Additive Anticonvulsive Effects of Sumatriptan and

Morphine on Pentylenetetrazole-Induced Clonic Seizures

in Mice
1,2,3 2,4,5 2,5,6
Ramtin Gholizadeh, DVM , Faezeh Eslami, PharmD , Pegah Dejban, MD ,
7 2,5 2,5
Mehdi Ghasemi, MD, MPH , Nastaran Rahimi, MS , Ahmad Reza Dehpour, PharmD, PhD
1
Department of Pharmaceutical Sciences, College of Pharmacy University of Kentucky, Lexington, KY, USA;
2
Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Departments of
3
Pharmacology, College of Veterinary Medicine, Islamic Azad University, Karaj, Iran; 4Neurology and Rehabilitation,
5
Original Article University of Illinois Chicago, Chicago, IL, USA; Pharmacology, School of Medicine, Tehran University of Medical
6 7
Journal of Epilepsy Research Sciences, Tehran, Iran; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; Neurology, Lahey
pISSN 2233-6249 / eISSN 2233-6257 Hospital & Medical Center, Burlington, MA, USA

Background and Purpose: Sumatriptan protects the brain from damage and enhance the anti-seizure
effect of morphine. There is evidence that nitric oxide (NO) may mediate these effects of both drugs. In
the present study, we investigated the effects of sumatriptan (0.1-20 mg/kg, intraperitoneal [i.p.]) and
morphine (0.1-20 mg/kg, i.p.) alone or in combination on seizure thresholds in an in vivo model of seizure
in mice. Using various NO synthase inhibitors as well as the NO precursor, we assessed possible
involvement of NO signaling in these effects.
Methods: Clonic seizures were induced in male Naval Medical Research Institute mice by intravenous
administration of pentylenetetrazol (PTZ).
Results: Acute sumatriptan administration exerted anti-convulsive effects at 0.5 (p<0.01) and 1 mg/kg
(p<0.05), but pro-convulsive effects at 20 mg/kg (p<0.05). Morphine had anti-convulsive effects at 0.5
(p<0.05) and 1 mg/kg (p<0.001), but exerted pro-convulsive effect at 20 mg/kg (p<0.05). Combination
treatment with sub-effective doses of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) significantly
(p<0.05) exerted an anti-convulsive effect. Co-administration of the NO precursor L-arginine (60 mg/kg)
with sub-effective doses of sumatriptan and morphine significantly (p<0.05) increased seizure threshold
Received November 10, 2023
Revised December 6, 2023 compared with sumatriptan alone, but not sumatriptan+morphine group. While concomitant administration
Accepted January 3, 2024 of either the non-selective NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (5 mg/kg) or the
Corresponding author: selective inducible NOS inhibitor aminoguanidine (50 mg/kg) with combined sub-effective doses of
Ahmad Reza Dehpour, PharmD, PhD
Department of Pharmacology, School of morphine and sumatriptan produced significant anticonvulsive effects, concomitant administration with
Medicine, Tehran University of Medical the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg) inhibited this effect.
Sciences, Tehran Province, Tehran
Conclusions: Our data suggest a possible role for the NO signaling in the anticonvulsive effects of
1416753955, Iran
Tel. +98-21-8897-3652 combined sumatriptan and morphine on the PTZ-induced clonic seizures in mice. (2024;14:9-16)
Fax. +98-21-6640-2569
E-mail; dehpour@yahoo.com Key words: Sumatriptan, Morphine, Seizure, Pentylenetetrazole, Nitic oxide, Mice

Introduction found to have both anti-convulsive and pro-convulsive effects, de-

pending on the dosage, when it comes to seizures triggered by pen-
4
Sumatriptan is a drug that activates 5-hydroxytryptamine (5-HT)1B/1D tylenetetrazole (PTZ). Additionally, sumatriptan has other effects on
receptors, which are found on serotonergic nerve terminals that re- the nervous system. For instance, it can protect against nerve dam-
1 5
lease serotonin (5-HT). The levels of serotonin in the brain can have age induced by vincristine in rats, and it provides relief from pain
2,3 6
an impact on seizure activity. As a result, sumatriptan has been during migraine attacks.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
10 Journal of Epilepsy Research Vol. 14, No. 1, 2024

