Neuroscience Letters 760 (2021) 136095
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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet
Research article
Synergistic effect between imipramine and citicoline upon induction of
analgesic and antidepressant effects in mice
Fatemeh Khakpai a, Mahsa Ramezanikhah b, Farhad Valizadegan b,
Mohammad-Reza Zarrindast c, *
a
b
c
Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Department of Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords:
Imipramine
Citicoline
Analgesic
Antidepressant
Mice
Imipramine is a tricyclic antidepressant (TCA) drug that is sometimes used to treat neuropathic pain. Citicoline is
a dietary supplement that has been used as a neuroprotective agent for neurological disorders. Probable inter­
action between imipramine and citicoline on pain and depression behaviors was examined in mice using a tailflick test, open field test (OFT), forced swimming test (FST), and tail suspension test (TST). The results indicated
that the intraperitoneal (i.p.) administration of citicoline (50 mg/kg) induced analgesic and antidepressant-like
behaviors in mice. Similarly, i.p. injection of imipramine (5 mg/kg) induced dose-dependent anti-nociceptive
and anti-depressive effects. Co-administration of different doses of imipramine (1.25, 2.5, and 5 mg/kg) along
with an ineffective dose of citicoline (6.25 mg/kg) increased tail-flick latency and decreased immobility time in
the FST, suggesting an analgesic and antidepressant-like behaviors. Interestingly, there is a synergistic effect
between imipramine and citicoline upon the induction of analgesic and antidepressant effects. All doses of the
drugs had no significant effect on the locomotor activity. Based on these results, it can be concluded that the
administration of citicoline (as an adjuvant drug) in combination with imipramine increased the efficacy of TCA
drugs for modulation of pain and depression behaviors.
1. Introduction
Imipramine is a tricyclic antidepressant (TCA) that is most
commonly used to treat depressive illness. It is occasionally used to treat
neuropathic pain and other painful conditions including fibromyalgia,
headaches, or chronic low-back pain [18]. Imipramine is partly con­
verted in the body to an active metabolite, desipramine, which is
another of TCA. Desipramine is conversely a very potent reuptake in­
hibitor of norepinephrine and, to a lesser amount, serotonin [13]. The
mechanism of the medicinal function of TCA such as imipramine asso­
ciation with the monoaminergic system has been well recognized. These
drugs prevent the reuptake of serotonin, norepinephrine, and dopamine
through direct inhibition of neurotransmitter transporters [27]. Neuro­
transmitter transporters for serotonin, norepinephrine, and dopamine in
the presynaptic neuron limits the neuronal signal transmission, and
drugs used to prevent these systems have been used successfully for the
treatment of depression and pain [16].
Citicoline is a mononucleotide composed of cytosine, choline,
pyrophosphate, and ribose which is both an essential intermediate and
an inducer in the synthesis pathways of structural membrane phos­
pholipids i.e. Phosphatidylcholine and Acetylcholine, a key neuro­
transmitter [23]. It enhances phospholipid incorporation into
membranes and increases biosynthesis of structural phospholipids [1],
as well as increases acetylcholine, norepinephrine, dopamine, and se­
rotonin levels in particular brain areas [23]. Also, citicoline may have
neuroprotective and cognitive improving effects [4]. Administration of
citicoline has been related to the improvement of attention, memory,
and some neurophysiological parameters [5]. Moreover, citicoline
showed beneficially effects in the treatment of depressive symptoms and
neuropathic pain [4,11]. We hypothesized that imipramine and citico­
line modulate pain and depression behaviors as well as increase some
neurotransmitters such as norepinephrine, serotonin, and dopamine,
this research aimed to evaluate a possible interaction between imipra­
mine and citicoline that may increase the effectiveness of analgesic and
antidepressant effects and/or decrease their side effects which help to
develop therapeutic approaches for pain and depression treatment.
* Corresponding author.
E-mail address: zarinmr@ams.ac.ir (M.-R. Zarrindast).
https://doi.org/10.1016/j.neulet.2021.136095
Received 2 September 2020; Received in revised form 11 June 2021; Accepted 28 June 2021
Available online 30 June 2021
0304-3940/© 2021 Elsevier B.V. All rights reserved.
