Volume 8, Issue 2 (May 2021)                   Avicenna J Neuro Psycho Physiology 2021, 8(2): 64-70 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Jabbari S, Bananej M, Zarei M, Komaki A, Hajikhani R. Possible Involvement of Serotonergic Mechanism(s) in the Antinociceptive Effects of kaempferol. Avicenna J Neuro Psycho Physiology 2021; 8 (2) :64-70
URL: http://ajnpp.umsha.ac.ir/article-1-285-en.html
1- Department of Biology, Faculty of Life Sciences, Islamic Azad University, Tehran North Branch, Tehran, Iran.
2- Department of Biology, Faculty of Life Sciences, Islamic Azad University, Tehran North Branch, Tehran, Iran , Maryam.bananej23@gmail.com
3- Department of Physology, Scihool of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
4- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
5- Department of Biology, Faculty of Life Sciences, Islamic Azad University, Tehran North Branch, Tehran, Iran
Full-Text [PDF 637 kb]   (556 Downloads)     |   Abstract (HTML)  (1267 Views)
Full-Text:   (730 Views)
Background
Pain is a major problem worldwide [1]. According to statistics, in Americans, 1 in 5 adults experiences pain each year. In addition to decreasing life quality, the pain increases the cost of general health leading to economic loss to society [2]. However, the present analgesic drugs (e.g., morphine or diclofenac [Dic]) have several side effects that are either too potent or too weak [3, 4].
Flavonoids (FV) have been known as polyphenolic compounds abundantly observed in fruits and are classified as flavones, flavanols, isoflavones, flavanones, flavonols, and anthocyanins. According to the epidemiological and pharmacological studies, the application of FV components has much effectiveness, such as anti-oxidative, anti-cancer, and anti-viral properties [5, 6]. Kaempferol (KM) (Figure 1) as an FV is available in several plants and fruits (e.g., tea leaves, endive, broccoli, strawberries, tomato, and grapes) and herbal products commonly applied in botanical medicine (e.g., Sophora japonica and Moringa oleifera). The intake of KM-containing foods and a lower risk of many disorders, including cancer and cardiovascular diseases, are positively correlated.
The KM and some glycosides of KM show diverse pharmacological activities, such as antioxidant,
anti-microbial, neuroprotective, anti-osteoporotic, anxiolytic, and anti-allergic properties [7-9]. Bian et al. demonstrated that KM inhibited many pathways associated with releasing inflammatory mediators from lipopolysaccharides‑related intestinal micro-vascular endothelial cells in rats [10]. Furthermore, Qian et al., 2019 have shown that KM reduced K63-associated polyubiquitination for the inhibition



 Figure 1. Chemical structure of kaempferol (C15H10O6)
of unknown factor-kappa B and inflammatory reactions in acute pulmonary injuries in mice [11].
Nevertheless, limited reports have been issued on the antinociceptive effects of kaempferol, such as a study by Kim et al. (2015) [12-14]. None of the aforementioned studies assessed the involvement of serotonergic mechanism(s) in the antinociceptive effects of kaempferol in rats.
 
Objectives
The present study aimed to investigate the intracerebroventricular (ICV) antinociceptive effects of kaempferol and identify its possible causal mechanism (the involvement of selective serotonin receptors) using the tail-flick test in male rats.
 
Materials and Methods
Animals
Adult male Wistar rats (weighing 180-250 g) provided by Pasteur Institute, Iran, with water and food ad libitum were maintained in a 12:12 h light-dark cycle (humidity: 50±5%; temperature: 22±2°C). The experiments were carried out in the light period (10:00-16:00). The examiner was blinded to the treatments, and the rats were randomly divided into different groups. There were six rats in each experimental group. All testing and animal care procedures were approved by the Ethics Committee of Hamadan University of Medical Sciences, Hamadan, Iran (IR.UMSHA.REC.1397.
139). Moreover, the experiments were performed following the National Institutes of Health publication No. 85-23, revised in 1985.
 