Opioids have been used by humans for pleasure and for treating Chemicals
7
various conditions, particularly pain, for almost 6 millennia. One Sumatriptan, morphine sulfate, PTZ, L-arginine (a NO precursor),
area of investigation that is not well-known is the impact of opioids G
L-N -nitroarginine methyl ester (L-NAME, a non-specific NOS in-
on seizure susceptibility. Previous studies have demonstrated that hibitor), aminoguanidine (a specific iNOS inhibitor), and 7-nitro-
opioids can have different effects on convulsive events. There is a indazole (a specific nNOS inhibitor) were purchased from Sigma (St.
growing body of evidence that indicates opioids have both anti-con- Louis, MO, USA). All drugs were dissolved in normal saline (0.9%)
vulsive and pro-convulsive properties in different experimental mod- except 7-nitroindazole, which was suspended in an aqueous solution
8,9
els of seizures. Specifically, low doses of morphine, an opioid-re- ®
of Tween (Sigma) 80 (1%). All drug solutions and suspensions were
ceptor agonist, have an anti-convulsive effect, while higher doses de- prepared freshly on the day of the experiment. PTZ was injected in-
crease the seizure thresholds induced by agents like picrotoxin, bicu- travenously in the tail vein (0.5%). Sumatriptan, morphine sulfate,
10
culline, and PTZ. L-NAME, 7-nitroindazole, and aminoguanidine were administered
Nitric oxide (NO) is one of the most important neurotransmitters in intraperitoneally (i.p.). The dosage selections, route of drug admin-
both central (CNS) and peripheral nervous system. It is synthesized by istration, and injection time of different compounds were based on
three NO synthase (NOS) enzyme isoforms (neuronal NOS [nNOS], previously published data, preliminary experiments, and pharmacoki-
endothelial NOS [eNOS], and inducible NOS [iNOS]) from the amino netic considerations.
4,10,15,16
11
acid L-arginine. Compelling evidence suggest that NO modulates
12,13
the susceptibility to seizure in a bimodal direction. Additionally, Experimental groups
studies reported that low doses of sumatriptan exert anti-convulsive
In experiment 1, animals received different doses of sumatriptan
effects on the PTZ-induced seizure in mice via mediating the NO
4
(0.1, 0.5, 1, 10, and 20 mg/kg, i.p.) or its vehicle (normal saline, as
pathway. In addition, the involvement of NO in the biphasic effects
control group) 30 minutes before PTZ injection. In this step, the sub-
of morphine on the PTZ-induced seizure susceptibility has been
10,14
effective dose of sumatriptan was selected for subsequent experiments.
reported. In the present study, we aimed to investigate the ef-
In experiment 2, animals received different doses of morphine
fects of combining sumatriptan and morphine on the seizure thresh-
(0.1, 0.5, 1, 10, and, 20 mg/kg, i.p.) or its vehicle (normal saline, as
old and explore the possible role of the NO pathway.
control group) 30 minutes before PTZ injection. In this step, the sub-
effective dose of morphine was selected for subsequent experiments.
Methods In experiment 3, a sub-effective dose of sumatriptan (0.1 mg/kg,
i.p.) was concurrently administered with a sub-effective dose of mor-
Animals
phine (0.1 mg/kg, i.p.). The seizure was induced by PTZ injection 30
All animal procedures were performed under the guidelines for the minutes after the drugs injection.
care and use of laboratory animals, Tehran University of Medical In experiments 4 through 7, the role of NO and opioids in the anti-
Sciences as well as the National Institutes of Health (NIH publication convulsant effects of sumatriptan injection was assess. The non-ef-
NO. 85-23; revised 1985). Male adult Naval Medical Research fective doses of the NO donor L-arginine (60 mg/kg, i.p.), the non-se-
Institute mice, weighting 23-30 g and aged 6-8-week, were provided lective NOS inhibitor L-NAME (5 mg/kg, i.p.), the selective iNOS in-
from the Department of Pharmacology, Tehran University of Medical hibitor aminoguanidine (50 mg/kg, i.p.), and the selective nNOS in-
Sciences. Animals were housed in standard polycarbonate cages at hibitor 7-nitroidazole (30 mg/kg, i.p.) were administered 15 minutes
an ambient temperature of 24ºC and a cycle of 12 horus-light/12 ho- before saline, sumatriptan (0.1 mg/kg, i.p.), morphine (0.1 mg/kg, i.p.),
rus-dark. They also had free access to food and tap water. All behav- and combined sumatriptan (0.1 mg/kg, i.p.)+morphine (0.1 mg/kg, i.p.)
ioral trials were carried out at the same time of the day between 8:00 injection in separate groups. The seizure was induced by PTZ in-
and 11:00 AM to minimize diurnal variations. Each mouse was used jection 30 minutes after the drugs injection.
only once, and each group consisted of four to eight animals.