F. Khakpai et al.
Neuroscience Letters 760 (2021) 136095
2. Materials and methods
2.4. Experimental design
2.1. Animals
This research consisted of three experiments. In experiment 1, the
effects of saline (10 ml/kg) and different doses of citicoline (6.25, 12.5,
25 and 50 mg/kg) on tail-flick latency, locomotor activity in the OFT as
well as immobility time of FST and TST were investigated. In experiment
2, the effects of alone administration of saline (10 ml/kg) or different
doses of imipramine (1.25, 2.5, and 5 mg/kg), as well as coadministration of different doses of imipramine (1.25, 2.5, and 5 mg/
kg) [10,26] plus an ineffective dose of citicoline (6.25 mg/kg), were
examined on the performance of mice in the tail-flick test, OFT, FST, and
TST. In experiment 3, the effects of co-administration of imipramine 2.5
mg/kg + citicoline 25 mg/kg, and imipramine 1.25 mg/kg + citicoline
12.5 mg/kg, as well as imipramine 0.625 mg/kg + citicoline 6.25 mg/kg
on pain and depression-related behaviors were tested. We used different
groups of mice for study of tail-flick, OFT, FST, and TST and each mouse
only used for one test. 10 min after drug administration, tail-flick test,
OFT, FST, and TST were performed in separate groups.
Male mice (weighing 25–30 g) of the Naval Medical Research Insti­
tute (NMRI) strain were obtained from the University of Tehran (Tehran,
Iran). Mice were housed in groups of 4–6 per cage and were kept under
standard controlled laboratory conditions (12:12 h light/dark cycle, 22
± 2 C, 50% humidity, pelleted food, and water ad libitum). All the
experimental protocols were approved by the Research and Ethics
Committee of the University of Tehran and were done under the Na­
tional Institutes of Health Guide for Care and Use of Laboratory Animals.
2.2. Drugs and treatments
Citicoline sodium (Minoo, Tehran, Iran) and imipramine (CibaGeigy, Switzerland) were used in this research. Both drugs were dis­
solved in 0.9% saline and were injected intraperitoneally (i.p.) in a
volume of 10 ml/kg. The control mice received injections of 0.9% saline
(10 ml/kg).
2.5. Statistical analysis
All data obtained are expressed as the mean ± standard error of the
mean (SEM). One- and two-way analysis of variance (ANOVA) followed
by Tukey’s multiple comparisons were used. The differences between
groups were significant if the P-value was below 0.05.
Isobolographic analysis was done to identify the interaction
following the injection of the two drugs. The ED50 of each drug (2.5 mg/
kg for imipramine and 25 mg/kg for citicoline) was examined by linear
regression analysis and a combination of the two drugs was adminis­
trated in a constant dose ratio upon the ED50 values. For drug combi­
nations, the theoretic ED50 is imipramine ED50/2 + citicoline ED50/2.
Additionally, experimental values of drug combinations from fixed
ratio-calculated were analyzed by the regression analysis, after which
the experimental ED50 value of the drug combinations was determined
(%50 tail-flick latency and FST). The statistical significance of the dif­
ference between the theoretical ED50 and experimental ED50 of the
drug combination was calculated by a one-sample t-test. When the
experimental ED50 was meaningfully lower than the theoretical ED50 a
synergistic interaction between imipramine and citicoline could be
concluded, but there was not any difference between them presenting
additive interaction rather than the synergistic effect [15]. Differences
with P < 0.05 between the experimental groups at each point were
revealed statistically significant.
2.3. Apparatus
2.3.1. Tail-flick
A tail-flick apparatus was used for evaluating the nociceptive
response to thermal stimulation (Borj Sanat Company, Iran). The
response time between the start of the heat stimulus and the removal of
the tail from the heat source was documented via a sensor as the tailflick latency. Each animal was gently wrapped in a soft towel and the
dorsal surface of the tail from its distal end was located in the apparatus
every 15 min (for 60 min) after the drug/saline application. The heat
source and a timer were started simultaneously by a pedal. Both were
ended automatically by a tail movement which exposed a photocell
under the tail and/or by the experimenter at the end of a 10 s cut-off
time. This cut-off time was set to evade skin injury. Individual tail
withdrawal latencies were changed to the percentage of maximum
possible effect (%MPE) through the following formula: %MPE = [(test
latency-baseline latency)/ (cut-off latency-baseline latency)] × 100.