Drugs and chemical compounds
The KM (10, 20, 40 µg/rat), dimethyl sulfoxide (DMSO), formaldehyde solution, ketamine hydrochloride, and xylazine, were all purchased from Sigma-Aldrich Corporation, USA. After dissolving KM in DMSO, it was diluted with normal saline (NS) before administration. The NS was applied for the dilution of Dic and morphine as positive controls. WAY 100635 (5-HT1A receptor antagonist; Sigma-Aldrich Co., USA), penbutolol (5-HT1B antagonist; Sigma-Aldrich Co., USA), ketanserin (5-HT2A receptor antagonist; Glaxo, UK), tropisetron (5-HT3 receptor antagonist; Sigma-Aldrich Co., USA), and GR113808 (5-HT4 receptor antagonist, ICS205930; Sandoz, France) were dissolved in DMSO. The solutions were prepared immediately prior to testing. The selected concentrations of KM and all drugs were based on previous studies and outcomes of the initial experiments of the authors of the present study
[9, 15-20]. Furthermore, since NS or DMSO administration has shown the same results without any acute or chronic toxicity, it was decided to use DMSO as a control or vehicle (Veh) group in all the experiments.
 
Intracerebroventricular cannulation
Firstly, the anesthetization of the rats was intraperitoneally performed using ketamine-xylazine (80 and 10 mg/kg, respectively). Then, a stainless-steel cannula (21-gauge, 12 mm) was implanted in the right lateral ventricle for ICV injection. According to the Paxinos and Watson rat brain atlas [21, 22], the stereotaxic coordinates were 1.5 mm right lateral, 0.8 mm posterior, and 4.0 mm ventral toward the bregma. Following securing the guide cannula by dental cement, it was anchored by stainless steel screws (fixed to the skull) and then sealed using stainless steel wire for the inhibition of occlusion. After 7 days of recovery, the rats were separately housed before the experiments. The drug solution was added to the injection cannula (29-gauge, 15 mm), which was attached to a Hamilton syringe (10-μL) by a PE-20 catheter, added to the guide cannula, and extended 1 mm over the guide cannula tip. Within 20 min, 10 μL of 100% DMSO or KM (10, 20, and 40 mg/rat) were administered. 
 
Tail-flick test
The antinociceptive reaction to the thermal stimulus was measured using the tail-flick test (PANLAB 7160, Spain). The rats were restrictively held with the tail on a slot (adjustable width) with a groove to ensure accurate placement in the tail-flick apparatus to apply radiant heat to the dorsal surface of the rear set for forcing the rat to flick its tail in 2-4 sec as the tail-flick latency baseline. The gap between the start of heat exposure and tail withdrawal was calculated to determine the tail-flick latency that was assessed before and 30, 60, 90, and 120 min following the central administration of the drugs. The cut-off time was adjusted at 10 sec for minimizing tissue injury [23, 24].
 
Treatment protocol
The administration of 1 and 10 mg/rat doses of the 5-HT receptor antagonist was carried out 5 min before KM ICV injection. The latency time was determined at 30, 60, 90, and 120 min at the end of the second injection. For the first experiment, the rats were assigned to the Veh, KM (10, 20, and 40 mg/rat), morphine (1 mg/rat), and Dic (1 mg/rat) groups. In the second experiment, the investigation of the 5-HT1 receptor in the antinociceptive effects of kaempferol, the rodents were scrutinized to the Veh, Veh+KM, WAY100635 (1 and 10 mg/rat), and penbutolol (1 and 10 mg/rat) groups. In the third experiment, the investigation of the 5-HT2 receptor in the antinociceptive effects of kaempferol, the rodents were scrutinized to the Veh, Veh+KM, and ketanserin (1 and 10 mg/rat) groups. In the fourth experiment, the investigation of the 5-HT3 receptor in the antinociceptive effects of kaempferol, the rodents were scrutinized to the Veh, Veh+KM, and tropisetron (1 and 10 mg/rat) groups. In the final experiment, the investigation of the 5-HT4 receptor in the antinociceptive effects of kaempferol, the rodents were scrutinized to the Veh, Veh+KM, and GR113808 (1 and 10 mg/rat) groups [9, 25, 26]. In each group, six rats were tested.
 
Rotarod experiment
According to the literature [27, 28], a model 47700 accelerating rotarod (Ugo Basile, Italy) was used to examine the effect of KM on motor performance. The time to falling was calculated in seconds by placing the normal rats on a rotating drum with increasing speed (from 4 to 40 rpm in 5 min), which forced them to move onward to avoid falling. The animals’ baseline responses were determined on the experiment day and the impacts of ICV and intrathecal injection of DMSO and KM on motor performance were repetitively studied for 120 min after the injections.
 
Safety assessment: Acute and chronic toxicity of KM
Acute and chronic toxicity testing was carried out for the assessment of KM safety. Abnormal behaviors, anomalies in terms of food intake, body weight, activities, feces, hair, and gross anatomy following Veh or KM ICV administration (10, 20, or 40 mg/kg) were studied in the first 3 days and after 14 days [29].
 