Copyright ⓒ 2024 Korean Epilepsy Society

 Gholizadeh R, et al. Sumatriptan, Morphine & Seizure: Nitric Oxide 11

Evaluation of seizure threshold Results

To assess the clonic seizure thresholds, a 30-gauge butterfly nee-
dle was inserted into the tail vein and fixed by a piece of adhesive Effect of sumatriptan and morphine on the
tape while the animal was placed in a mouse restrainer. The infusion PTZ- induced seizure threshold
pump was adjusted to deliver PTZ (0.5%) at a constant rate of 1 Fig. 1A illustrates the biphasic effects of sumatriptan (0.1, 0.5, 1,
mL/minutes in all the experiments, and animals were allowed to 10, and 20 mg/kg, i.p.) on PTZ-induced seizure thresholds (F 5,33=15.01;
move freely. All these steps take less than 10 seconds and normally p <0.001). Sumatriptan at doses of 0.5 mg/kg (p <0.01) and 1 mg/kg
no mortality was seen. The infusion of PTZ was immediately dis- (p <0.05) exerted anti-convulsive effects, whereas sumatriptan at 20
continued when forelimb clonus was observed which is normally fol- mg/kg decreased the seizure threshold compared with the control
16
lowed by full clonus of the body. The minimal dose of PTZ (mg/kg of (saline-treated) group (p <0.05). Notably, sumatriptan at 0.1 mg/kg
mice weight) needed to induce general clonus was recorded as an in- did not exert any significant anti-convulsive effects on the seizure
15,16
dex of clonic seizure threshold. threshold compared to the control group and was selected as a
sub-effective dose for anti-convulsive activity in our experiments.
Statistical analysis Fig. 1B shows the effects of different doses of morphine (0.1, 0.5,
The data were analyzed using the Graph pad Prism data analysis 1, 10, and 20 mg/kg, i.p.) on the PTZ-induced seizure thresholds
program (Graph pad Software; San Diego, CA, USA) and presented (F 5,30=12.19; p <0.001). Morphine at 0.5 mg/kg (p <0.05) and
as the mean±standard error of mean. One-way ANOVA (Graph pad 1 mg/kg (p <0.001) increased seizure thresholds compared to the
Software) followed by Tukey's multiple comparisons of variances was saline-treated control group. However, morphine at the highest dose
used to analyze data where appropriate. In all experimental groups, (20 mg/kg, i.p.) exerted a significant (p <0.05) pro-convulsive effect
differences were considered statistically significant in case the proba- compared to the control group. Notably, morphine at 0.1 mg/kg did
bility of type I error (p -value) was less than 0.05. not exert any anti-convulsive effects and was considered as a sub-ef-
fective dose.