There were no meaningful differences in baseline tail-flick latencies
between the experimental groups before the application of the drugs
and/or saline. For all data, the area under the curve (AUC) of %MPE vs.
time was calculated from 0 to 60 min by the trapezoidal rule to deter­
mine the overall magnitude and duration of effect for the tail-flick test.
3. Results
2.3.2. Open field test (OFT)
The size of the apparatus (open field cage) in this research was 40 cm
× 60 cm × 50 cm which was prepared for white plastic. Each animal was
located in the center of the apparatus. The number of locomotor activity
in the apparatus was counted for 6 min [10]. The apparatus was cleaned
with ethanol 70% after each test.
3.1. Effect of citicoline on pain, locomotion, and depression
Fig. 1 indicated the effect of citicoline on tail-flick latency, locomotor
activity in OFT as well as immobility time of FST and TST. Two-way
ANOVA revealed no significant interaction between citicoline doses
and time intervals on %MPE (time intervals effect F (3,84) = 0.135, P =
0.939; citicoline effect F (4, 84) = 23.362, P = 0.000; time intervals ×
citicoline interaction F (12, 84) = 0.378, P = 0.769) (Fig. 1A). Regarding
the time interval effect and citicoline effect, Tukey’s multiple compari­
sons indicated that citicoline (50 mg/kg) at the time intervals of 30, 45
and 60 min and citicoline (25 mg/kg) only at the time interval of 45 min
after injection increased %MPE, suggesting an anti-nociceptive effect.
Also, as presented in Fig. 1B, one-way ANOVA followed by the Tukey’s
Post-hoc test for normalized AUC values indicated that citicoline (50
mg/kg) enhanced the AUC of %MPE [F (4, 35) = 3.557, P = 0.003],
indicating an analgesic effect.
One-way ANOVA showed no significant effect of citicoline on loco­
motor activity (F (4, 35) = 0.199, P = 0.937) compared to the saline
control group (Fig. 1C).
As seen in Fig. 1D and Fig. 1E, one-way ANOVA and post hoc analysis
2.3.3. Forced swimming test (FST)
Animals were located individually into glass cylinders (height 25 cm
and diameter 10 cm) containing 19 cm of water and maintained at 25 ±
2 ◦ C. There was no way to escape. Thus, mice were forced to swim. Mice
were given 2 min for habituation. In the remaining 4 min, the total
immobility duration was measured. Mice were removed from the water,
dried with a towel, and located in their cages.
2.3.4. Tail suspension test (TST)
The total time of immobility produced via tail suspension was
measured. Mice both acoustically and visually isolated were suspended
50 cm above the floor through adhesive tape placed nearly 1 cm from
the tip of the mouse tail. Animals were given 2 min for habituation and
in the remaining 4 min, immobility time was recorded.
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F. Khakpai et al.
Neuroscience Letters 760 (2021) 136095
Fig. 1. The effects of diverse doses of citicoline (6.25, 12.5, 25, and 50 mg/kg) on tail-flick latency (A and B), locomotor activity in OFT (C), immobility time of FST
(D), and immobility time of TST (E). Data presented as mean ± S.E.M (n = 8). *P < 0.05 and **P < 0.01 as compared with saline group.
revealed that citicoline at the doses of 50 mg/kg decreased immobility
time in the FST (F (4, 35) = 10.807, P = 0.000) and TST (F (4, 35) =
8.994, P = 0.000) compared to the saline control group, showing an
antidepressant-like effect.
different doses of imipramine (1.25, 2.5, and 5 mg/kg) along with an
ineffective dose of citicoline (6.25 mg/kg) on the tail-flick test. Two-way
ANOVA analyses exhibited no significant interaction between drug
combination doses and time intervals on %MPE (time intervals effect F
(3,84) = 0.040, P = 0.989; drugs-administration effect F (3, 84) =
46.690, P = 0.000; time intervals × drugs-administration interaction F
(9, 84) = 0.223, P = 0.880) (Fig. 2A, right panel). Regarding the time
interval effect and drugs-administration effect, Tukey’s multiple com­
parisons displayed that co-administration of imipramine and citicoline
enhanced %MPE in the tail-flick at the time intervals of 15, 30, 45 and
60 min after co-administration, displaying an anti-nociceptive response.
Co-administration of imipramine (5 mg/kg) and citicoline (12.5 mg/kg)
enhanced the AUC of %MPE [F (3, 28) = 6.783, P = 0.002; Fig. 2B, right
panel], presenting an analgesic effect.