Data analysis
All data were expressed as mean±standard error of mean. Data analysis was carried out using SPSS software (version 16.0) and one-way or two-way repeated measures analysis of variance (ANOVA) followed by the Bonferroni post hoc test (multiple-comparison test). In each statistical comparison, a p-value of less than 0.05 was considered statistically significant.
 
Results
Time courses of the tail-flick response against KM ICV injection
According to the results of Figure 2, two-way repeated measures ANOVA showed a time effect




Figure 2. Time course regarding alterations in the tail-flick reaction against intracerebroventricularly administered kaempferol (KM) and dimethyl sulfoxide (vehicle [Veh]/control); groups of rats injected with KM (10, 20 or 40 mg/rat), morphine (Mor), diclofenac (Dic), or control/Veh (5 μl); the tail-flick responses determined at 0, 30, 60, 90, and 120 min; all data expressed as mean± standard error of mean; * P<0.05 and *** P<0.001 vs. the Veh group (n=6)
 
(F [4, 20]=52.78; P<0.001), group effect (F [5, 25]=117.7; P<0.001), and time × group interaction effect (F [20, 100]=14.58; P<0.001). Moreover, the obtained data demonstrated that KM (40 mg/rat) showed significant antinociceptive activities at
30 and 60 min, compared to the Veh group
(P<0.001 and P<0.05, respectively). Furthermore,
the microinjection of either morphine or Dic completely showed the antinociceptive effects at 30 and 60 min (P<0.001).
 
Impacts of 5-HT1 receptor antagonists on KM-related antinociceptive effects
According to Figure 3A, two-way repeated measures ANOVA indicated a time effect (F [4, 20]=32.62; P<0.001), group effect (F [3, 15]=12.12; P<0.001), and time × group interaction effect (F [12, 60]=5.391; P<0.001). Moreover, 5-HT1A receptor antagonist WAY 100635 at the employed doses (1 and 10 mg/rat) did not alter antinociceptive effects induced by KM. According to Figure 3A, two-way repeated measures ANOVA showed a time effect (F [4, 20]=18.31; P<0.001), group effect (F [3, 15]=10.55; P<0.001), and time × group interaction effect (F [12, 60]=4.585; P<0.001). In a similar range of dosage, the 5-HT1B antagonist penbutolol also caused no significant alteration in the antinociceptive effects of KM.
 
Impacts of 5-HT2 receptor antagonists on KM-related antinociceptive effects
According to Figure 4, two-way repeated measures ANOVA demonstrated a time effect (F [4, 20]=26.05; P<0.001), group effect (F [3, 15]=8.817; P<0.001), and  time × group interaction effect (F [12, 60]=4.187; P<0.001). Moreover, 5-HT2A receptor antagonist ketanserin at the high dose





Figure 3. Role of 5-HT1 receptor antagonists in the antinociceptive effects of kaempferol (KM) with dose of 40 mg/rat after intracerebroventricular injection in tail-flick test; vehicle (Veh), WAY 100635 (WAY; 1 and 10 mg/rat [A]), and penbutolol (Pen; 1 and 10 mg/rat [B]): * P<0.05, ** P<0.01, and *** P<0.001 vs. the Veh group (n=6)
 
(10 mg/rat) significantly altered antinociceptive effects induced by KM (P<0.01).
 
Impacts of 5-HT3 receptor antagonists on KM-related antinociceptive effects
According to Figure 5, two-way repeated measures ANOVA showed a time effect (F [4, 20]=15.90; P<0.001), group effect (F [3, 15]=5.801; P<0.001), and time × group interaction effect (F
[12, 60]=5.428; P=0.007). In addition, the KM antinociceptive activity was completely blocked during the experimental procedure following the pretreatment with tropisetron (P<0.001).
 