A B

Figure 1. Effects of different doses of (A) sumatriptan (0.1, 0.5, 1, 10, and 20 mg/kg, i.p.) or its solvent (saline, i.p., as control group) and (B) morphine (0.1,
0.5, 1, 10, and 20 mg/kg, i.p.) or its solvent (saline, i.p., as control group) on the pentylenetetrazole (PTZ)-induced clonic seizure threshold in mice.
Sumatriptan or morphine were administered 30 minutes before determination of PTZ-induced clonic seizure threshold. Data are expressed as the
mean±standard deviation of seizure threshold in each group. Each group consisted of 5 to 8 mice. i.p., intraperitoneal. *p <0.05; **p <0.01; and
***p <0.001 compared with corresponding saline-treated control group.

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12 Journal of Epilepsy Research Vol. 14, No. 1, 2024

Effect of acute co-administration of morphine and (p >0.05) in comparison with sumatriptan (0.1 mg/kg, i.p.) plus mor-
sumatriptan on the PTZ-induced seizure threshold phine (0.1 mg/kg, i.p.) group (F 7,43=4.766; p <0.001).
Fig. 2 demonstrates the effects of co-administration of the sub-ef-
fective doses of morphine (0.1 mg/kg, i.p.) and sumatriptan (0.1 Effects of NOS inhibitors on the anti-convulsive
mg/kg, i.p.) on the PTZ-induced seizure threshold (F 3,26=8.771; effects of sumatriptan, morphine, or their
p <0.001). This combined administration significantly increased the combination on the PTZ-induced seizure threshold
seizure thresholds in comparison with sumatriptan (p <0.05) or mor- Fig. 4A shows that L-NAME at 5 mg/kg (i.p.) alone did not have
phine (p <0.05) alone groups. any significant effect on the PTZ-induced seizure threshold compared
with the saline-treated control group. However, co-treatment of L-NAME
Effects of L-arginine on the anti-convulsive effects of (5 mg/kg, i.p.) with the sub-effective dose of sumatriptan (0.1 mg/kg,
sumatriptan, morphine, or their combination on the i.p.) significantly increased the seizure threshold in comparison with
PTZ-induced seizure threshold sumatriptan (0.1 mg/kg, i.p.) alone (p <0.001). Moreover, co-admin-
As shown in Fig. 3, L-arginine at 60 mg/kg did not have any sig- istration of L-NAME (5 mg/kg, i.p.) with a sub-effective dose of mor-
nificant effect on the seizure threshold compared with the sal- phine (0.1 mg/kg, i.p.) did not alter the seizure threshold in compar-
ine-treated control group. Moreover, L-arginine (60 mg/kg, i.p.) plus ison with the morphine (0.1 mg/kg) alone. Notably, concurrent ad-
sub-effective dose of sumatriptan (0.1 mg/kg, i.p.) or L-arginine (60 ministration of L-NAME (5 mg/kg, i.p.), sumatriptan (0.1 mg/kg, i.p.),
mg/kg, i.p.) plus sub-effective dose of morphine (0.1 mg/kg, i.p.) did and morphine (0.1 mg/kg, i.p.) significantly increased the PTZ-in-
not exert any significant effect on the PTZ-induced seizure threshold duced seizure threshold compared with sumatriptan alone (p <0.001),
compared with sumatriptan (0.1 mg/kg, i.p.) or morphine (0.1 morphine alone (p <0.001), or morphine plus sumatriptan (p <0.05)
mg/kg, i.p.) alone group. Notably, co-administration of L-arginine (60 groups (F 7,42=13.18; p <0.001).
mg/kg, i.p.), sumatriptan (0.1 mg/kg, i.p.), and morphine (0.1 mg/kg, Fig. 4B shows that aminoguanidine at 50 mg/kg (i.p.) alone did
i.p.) significantly (p <0.05) increased seizure threshold compared not exert any significant effect on the PTZ-induced seizure threshold
with sumatriptan (0.1 mg/kg) alone group. However, this combined
three-agent treatment did not significantly alter the seizure threshold

