back to almost 210 years ago, it was about the effects of this system is useful in understanding found that morphine exhibits anticonvulsant effect. Some the susceptibility of seizure to various drugs and their clinical trials report the anticonvulsant properties of doses, as well as the possible interaction with NO morphine as well [25]. Various experimental studies system. The present review aims to discuss the have also shown the anticonvulsant effects of morphine. underlying mechanisms of opioids and NO system in For instance, morphine was found to delay the onset of seizure and finally to rearrange these pleiotropic actions PTZ-induced seizures in experimental animal models of in a comprehensive way. seizure [1]. These results were further confirmed by the study where the subcutaneous administration of acute Methods lower doses of morphine (0.5, 1, and 3 mg/kg) postponed Literature search strategy and selection criteria the onset of PTZ-induced seizure [7]. Similarly, morphine Literature concerned to these systems with their possible decreases the intensity of maximal electroshock interaction was sorted out using key words such as seizures[26]. Acute doses of morphine also illustrate an morphine, opioids, nitric oxide and seizure in google anticonvulsant effect against various seizure models scholar and web. The relevant literature based on their induced by gamma-Aminobutyric acid (GABA) contents was selected and was pen down into this transmission blockers, such as picrotoxin, bicuculline, comprehensive and conceptual review. PTZ, and isoniazid [27]. Similar to morphine, other opioids such etorphine and β-endorphin also increase Discussion the seizure threshold and demonstrate anticonvulsant Opioids and epileptic seizures effects [28,29]. Different species may respond The effect of opioids on epileptic seizures is still asymmetrically to these effects. For example, morphine controversial. Both proconvulsant and anticonvulsant acts as a proconvulsant to PTZ-induced seizure model effects of opioids such as tramadol [11] and morphine of mice [30], while on the contrary, it might act as an have been reported to be mediated by μ-(mu), δ-(delta), anticonvulsant following PTZ administration in rat model and κ-(kappa) opioid receptors (MOR, DOR, KOR, [31]. respectively) in various species including rats [12], Morphine and endogenous opioids possess human being [13], mice [14], and monkeys [15]. Rubaj proconvulsant effects etal. highlighted that normobaric hypoxia can reduce the susceptibility to pentylenetetrazole (PTZ)-induced Previously, it was reported that morphine under certain convulsions, which could be mimicked by μ-or κ-receptor conditions, shows anticonvulsant effects. However, in agonists in the brain [16]. In experimental epileptic contrast, morphine also exerts proconvulsant effects models, it has been shown that epileptic seizures under certain conditions, for instance, when a high upregulate the opioid receptors [17], and potentiate the systemic dose of morphine is used. Data from the levels of endogenous opioid like enkephalins and previous research, found that epileptiform patterns and dynorphins in the brain [18,19]. Opioids might possess behavioral convulsions may be exacerbated by high anticonvulsant or proconvulsant effects in a dose- doses of morphine in various experimental animals such dependent manner in the brain. For instance, other as rabbits [32], mice [30], monkeys [33], and even in extensive studies confirmed that at low concentration, humans. Morphine can also initiate electrographic als Advancements in Life Sciences | www.als-journal.com | August 2020 | Volume 7 | Issue 4 194 You’re reading The role of opioid and nitrergic systems in dual modulation of seizure susceptibility seizures in rats following intracerebroventricular injection increase, which boost the PTZ-induced seizure threshold at high doses [34]. We also reported that apart from the in cholestasis [3]. proconvulsant behavior, morphine when used in subeffective proconvulsant dose, could enhance the Opioid receptors involved in proconvulsant effects proconvulsant effects of Sildenafil [14]. Surprisingly, we Different opioid receptors are involved in mediating the showed that injection of anticonvulsant dose of morphine proconvulsant effects of morphine and other related (1mg/kg) in post weaning social isolation stress model in opioids. It is reported that neuroexcitatory
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