Figure 4. Role of 5-HT2 receptor antagonists in the antinociceptive effects of kaempferol (KM) with dose of 40 mg/rat after intracerebroventricular injection in tail-flick test; vehicle (Veh), ketanserin (Ket; 1 and 10 mg/rat): * P<0.05, ** P<0.01, and *** P<0.001 vs. the Veh group;  ++P<0.01 vs. (Veh-KM)-treated group (n=6)



Figure 5. Role of 5-HT3 receptor antagonists in the antinociceptive effects of kaempferol (KM) with dose of 40 mg/rat after intracerebroventricular injection in tail-flick test; vehicle (Veh), tropisetron (Tro; 1 and 10 mg/rat): * P<0.05, ** P<0.01, and *** P<0.001 vs. the Veh group; +++P<0.001 vs.  (Veh-KM)-treated group (n=6)
 
Impacts of 5-HT4 receptor antagonists on KM-related antinociceptive effects
According to Figure 6, two-way repeated measures ANOVA indicated a time effect (F [4, 20]=33.19; P<0.001), group effect (F [3, 15]=11.94; P<0.001), and time × group interaction effect (F [12, 60]=5.402; P=0.007). However, the GR113808A highest dosage (10 mg/rat) caused a slight reduction in the KM antinociceptive activity (P<0.05).
 
Effect of kaempferol on locomotor function and motor reactions
The KM impact on locomotor function and motor reactions was explored to eliminate the probability that the KM-related antinociceptive activity is less vital compared to its sedative or muscle-relaxant properties. The dosage at which KM exerted intense antinociceptive activities did not significantly (P>0.05) affect the locomotor function or motor reactions in comparison to that of the control group (Figure 7).
 
Safety assessment: Acute and chronic toxicity of KM
The ICV administration of KM did not lead to any



Figure 6. Role of 5-HT4 receptor antagonists in the antinociceptive effects of kaempferol (KM) with dose of 40 mg/rat after intracerebroventricular injection in the tail-flick test; vehicle (Veh), GR113808A (GR; 1 and 10 mg/rat): ** P<0.01 and *** P<0.001 vs. the Veh group; +P<0.05 vs. (Veh-KM)-treated group (n=6)


Figure 7. Role of kaempferol (KM) in locomotor activity and motor responses (n=6)
 
abnormal behaviors or anomalies in food intake, body weight, hair, activity, feces, and gross anatomy among the rats. There were no significant effects within the first 3 days or after 14 days, indicating no acute or chronic toxicity due to KM (data not shown).
 
Discussion
The most important finding of the present study was a reduction in the KM antinociceptive activity caused by the ICV injection of 5-HT3, 5-HT2, and 5-HT4, but not 5-HT1 receptor antagonists. Pain is not a unitary phenomenon; therefore, nociceptive methods with various strategies are required for the exact evaluation of the antinociceptive activity [30].
Wei-Han et al in 2019 showed that KM can attenuate neuroinflammation through passing the blood-brain barrier in the brain of rats [31]. The results obtained from the tail-flick test showed that KM ICV microinjection partially led to a decrease in thermal nociception. As a result, KM possibly exerts its antinociceptive activity affecting the brain. The results of the current study confirmed the findings of a previous study conducted by Zarei et al. [32], in which they proposed that the ICV injection of KM in the tail-flick test has antinociceptive effects (through the interaction with the transient receptor potential vanilloid-1). This finding is in contrast to the results of the present study [12].
It has been widely shown that the ICV injection of 5-HT receptor antagonists in rats or lesions in different sections of the brain related to the 5-HT system can cause hyperalgesia in the tail-flick test [33-35], indicating exerting a tonic inhibitory effect on nociceptive neurotransmission by 5-HT. Many receptors may be involved in the central antinociceptive effects of KM [32]. The findings regarding the 5-HT3 and 5-HT2 receptors should also be considered. The KM impact was fully reversed by tropisetron indicating the possible role of this receptor. The role of 5-HT3 in 5-HT antinociception has been widely reported [36, 37]. Nevertheless, the 5-HT3 ICV administration is not effective [38] or facilitates [39] nociceptive reactions. Moreover, it has been announced that the 5-HT antinociceptive activity is not associated with 5-HT3 receptors. Tropisetron prevented KM-associated antinociception at low and high doses, demonstrating that this receptor strongly plays a role in this mechanism.
In addition, the activation of 5-HT2 and 5-HT3 receptor subtypes can induce a cellular excitation against the 5-HT1A receptor family. 5-HT2 increases phospholipase activity and 5-HT3 is a 5-HT ligand-gated cation channel that when activated can increase potassium/sodium conductance, resulting in cell depolarization. Furthermore, there would be a similar target for their effects on pain relief [40].
According to Dupuis et al. (2017), inhibitory potentials in rat trigeminal neurons are mediated by 5-HT2 receptors through the activation of GABAergic/glycinergic interneurons [41]. Con-cerning 5-HT3 receptors, another pharmacological study reported the blockage of the inhibitory activity of 2-methyl serotonin affecting nociceptive projection neurons through 5-HT3 or GABAA receptor antagonists [42]. Therefore, 5-HT2 and 5-HT3 receptors on GABAergic neurons can be targeted for the KM antinociceptive activity by activating such neurons providing a secondary inhibitory effect on the nociceptive projection neurons.
In the present study, the injection of both ketanserin and GR113808A partly inhibited the KM antinociceptive activity. Accordingly, some KM effects are mediated by such receptors. The effects of 5-HT1 receptors on the modulation of nociception have been widely studied [43, 44]; however, it is required to obtain exact data on the antinociceptive activities of 5-HT2 areas [34]. Nonetheless, 5-HT2 receptors are possibly involved in the antinociceptive impacts of periaqueductal grey stimulation and stress [45].
Both the selective 5-HT1A and 5-HT1B receptor antagonists, WAY 100635 and penbutolol, had no significant effect on antinociception induced by 5-HT, respectively. This seems to exclude a mediation by these receptors of the antinociceptive effect of KM on a thermal pain test. The potential role of 5-HT4 receptors in mediating pain has not yet been perceived. However, 5-HT4 receptors possibly decrease pain [46], and 5-HT4 agonists cause antinociception through cholinergic strategies [47]. The results of the present study showed that KM-induced antinociception was not reversed by a 5-HT4 receptor antagonist.
According to the results of the rotarod test, KM did not cause any significant skeletal muscle relaxation or sedative impacts on the central nervous system. Consequently, the behavioral reactions detected in the tail-flick test were not caused by motor dysfunction or sedation; however, they revealed real antinociceptive properties.
 