Fig. 2C exhibited the effect of alone injection of different doses of
imipramine (1.25, 2.5, and 5 mg/kg) as well as co-administration of
these doses along with ineffective dose of citicoline (6.25 mg/kg) on
locomotor activity in the OFT. One-way ANOVA revealed no significant
effect of different doses of imipramine on locomotor activity (F (3, 28) =
1.138, P = 0.351; Fig. 2C, left panel). Also, two-way ANOVA displayed
no significant effect of co-administration of imipramine and citicoline on
3.2. Effect of imipramine and citicoline co-administration on pain,
locomotion, and depression
In Fig. 2A and 2B, left panels are seen the effect of different doses of
imipramine (1.25, 2.5, and 5 mg/kg) on tail-flick latency. Two-way
ANOVA analyses indicated no significant interaction between imipra­
mine doses and time intervals on %MPE (time intervals effect F (3,84) =
0.095, P = 0.962; imipramine effect F (3, 84) = 10.015, P = 0.003; time
intervals × imipramine interaction F (9, 84) = 0.183, P = 0.908)
(Fig. 2A, left panel). Regarding the time interval effect and imipramine
effect, Tukey’s multiple comparisons showed that imipramine (5 mg/kg)
at the time intervals of 15, 45, and 60 min after application increased %
MPE, showing an anti-nociceptive effect. Imipramine (5 mg/kg)
enhanced the AUC of %MPE [F (3, 28) = 4.071, P = 0.013; Fig. 2B, left
panel], proposing an analgesic effect.
Fig. 2A and 2B, right panels showed the effect of co-administration of
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Neuroscience Letters 760 (2021) 136095
Fig. 2. The effects of alone administration of imipramine and co-administration of it along with citicoline on pain (A and B), locomotion (C) and depression be­
haviors in mice (D and E). Data expressed as mean ± S.E.M (n = 8). *P < 0.05, **P < 0.01 and ***P < 0.001 as compared with saline group. + P < 0.05 in comparison
to the saline/ imipramine group.
locomotion (imipramine effect F (3, 56) = 1.456, P = 0.233; citicoline
effect F (1, 56) = 0.397, P = 0.775; imipramine × citicoline interaction F
(3, 56) = 0.578, P = 0.632; Fig. 2C, right panel).
In Fig. 2D is seen the effect of different doses of imipramine (1.25,
2.5, and 5 mg/kg) as well as co-injection of them with an ineffective dose
of citicoline (6.25 mg/kg) on immobility time of FST. One-way ANOVA
and post hoc analysis showed that imipramine at the doses of 2.5 and 5
mg/kg decreased immobility time in the FST (F (3, 28) = 7.408, P =
0.001; Fig. 2D, left panel) compared to control group, indicating an
antidepressant-like response. Furthermore, two-way ANOVA indicated a
significant interaction between imipramine and citicoline on immobility
time in the FST (imipramine effect F (3, 56) = 24.978, P = 0.000; cit­
icoline effect F (1, 56) = 14.205, P = 0.000; imipramine × citicoline
interaction F (3, 56) = 3.021, P = 0.031; Fig. 2D, right panel). Further
analysis revealed that co-administration of imipramine (5 mg/kg) and
citicoline (12.5 mg/kg) significantly decreased immobility time in the
FST, demonstrating an antidepressant-like effect.
Fig. 2E showed the effect of different doses of imipramine (1.25, 2.5,
and 5 mg/kg) and co-injection of them along with ineffective dose of
citicoline (6.25 mg/kg) on immobility time in the TST. One-way ANOVA
and post hoc analysis showed that imipramine at the dose of 5 mg/kg
decreased immobility time in the TST (F (3, 28) = 3.766, P = 0.022;
Fig. 2E, left panel) compared to control group, showing an
antidepressant-like response. Additionally, two-way ANOVA displayed
no interaction between imipramine and citicoline on immobility time in
the TST (imipramine effect: F (3,56) = 14.203, P = 0.000; citicoline
effect: F (1,56) = 10.505, P = 0.002; imipramine × citicoline interac­
tion: F (3,56) = 1.095, P = 0.359; Fig. 2E, right panel).