Figure 3. Effect of pretreatment with L-arginine (60 mg/kg, i.p.) on the

Figure 2. Effect of co-administration of sub-effective doses of morphine (0.1 effects of sumatriptan (0.1 mg/kg, i.p.) and morphine (0.1 mg/kg, i.p.),
mg/kg, i.p.) and sumatriptan (0.1 mg/kg, i.p.) on the pentylenetetrazole alone or in combination, on the pentylenetetrazole (PTZ)-induced seizure
(PTZ)-induced clonic seizure threshold in mice. Morphine and sumatriptan were threshold in mice. L-arginine was administered 15 minutes before sumatriptan
administered concurrently 30 minutes before PTZ. Data are expressed as or morphine, or their co-administration, and 45 minutes before PTZ. Data
mean±standard deviation. The number of mice in each group is indicated are expressed as mean±standard deviation. The number of mice in each
below the corresponding bar. i.p., intraperitoneal. *p <0.05 compared with group is indicated below the corresponding bar. i.p., intraperitoneal.
corresponding group as shown by lines connecting each of the two *p <0.05 and **p <0.01 compared with corresponding group as shown by
comparison groups. lines connecting each of the two comparison groups.

Copyright ⓒ 2024 Korean Epilepsy Society

 Gholizadeh R, et al. Sumatriptan, Morphine & Seizure: Nitric Oxide 13

A compared with the saline-treated control group. Moreover, co-ad-

ministration of aminoguanidine (50 mg/kg, i.p.) with either the
sub-effective dose of sumatriptan (0.1 mg/kg, i.p.) or morphine (0.1
mg/kg, i.p.) did not exert any significant effect on the PTZ-induced
seizure thresholds in comparison with either sumatriptan or mor-
phine group, respectively. Notably, the administration of amino-
guanidine (50 mg/kg, i.p.) along with sumatriptan (0.1 mg/kg, i.p.)
and morphine (0.1 mg/kg, i.p.) significantly increased seizure thresh-
old compared with sumatriptan (p <0.001) and morphine (p <0.01)
groups (F 7,44=8.771; p <0.001). However, this combined three-agent
treatment did not alter the seizure threshold compared to suma-
triptan plus morphine group (p >0.05).
B Fig. 4C shows that 7-nitroindazole at 30 mg/kg (i.p.) did not have
any significant effect on the seizure threshold compared with the sal-
ine-treated control group. Moreover, co-treatment of 7-nitroindazole
(30 mg/kg, i.p.) with the sub-effective dose of either sumatriptan
(0.1 mg/kg, i.p.) or morphine (0.1 mg/kg, i.p.) did not exert any sig-
nificant effect on the PTZ-induced seizure threshold compared with
corresponding sumatriptan or morphine group, respectively. Notably,
co-administration of 7-nitroindazole (30 mg/kg, i.p.) with combined
sumatriptan (0.1 mg/kg, i.p.) and morphine (0.1 mg/kg, i.p.) sig-
nificantly reduced seizure activity induced by PTZ in comparison with
morphine (p <0.001) or sumatriptan plus morphine (p <0.001), and
not with sumatriptan alone group (F 7,47=5.154; p <0.001).
C