Conclusions
The obtained results of the current study demonstrated the complete inhibition of the KM antinociceptive properties via 5-HT3 receptor antagonist, limited influence of 5-HT2 and 5-HT4 receptor antagonists, and no contribution of the
5-HT1 receptor. Nonetheless, through the use of low doses and receptor profiles of the ligands, some receptors’ contributions could be suspected and a degree of nonselectivity cannot be excluded. Therefore, the presence of novel and more selective 5-HT agonists and antagonists is essential to perceive the serotonergic strategy involved in pain management.
 
Compliance with ethical guidelines
All testing and animal care procedures were approved by the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.139).
 
Acknowledgments
The present study was based on the PhD thesis submitted by Sajjad Jabbari. The authors would like to express their gratitude to the Neurophysiology Research Center of Hamadan University of Medical Sciences for its contribution to the current project.
 
Authorsʼ contributions
Maryam Bananej and Ramin Hajikhani conceived the experiments. Sajjad Jabbari performed the research. Alireza Komaki analyzed the results and conducted the experiments, and Mohammad Zarei wrote the main manuscript. All the authors reviewed the final manuscript.
 
Funding/Support
The current study was financially supported by North Branch, Islamic Azad University, Tehran, Iran (No. 1573519952003).
 
Conflicts of Interest
The authors declare that there is no conflict of interest.
 