Fig. 3. The isobologram analysis of the effects of drug treatment revealed the synergistic effect of imipramine and citicoline on the induction of anti-nociceptive- and
antidepressant-like effects in mice. Statistical analysis revealed that there is a significant difference between experimental ED50 and theoretical ED50 points, showing
a synergistic effect of the administration of the drug ((A) for tail-flick latency and (B) for FST. ED50, effective dose 50.
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Neuroscience Letters 760 (2021) 136095
3.3. The synergistic effect between imipramine and citicoline on antinociceptive- and antidepressant-like effects
imipramine can be achieved during 4–6 days. The anti-nociceptive effect
of the drugs in the rat may be elicited as early as 5–10 min after appli­
cation [22]. Several clinical types of research have indicated beneficial
effects of TCAs in the treatment of chronic pain syndromes in nondepressed patients [18]. Nonetheless, their analgesic mechanism of ac­
tion is not clear, activation of a mixed analgesic effect mediated through
noradrenergic and/or serotonergic pathways or combination of these
mechanisms [24], as well as interaction with other neurotransmitter
systems, for example, opioidergic and nicotinic systems also has been
suggested [25].
Furthermore, the obtained results displayed that co-administration
of imipramine and citicoline enhanced tail-flick latency and reduced
immobility time in the FST, whereas their effect on TST and locomotor
activity were not significant. It is usually considered that diverse anti­
depressants have alike efficacy [6]. In this investigation, both imipra­
mine and citicoline exhibited good efficacy on the induction of analgesic
and antidepressant responses. Thus, the application of new drugs that
can enhance the efficacy of anti-nociceptive and antidepressant prop­
erties and/or reduce their side effects will help to improve therapeutic
strategies for pain and depression treatment. The results of this research
for the first time revealed the synergistic effect between imipramine and
citicoline on analgesic and antidepressant-like effects in mice. Citicoline
induced effects similar to those caused by TCA including enhancement
of brain levels of norepinephrine and dopamine [7] thus, we proposed
that co-treatment with imipramine and citicoline induced more anal­
gesic and antidepressant effects. Nowadays, pain and depression treat­
ment are commonly performed through the application of a combination
of some drugs with different mechanisms of action instead of using a
single drug [17]. Hence, administrations of new drugs and substances
can enhance the efficacy of analgesic and antidepressant drugs which
cause a reduction in their administered doses and a reduction in side
effects of their long-term use. Our results indicated that citicoline was an
effective adjuvant to imipramine in the treatment of pain and
depression.
The theoretical additive line indicated that at all points, imipramine
and citicoline combination induced an effect of theoretical %50 tail-flick
latency and theoretical %50 FST (theoretical ED50) according to an
additive interaction (Fig. 3). One sample t-test showed that there is a
significant difference between experimental ED50 and theoretical ED50.
Our results suggested a synergistic effect of imipramine and citicoline
co-injection upon induction of anti-nociceptive- and antidepressant-like
effects in mice (Fig. 3).
4. Discussion
The results of the current study indicated that i.p. administration of
citicoline increased tail-flick latency and decreased immobility time in
the FST and TST which showing anti-nociceptive- and anti-depressivelike behaviors, respectively. This administration had no significant ef­
fect on locomotor activity. Researches have been revealed the role of
citicoline in the treatment of cognitive disorders, maybe because of its
ability to increase the integrity and function of neuronal membranes as
well as neurological and functional recovery [23]. Citicoline has a main
role in neuronal structure and signaling [3]. When administered exog­
enously may help to preserve the integrity of the neuronal membrane
and increase the synthesis of structural phospholipids [23]. Further­
more, citicoline affects neurotransmitter levels mainly via the modula­
tion of catecholaminergic neurotransmission [2]. Citicoline has been
reported to act as a dopaminergic agonist. It also has some effects based
on the other monoamines, serotonin and norepinephrine, muscarinic
receptors, glutamate, and GABA [9]. It prevents catabolism of cerebral
phospholipids and produces a protective role upon membrane ATPase
and enzymes participated in brain energy metabolism, mainly succinyl
dehydrogenase and citrate synthetase [19]. Studies indicated that anti­
depressant drugs produce their effects through neurotransmitter sys­
tems, particularly serotonergic and noradrenergic synaptic transmission
[17]. Also, the noradrenergic and serotonergic systems include one of
the main components of the descending monoaminergic pain modula­
tion pathways [14]. Noradrenergic and serotonergic projections have
been revealed to prevent nociceptive afferents at the level of the spinal
dorsal horn neurons [12]. There is growing evidence that the mono­
aminergic neurons play a key role as an underlying neurobiological
mechanism to control acute and chronic pain [8]. We proposed antinociceptive- and antidepressant-like behaviors induced by citicoline
due to its ability to increase serotonergic and noradrenergic synaptic
transmission. Inconsistent with our result, reports are indicating that the
administration of citicoline blocks the occurrence of neuropathic pain in
rats [11], and decreases depression in mice [17]. These effects may be
due to the potential effect of citicoline in inducing optimal axonal
regeneration and enhancement the level of various neurotransmitters
[11,17].