Discussion

Seizure induction by PTZ is a recognized and widely used ex-

17,18
perimental model for studying clonic seizures in a clinical setting.
PTZ specifically binds to the picrotoxin site of the γ-aminobutyric acid
(GABA) receptor complex, disrupting GABA-mediated inhibition and
potentially activating the N-methyl-D-aspartate receptor. This in turn
increases activity in key epileptogenic centers of the forebrain such as
19
the amygdala and piriform cortex. These neurochemical processes
20
Figure 4. Effect of pretreatment with (A) L-NAME (5 mg/kg, i.p.), (B) contribute to the onset and spread of PTZ-induced seizures.
aminoguanidine (AG, 50 mg/kg, i.p.), and (C) 7-NI (30 mg/kg, i.p.) on the While it was previously believed that sumatriptan only had an ef-
effects of combined morphine (0.1 mg/kg, i.p.) and sumatriptan (0.1 mg/kg,
fect on the peripheral nervous system, recent findings have shown
i.p.) on the PTZ-induced seizure threshold in mice. L-NAME, 7-NI, or AG were 4,21-23
administered 15 minutes before sumatriptan or morphine, or their co- that it also affects the CNS. An increase in sumatriptan concen-
administration, and 45 minutes before PTZ. Data are expressed as mean± tration in the spinal fluid after oral administration and high levels of
standard deviation. The number of mice in each group is indicated below 23
sumatriptan in the brain after intravenous injection confirm this.
G
the corresponding bar. PTZ, pentylenetetrazole; L-NAME, L-N -nitroarginine
Sumatriptan is commonly used to treat migraines and works by tar-
methyl ester; 7-NI, 7-nitroindazole; i.p., intraperitoneal. *p <0.05; **p <0.01;
and ***p <0.001 compared with corresponding group as shown by lines geting 5-HT1B/1D receptors. There is a connection between migraines
24
connecting each of the two comparison groups. and epilepsy, known as migralepsy, suggesting that seizures can be