References
  1. Craig KD, Holmes C, Hudspith M, Moor G, Moosa-Mitha M, Varcoe C, et al. Pain in persons who are marginalized
    by social conditions. Pain. 2020; 161(2):261-5.
    [DOI:10.1097/j.pain.0000000000001719] [PMID] [PMCID]
  2. Losin EAR, Woo CW, Medina NA, Andrews-Hanna JR, Eisenbarth H, Wager TD. Neural and sociocultural mediators of ethnic differences in pain. Nature Human Behaviour. 2020; 4(5):517-30. [DOI:10.1038/s41562-020-0819-8] [PMID] [PMCID]
  3. Zarei M, Mohammadi S, Komaki A. Antinociceptive activity of Inula britannica L. and patuletin: In vivo and possible mechanisms studies. Journal of Ethnopharmacology. 2018; 219:351-8. [DOI:10.1016/j.jep.2018.03.021] [PMID]
  4. Mahmoodi M, Mohammadi S, Enayati F. Evaluation of the antinociceptive effect of hydroalcoholic extract of Potentilla reptans L. in the adult male rat. Journal of Shahid Sadoughi University of Medical Sciences. 2016; 24(3):201-10.
  5. Li X, Wang X, Li C, Khutsishvili M, Fayvush G, Atha D, et al. Unusual flavones from primula macrocalyx as inhibitors of OAT1 and OAT3 and as antifungal agents against
    Candida rugosa. Scientific Reports. 2019; 9(1):9230.
    [DOI:10.1038/s41598-019-45728-5] [PMID] [PMCID]
  6. Asgari NM, Mohammadi S. The analgesic effect of Echinophora platyloba hydroalcoholic extract in male rats. Journal of Babol University of Medical Sciences. 2016; 18(5):31-7.
  7. Lin C, Wu F, Zheng T, Wang X, Chen Y, Wu X. Kaempferol attenuates retinal ganglion cell death by suppressing NLRP1/NLRP3 inflammasomes and caspase-8 via JNK and NF-κB pathways in acute glaucoma. Eye. 2019; 33(5):777-84. [DOI:10.1038/s41433-018-0318-6] [PMID] [PMCID]
  8. Imran M, Rauf A, Shah ZA, Saeed F, Imran A, Arshad MU, et al. Chemo‐preventive and therapeutic effect of the dietary flavonoid kaempferol: a comprehensive review. Phytotherapy Research. 2019; 33(2):263-75. [DOI:10.1002/ptr.6227] [PMID]
  9. Zarei M, Mohammadi S, Jabbari S, Shahidi S. Intracerebroventricular microinjection of kaempferol on memory retention of passive avoidance learning in rats: involvement of cholinergic mechanism (s). International Journal of Neuroscience. 2019; 129(12):1203-12. [DOI:10.1080/00207454.2019.1653867] [PMID]
  10. Bian Y, Liu P, Zhong J, Hu Y, Fan Y, Zhuang S, et al. Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS‑induced rat intestinal microvascular endothelial cells. Molecular Medicine Reports. 2019; 19(3):1958-64. [DOI:10.3892/mmr.2018.9777] [PMID]
  11. Qian J, Chen X, Chen X, Sun C, Jiang Y, Qian Y, et al. Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice. Toxicology Letters. 2019; 306:53-60. [DOI:10.1016/j.toxlet.2019.02.005] [PMID]
  12. Abo-Salem OM. Kaempferol attenuates the development of diabetic neuropathic pain in mice: Possible anti-inflammatory and anti-oxidant mechanisms. Macedonian Journal of Medical Sciences. 2014; 7(3):424-30. [DOI:
    10.3889/mjms.1857-5773.2014.0401]
  13. Kim SH, Park JG, Sung GH, Yang S, Yang WS, Kim E, et al. Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain. Molecular Nutrition & Food Research. 2015; 59(7):1400-5. [DOI:10.1002/mnfr.
    201400820]
    [PMID]
  14. De Melo GO, Malvar Ddo C, Vanderlinde FA, Rocha FF, Pires PA, Costa EA, et al. Antinociceptive and
    anti-inflammatory kaempferol glycosides from Sedum dendroideum. Journal of Ethnopharmacology. 2009; 124(2):228-32.
    [DOI:10.1016/j.jep.2009.04.024] [PMID]
  15. Darbandi N, Ramezani M, Khodagholi F, Noori M. Kaempferol promotes memory retention and density of hippocampal CA1 neurons in intra-cerebroventricular STZ-induced experimental AD model in Wistar rats. Biologija. 2016; 62(3):157-68. [DOI:10.6001/biologija.v62i3.3368]
  16. Sun J, Chen SR, Pan HL. μ-Opioid receptors in primary sensory neurons are involved in supraspinal opioid analgesia. Brain Res. 2020; 1729:146623. [DOI:10.1016/j.
    brainres.2019.146623]
    [PMID] [PMCID]