Moreover, the obtained results showed that imipramine induced
analgesic and antidepressant effects without affecting locomotor activ­
ity. The rationale for an analgesic response is the regulating function at
the serotonergic and noradrenergic pathways that participated in the
nociceptive transmission and endogenous pain control [21]. Also, the
anti-depressive mechanism of TCAs such as imipramine is believed to its
an effect on the central monoaminergic pathways [26]. This hypothesis
supported by findings displaying the anti-nociceptive effect of TCAs can
be blocked by alpha-methyltyrosine and p-chlorophenylalanine [20].
Additionally, alterations in insensitivity of α- and β-adrenergic receptors
and serotonergic receptors in the CNS have been suggested to clarify the
action of the chronic application of TCAs. The agents that inhibit the
neuronal norepinephrine and/or serotonin reuptake are the most
constantly effective therapies in relieving chronic pain [26]. Neverthe­
less, the effects of these drugs on depression need 2–3 weeks to become
obvious, whereas the maximal pain relief during treatment with
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
References
[1] R.M. Adibhatla, J.F. Hatcher, Cytidine 5’-diphosphocholine (CDP-choline) in
stroke and other CNS disorders, Neurochem. Res. 30 (1) (2005) 15–23.
[2] J. Agut, J.A. Ortiz, R.J. Wurtman, Cytidine (5’)diphosphocholine modulates
dopamine K(+)-evoked release in striatum measured by microdialysis, Annals of
the New York Academy of Sciences 920 (2000) 332-335.
[3] P.M. Arenth, K.C. Russell, J.H. Ricker, R.D. Zafonte, CDP-choline as a biological
supplement during neurorecovery: a focused review, PM & R : the journal of injury,
function, and rehabilitation 3 (2011) S123–S131.
[4] E.S. Brown, B. Gabrielson, A randomized, double-blind, placebo-controlled trial of
citicoline for bipolar and unipolar depression and methamphetamine dependence,
J. Affect. Disord. 143 (1-3) (2012) 257–260.
[5] S.E. Bruce, K.B. Werner, B.F. Preston, L.M. Baker, Improvements in concentration,
working memory and sustained attention following consumption of a natural
citicoline-caffeine beverage, Int. J. Food Sci. Nutr. 65 (8) (2014) 1003–1007.
[6] J. Bruijn, P. Moleman, P. Mulder, W. van den Broek, Depressed in-patients respond
differently to imipramine and mirtazapine, Pharmacopsychiatry 32 (03) (1999)
87–92.
[7] W.A. Carlezon, A.M. Pliakas, A.M. Parow, M.J. Detke, B.M. Cohen, P.F. Renshaw,
Antidepressant-like effects of cytidine in the forced swim test in rats, Biol.
Psychiatry 51 (11) (2002) 882–889.
[8] Y. Cui, J. Xu, R. Dai, L. He, The interface between inhibition of descending
noradrenergic pain control pathways and negative affects in post-traumatic pain
patients, Upsala J. Med. Sci. 117 (3) (2012) 293–299.
[9] S.R. Dowd, M.E. Bier, J.L. Patton-Vogt, Turnover of phosphatidylcholine in
Saccharomyces cerevisiae, The role of the CDP-choline pathway, The Journal of
biological chemistry 276 (6) (2001) 3756–3763.
[10] A.S. Elhwuegi, K.M. Hassan, The analgesic effect of different antidepressants
combined with aspirin on thermally induced pain in Albino mice, Libyan Journal of
Medicine 7 (2012) 17251.
5
F. Khakpai et al.
Neuroscience Letters 760 (2021) 136095
[20] F. Sierralta, G. Pinardi, H.F. Miranda, Effect of p-chlorophenylalanine and alphamethyltyrosine on the antinociceptive effect of antidepressant drugs, Pharmacol.