www.kes.or.kr
14 Journal of Epilepsy Research Vol. 14, No. 1, 2024

triggered by migraines and followed by headaches and more age administered. Moreover, there is evidence that sumatriptan re-
39
migraines. This raises questions about how sumatriptan affects duces levels of NO. Additional studies have suggested that suma-
seizures. It has been found that lower dose of sumatriptan (1 mg/kg) triptan aids in alleviating migraine headaches by decreasing the pro-
40 41
can increase the threshold for clonic seizures induced by PTZ via in- duction of NO. In our recent study, we observed an increase in NO
volvement of the nNOS/NO pathway in the hippocampus and tempo- levels following the induction of status epilepticus (SE) in rats, but
ral cortex, whereas higher dose (20 mg/kg) can actually lower the treatment with sumatriptan resulted in a significant decrease in NO
seizure threshold via the activation of iNOS/NO pathway in the levels in the rats' brain tissues post-seizure. On the other hand, a
4
brain. A study in mice showed anti-convulsive effects of suma- more substantial reduction in NO levels could potentially lead to
22
triptan, but another study in rats reported pro-convulsive effects on more brain damage. This was evident in our experiment when we
21
the PTZ-induced seizures. Our present study found that low doses combined sumatriptan with NOS inhibitors (L-NAME and 7-nitro-
of sumatriptan (0.5 and 1 mg/kg) showed anti-convulsive effects, but indazole), which resulted in more brain injury. Moreover, there is evi-
a higher dose (20 mg/kg) had a pro-convulsive impact on the PTZ-in- dence that the NO pathway mediates both the anti- and pro-con-
10,29,42
duced seizures in mice. vulsive effects of morphine in seizures. For instance, Homayoun
10
Opioids, such as morphine, have a biphasic effect on seizure thresh- et al. demonstrated that the non-selective NOS inhibitor L-NAME
8,10,25-27
old depending on the dosage and models used. Lower doses was able to completely reverse the anticonvulsive effects of mor-
of morphine typically have an anti-convulsive effect against seizures in- phine on the PTZ-induced clonic seizures in mice, whereas the
duced by substances that block GABA transmission, such as PTZ, pic- pro-convulsive impact was only partially neutralized by L-NAME.
28
rotoxin, bicuculline, and isoniazid, in animal studies. Conversely, high- Other study also found that pre-treatment with different NOS in-
er doses of morphine actually increase the susceptibility of animals to hibitors, such as L-NAME (10 mg/kg, i.p.), 7-nitroindazole (30 mg/kg,
25
seizures. Moreover, endogenous opioids have the potential to protect i.p.), and aminoguanidine (50 mg/kg, i.p.), significantly reversed the
29
against seizures induced by electroconvulsive shocks and can play an inhibitory effects of morphine on the lithium chloride/pilocarpine-in-
30 43
anti-convulsive role in acute stress. However, at very high doses, mor- duced SE. Another study also demonstrated that constitutional
27
phine can induce seizures and heighten susceptibility to them. The NOS isoforms (i.e., eNOS and nNOS) may play an important role in
biphasic impact of morphine on seizures suggests that it activates both the modulation of anticonvulsive effects of morphine on electro-
31 29
excitatory and inhibitory mechanisms. Moreover, opioids can modu- shock-induced seizure in mice.
32
late the activity of stimulatory guanine nucleotide-binding (Gs) and In a study conducted in 2013, the researchers investigated the po-
33
inhibitory guanine nucleotide-binding (Gi) proteins, which are in- tential role of the NO pathway in the effects of combining morphine
34
volved in signal transduction pathways. Low doses of opioids have with agmatine (a compound derived from the chemical arginine) on
32 42
been shown to activate Gs proteins, which stimulate adenylate cyclase seizures induced by PTZ in mice. The results showed that when
and increase cyclic adenosine monophosphate (AMP) levels. High doses L-NAME (1 and 5 mg/kg, i.p.) or 7-nitroindazole (15 and 30 mg/kg,
33
of opioids, on the other hand, have been shown to activate Gi proteins, i.p.) were co-administered with a combination of morphine (0.1
which inhibit adenylate cyclase and decrease cyclic AMP levels. mg/kg) and agmatine (1 mg/kg), a significant anticonvulsive effect
Confirming earlier research, we also observed that administering low was observed. Additionally, the administration of the NO precursor
doses of morphine (0.5 and 1 mg/kg) increased the seizure threshold. L-arginine (30 and 60 mg/kg, i.p.) inhibited the anticonvulsive effects
On the other hand, higher doses (20 mg/kg) decreased the threshold of co-administering agmatine (3 mg/kg) and morphine (0.5 mg/kg),
42
and intensified susceptibility to seizures induced by PTZ in mice. suggesting the involvement of the NO pathway. These findings are
The NO pathway has been shown to influence seizure threshold in consistent with our present data that showed that different NOS in-
35-37
different ways depending on the study. Some researchers have hibitors could influence the effects of combined sumatriptan and
suggested that the alterations in the activity of three enzymes that morphine administration on PTZ-induced seizures in mice. The anti-
produce NO in a biological system are responsible for the seizures in- convulsive effect of morphine is connected to an increase in
38,39 38 26,44
duced by PTZ in animals. Kirkby et al. reported that the effects GABAergic transmission within the CNS. Interestingly, several
of NOS inhibitors on seizures, whether pro or anti-convulsive, depend studies have found a correlation between NOS activation and an in-
45,46
on genetic factors, the models employed in the seizures, and the dos- crease in GABAergic activity in the brain. Therefore, it is likely that

Copyright ⓒ 2024 Korean Epilepsy Society

 Gholizadeh R, et al. Sumatriptan, Morphine & Seizure: Nitric Oxide 15

NO plays a role in mediating the anticonvulsive effect of morphine by by nitric oxide synthase inhibitors in mice. Life Sci 1997;60:PL339-43.
enhancing GABAergic function. However, further investigation is 15. Dafe EA, Rahimi N, Javadian N, et al. Effect of lenalidomide on pentylene-
tetrazole-induced clonic seizure threshold in mice: a role for N-Methyl-
needed to clarify this point.
D-aspartic acid receptor/nitric oxide pathway. J Epilepsy Res 2021;11:6-13.
16. Gholizadeh R, Abdolmaleki Z, Bahremand T, Ghasemi M, Gharghabi M,
Conflicts of Interest
Dehpour AR. Involvement of N-Methyl-D-aspartate receptors in the anti-
The authors report no conflicts of interest related to the present convulsive effects of licofelone on pentylenetetrazole-induced clonic seiz-
study. ure in mice. J Epilepsy Res 2021;11:14-21.
17. Swinyard EA, Kupferberg HJ. Antiepileptic drugs: detection, quantifica-
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