  17. Yawata T, Higashi Y, Shimizu T, Shimizu S, Nakamura K, Taniuchi K, et al. Brain opioid and nociceptin receptors are involved in regulation of bombesin-induced activation of central sympatho-adrenomedullary outflow in the rat. Molecular and Cellular Biochemistry. 2016; 411(1-2):201-11. [DOI:10.1007/s11010-015-2582-0] [PMID]
  18. Norris C, Szkudlarek HJ, Pereira B, Rushlow W, Laviolette SR. The bivalent rewarding and aversive properties of Δ 9-tetrahydrocannabinol are mediated through dissociable opioid receptor substrates and neuronal modulation mechanisms in distinct striatal sub-regions. Scientific Reports. 2019; 9(1):9760. [DOI:10.1038/s41598-019-46215-7] [PMID] [PMCID]
  19. Jiang JH, Peng YL, Zhang PJ, Xue HX, He Z, Liang XY, et al. The ventromedial hypothalamic nucleus plays an important role in anxiolytic-like effect of neuropeptide S. Neuropeptides. 2018; 67:36-44. [DOI:10.1016/j.npep.2017.
    11.004]
    [PMID]
  20. Takechi K, Fujiwara A, Watanabe Y, Kamei C. Participation of GABA-ergic system in epileptogenic activity induced by teicoplanin in mice. Epilepsy Research. 2009; 84(2-3):127-34. [DOI:10.1016/j.eplepsyres.2009.01.006] [PMID]
  21. Friedrich T, Schalla M, Scharner S, Kühne S, Goebel-Stengel M, Kobelt P, et al. Intracerebroventricular injection of phoenixin alters feeding behavior and activates nesfatin-1 immunoreactive neurons in rats. Brain Research. 2019; 1715:188-95. [DOI:10.1016/j.brainres.2019.03.034] [PMID]
  22. Srisai D, Yin TC, Lee AA, Rouault AA, Pearson NA, Grobe JL, et al. MRAP2 regulates ghrelin receptor signaling and hunger sensing. Nature Communications. 2017; 8(1):713. [DOI:10.1038/s41467-017-00747-6] [PMID] [PMCID]
  23. Ineichen BV, Schnell L, Gullo M, Kaiser J, Schneider MP, Mosberger AC et al. Direct, long-term intrathecal application of therapeutics to the rodent CNS. Nature Protocols. 2017; 12(1):104-31. [DOI:10.1038/nprot.2016.151] [PMID]
  24. Zhang Y, Kahng MW, Elkind JA, Weir VR, Hernandez NS, Stein LM, et al. Activation of GLP-1 receptors attenuates oxycodone taking and seeking without compromising the antinociceptive effects of oxycodone in rats. Neuropsy-chopharmacology. 2020; 45(3):451-61. [DOI:10.1038/
    s41386-019-0531-4]
    [PMID]
  25. Mohammadi S, Golshani Y. Neuroprotective effects of rhamnazin as a flavonoid on chronic stress-induced cognitive impairment. Journal of Advanced Neuroscience Research. 2017; 4(2):30-7.
  26. Mahmoodi M, Mohammadi S, Zarei M. Antinociceptive effect of hydroalcoholic leaf extract of tribulus terrestris L. in male rat. Journal of Babol University of Medical Sciences. 2013; 15(6):36-43.
  27. Mohammadi S, Oryan S, Komaki A, Eidi A, Zarei M. Effects of hippocampal microinjection of irisin, an exercise-induced myokine, on spatial and passive avoidance learning and memory in male rats. International Journal of Peptide Research and Therapeutics. 2019; 26(1):357-67. [DOI:
    10.1007/s10989-019-09842-2]
  28. Mohammadi S, Oryan S, Komaki A, Eidi A, Zarei M. Effects of intra-dentate gyrus microinjection of myokine irisin on long-term potentiation in male rats. Arquivos de Neuro-Psiquiatria. 2019; 77(12):881-7. [DOI:10.1590/0004-282X2
    0190184]
    [PMID]
  29. Asgari Nematian M, Yaghmaei P, Mohammadi S. Assessment of the antinociceptive, antiinflammatory and acute toxicity effects of Ducrosia anethifolia essential oil in mice. Scientific Journal of Kurdistan University of Medical Sciences. 2017; 22:74-84.
  30. Meng W, Adams MJ, Reel P, Rajendrakumar A, Huang Y, Deary IJ, et al. Genetic correlations between pain phenotypes and depression and neuroticism. European Journal of Human Genetics. 2020; 28(3):358-66. [DOI:10.1038/s41431-019-0530-2] [PMID] [PMCID]
  31. Li WH, Cheng X, Yang YL, Liu M, Zhang SS, Wang YH, et al. Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats. Brain Research. 2019; 1722:146361. [DOI:10.1016/j.brainres.2019.146361] [PMID]
  32. Zarei M, Izadi Dastenaei Z, Jabbari S. Study of the effect of intracerebroventricular injection of kaempferol and its intraction with the transient receptor potential vanilloid 1 on pain in male rats. Pajouhan Scientific Journal. 2020; 18(2):67-74. [DOI:10.29252/psj.18.2.81]