Toxicol. 77 (1995) 276–280.
[21] S.H. Sindrup, M. Otto, N.B. Finnerup, T.S. Jensen, Antidepressants in the treatment
of neuropathic pain, Basic Clin. Pharmacol. Toxicol. 96 (6) (2005) 399–409.
[22] V. Ventafridda, M. Bianchi, C. Ripamonti, P. Sacerdote, F. De Conno, E. Zecca, A.
E. Panerai, Studies on the effects of antidepressant drugs on the antinociceptive
action of morphine and on plasma morphine in rat and man, Pain 43 (1990)
155–162.
[23] N.D. Wignall, E.S. Brown, Citicoline in addictive disorders: a review of the
literature, The American journal of drug and alcohol abuse 40 (4) (2014) 262–268.
[24] F. Yokogawa, Y. Kiuchi, Y. Ishikawa, N. Otsuka, Y. Masuda, K. Oguchi, A.
Hosoyamada, An investigation of monoamine receptors involved in antinociceptive
effects of antidepressants, Anesthesia and analgesia 95 (2002) 163-168, table of
contents.
[25] M.-R. Zarrindast, B. Baghdadi, M. Sahebgharani, Potentiation of imipramineinduced antinociception by nicotine in the formalin test, European
neuropsychopharmacology : the journal of the European College of
Neuropsychopharmacology 14 (1) (2004) 71–76.
[26] M.-R. Zarrindast, M. Sahebgharani, Effect of alpha-adrenoceptor agonists and
antagonists on imipramine-induced antinociception in the rat formalin test,
Pharmacology 64 (4) (2002) 201–207.
[27] Z. Zhou, J. Zhen, N.K. Karpowich, R.M. Goetz, C.J. Law, M.E.A. Reith, D.-N. Wang,
LeuT-desipramine structure reveals how antidepressants block neurotransmitter
reuptake, Science 317 (5843) (2007) 1390–1393.
[11] D.R. Emril, S. Wibowo, L. Meliala, R. Susilowati, Cytidine 5’-diphosphocholine
administration prevents peripheral neuropathic pain after sciatic nerve crush
injury in rats, Journal of pain research 9 (2016) 287–291.
[12] S. Fürst, Transmitters involved in antinociception in the spinal cord, Brain Res.
Bull. 48 (2) (1999) 129–141.
[13] L. Hearn, S. Derry, T. Phillips, R.A. Moore, P.J. Wiffen, Imipramine for neuropathic
pain in adults, The Cochrane database of systematic reviews (2014) CD010769.
[14] M.J. Millan, Descending control of pain, Prog. Neurobiol. 66 (6) (2002) 355–474.
[15] M. Nasehi, E. Ostadi, F. Khakpai, M. Ebrahimi-Ghiri, M.R. Zarrindast, Synergistic
effect between D-AP5 and muscimol in the nucleus accumbens shell on memory
consolidation deficit in adult male Wistar rats: An isobologram analysis, Neurobiol.
Learn. Mem. 141 (2017) 134–142.
[16] K. Ramirez, J.F. Sheridan, Antidepressant imipramine diminishes stress-induced
inflammation in the periphery and central nervous system and related anxiety- and
depressive- like behaviors, Brain Behav. Immun. 57 (2016) 293–303.
[17] M. Roohi-Azizi, A. Torkaman-Boutorabi, S. Akhondzadeh, A.-A. Nejatisafa, M.S. Sadat-Shirazi, M.-R. Zarrindast, Influence of citicoline on citalopram-induced
antidepressant activity in depressive-like symptoms in male mice, Physiol. Behav.
195 (2018) 151–157.
[18] J. Schliessbach, A. Siegenthaler, L. Bütikofer, A. Limacher, P. Juni, P.
H. Vuilleumier, U. Stamer, L. Arendt-Nielsen, M. Curatolo, I. Puebla, Effect of
single-dose imipramine on chronic low-back and experimental pain, A randomized
controlled trial, PloS one 13 (5) (2018) e0195776.
[19] J.J. Secades, J.L. Lorenzo, Citicoline: pharmacological and clinical review, 2006
update, Methods and findings in experimental and clinical pharmacology 28 Suppl
B (2006) 1-56.
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