  33. Xu Y, Lin D, Yu X, Xie X, Wang L, Lian L, et al. The antinociceptive effects of ferulic acid on neuropathic pain: involvement of descending monoaminergic system and opioid receptors. Oncotarget. 2016; 7(15):20455-68. [DOI:10.18632/oncotarget.7973] [PMID] [PMCID]
  34. Courteix C, Dupuis A, Martin PY, Sion B. 5-HT 2A receptors and pain. 5-HT2A receptors in the central nervous system. Cham: Humana Press; 2018. P. 339-52.
  35. Kilinc E, Guerrero-Toro C, Zakharov A, Vitale C, Gubert-Olive M, Koroleva K, et al. Serotonergic mechanisms of trigeminal meningeal nociception: implications for migraine pain. Neuropharmacology. 2017; 116:160-73. [DOI:
    10.1016/j.neuropharm.2016.12.024]
    [PMID]
  36. Costa‐Pereira JT, Serrão P, Martins I, Tavares I. Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy‐induced neuropathy: the role of spinal 5‐HT3 receptors. European Journal of Neuroscience. 2020; 51(8):1756-69. [DOI:
    10.1111/ejn.14614]
    [PMID] [PMCID]
  37. Patel R, Dickenson AH. Modality selective roles of pro-nociceptive spinal 5-HT2A and 5-HT3 receptors in normal and neuropathic states. Neuropharmacology. 2018; 143:29-37. [DOI:10.1016/j.neuropharm.2018.09.028] [PMID] [PMCID]
  38. Cortes-Altamirano JL, Olmos-Hernandez A, Jaime HB, Carrillo-Mora P, Bandala C, Reyes-Long S, et al. 5-HT1, 5-HT2, 5-HT3 and 5-HT7 receptors and their role in the modulation of pain response in the central nervous system. Current Neuropharmacology. 2018; 16(2):210-21. [DOI:
    10.2174/1570159X15666170911121027]
    [PMID] [PMCID]
  39. Nasirinezhad F, Hosseini M, Karami Z, Yousefifard M, Janzadeh A. Spinal 5-HT3 receptor mediates nociceptive effect on central neuropathic pain; possible therapeutic role for tropisetron. The Journal of Spinal Cord Medicine. 2016; 39(2):212-9. [DOI:10.1179/2045772315Y.0000000047] [PMID] [PMCID]
  40. Neugebauer V. Serotonin-pain modulation. Handbook of behavioral neuroscience. Amsterdam, Netherlands: Elsevier; 2020. P. 309-20.
  41. Dupuis A, Wattiez AS, Pinguet J, Richard D, Libert F, Chalus M, et al. Increasing spinal 5-HT2A receptor responsiveness mediates anti-allodynic effect and potentiates fluoxetine efficacy in neuropathic rats. Evidence for GABA
    release. Pharmacological Research. 2017; 118:93-103.
    [DOI:10.1016/j.phrs.2016.09.021] [PMID]
  42. Huang YJ, Grau JW. Ionic plasticity and pain: the loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain. Experimental Neurology. 2018; 306:105-16. [DOI:10.1016/j.expneurol.2018.05.002] [PMID] [PMCID]
  43. Haleem DJ. Serotonin-1A receptor dependent modulation
    of pain and reward for improving therapy of chronic
    pain. Pharmacological Research. 2018; 134:212-9.
    [DOI:
    10.1016/j.phrs.2018.06.030]
    [PMID]
  44. Ozdemir E, Demirkazik A, Taskıran AS, Arslan G. Effects of 5‐HT1 and 5‐HT 2 receptor agonists on electromagnetic field‐induced analgesia in rats. Bioelectromagnetics. 2019; 40(5):319-30. [DOI:10.1002/bem.22196] [PMID]
  45. Furuya-da-Cunha EM, de Souza RR, Canto-de-Souza A. Rat exposure in mice with neuropathic pain induces fear and antinociception that is not reversed by 5-HT2C receptor activation in the dorsal periaqueductal gray. Behavioural Brain Research. 2016; 307:250-7. [DOI:10.1016/j.bbr.2016.
    04.007]
    [PMID]
  46. Lyubashina O, Sivachenko I. The 5-HT4 receptor-mediated inhibition of visceral nociceptive neurons in the rat caudal ventrolateral medulla. Neuroscience. 2017; 359:277-88. [DOI:10.1016/j.neuroscience.2017.07.039] [PMID]
  47. Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Johnson AC, Brooks EM et al. Activation of colonic mucosal 5-HT4 receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology. 2012; 142(4):
    844-54.e4.
    [DOI:10.1053/j.gastro.2011.12.041] [PMID] [PMCID]

 
Article Type: Research Article | Subject: Cognition
Received: 2020/07/10 | Accepted: 2020/08/5 | Published: 2021/05/20

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY 4.0 | Avicenna Journal of Neuro Psycho Physiology

Designed & Developed by : Yektaweb