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Year : 2019  |  Volume : 62  |  Issue : 5  |  Page : 175-181

Action of citral on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in juvenile mice

1 Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, Republic of Korea; Faculty of Odonto – Stomatology, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
2 Department of Oral Physiology, School of Dentistry and Institute of Oral Bioscience, Jeonbuk National University, Jeonju, Republic of Korea
3 Department of Obstetrics and Gynecology, Jeonbuk National University Hospital-Jeonbuk, National University Medical School, Jeonju, Republic of Korea

Date of Submission11-Apr-2019
Date of Decision18-Sep-2019
Date of Acceptance04-Oct-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Prof. Dong Hyu Cho
20 Geonji-ro, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54907
Republic of Korea
Prof. Seong Kyu Han
567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896
Republic of Korea
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CJP.CJP_32_19

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The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) is admitted as a pivotal site of integrating and regulating orofacial nociceptive inputs. Although citral (3,7-dimethyl-2,6-octadienal) is involved in antinociception, the action mechanism of citral on the SG neurons of the Vc has not been fully clarified yet. In this study, we examined the direct membrane effects of citral and how citral mediates responses on the SG neurons of the Vc in juvenile mice using a whole-cell patch-clamp technique. Under high chloride pipette solution, citral showed repeatable inward currents that persisted in the presence of tetrodotoxin, a voltage-gated Na+ channel blocker, and 6-cyano-7-nitro-quinoxaline-2,3-dione, a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, D-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist. However, the citral-induced inward currents were partially blocked by picrotoxin, a gamma-aminobutyric acid (GABAA)-receptor antagonist, or by strychnine, a glycine receptor antagonist. Further, the citral-induced responses were almost blocked by picrotoxin with strychnine. We also found that citral exhibited additive effect with GABA-induced inward currents and glycine-induced inward currents were potentiated by citral. In addition, citral suppressed the firing activities by positive current injection on the SG neurons of the Vc. Taken together, these results demonstrate that citral has glycine- and/or GABA-mimetic actions and suggest that citral might be a potential target for orofacial pain modulation by the activation of inhibitory neurotransmission in the SG area of the Vc.

Keywords: Citral, gamma-aminobutyric acidA receptor, glycine receptor, patch clamp, substantia gelatinosa neuron

How to cite this article:
Nguyen TT, Jang SH, Park SJ, Cho DH, Han SK. Action of citral on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in juvenile mice. Chin J Physiol 2019;62:175-81

How to cite this URL:
Nguyen TT, Jang SH, Park SJ, Cho DH, Han SK. Action of citral on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in juvenile mice. Chin J Physiol [serial online] 2019 [cited 2023 Mar 28];62:175-81. Available from: https://www.cjphysiology.org/text.asp?2019/62/5/175/269833

  Introduction Top

The substantia gelatinosa (SG) or lamina II of the spinal dorsal horn has been admitted as a gate control for the transmission of peripheral pain signals to the higher nociceptive center,[1],[2] whereas the trigeminal subnucleus caudalis (Vc), which exhibits a structural homology with the spinal dorsal horn and is also termed the medullary dorsal horn, initially receives nociceptive inputs from the orofacial region.[3],[4] The SG neurons of the Vc play a critical role in receiving and regulating orofacial nociception from the thin myelinated Aδ and unmyelinated C primary afferent fibers.[5]

Natural compounds from medicinal plants, such as morphine, menthol, salicylate, and capsaicin, have been powerful tools about nociceptive mechanisms through their neuronal modulation abilities.[6] Citral (3,7-dimethyl-2,6-octadienal), also known as lemonal, is a monoterpene aldehyde consisting of isomers geranial and neral chemically.[7] It occupies 75%–85% of the components of Cymbopogon citrates,[7] commonly named lemongrass, a popular culinary herb in Asian cuisines or folk medicine in India.[8] With a typical lemon-like odor, citral is widely used as a flavoring agent, a scent in perfume, or an insect repellent.[9] During the past decades, there has been an increasing interest in elucidating its mechanism of action as well as its medical implications for human beings. A combination between citral and naproxen, a nonsteroidal anti-inflammatory drug may decrease nociception and administer minor gastric damage.[10] In addition, with an aldehyde function, citral can bind to proteins and induce a conformational change, and thus actively manifest antiseptic properties that fight both fungal and bacterial infection.[11] Citral and the leaf extract of lemongrass also act as a calcium antagonist and affect spasmolysis through visceral smooth muscle activity.[8] Although citral has been proved to have antinociceptive effects,[10],[12],[13] up to date, there have been little reports about an orofacial pain function of citral. To examine the action of citral on an orofacial nociception site in the central nervous system (CNS), we used a whole-cell patch-clamp recording to investigate the direct membrane currents induced by citral and involved receptors on the SG neurons of the Vc.

  Materials and Methods Top

Experimental procedure

Animals and brain slice preparation

Experiments were performed with the permission of the Experimental Animal Care and Ethics Committee of Jeonbuk National University (CBNU 2017–0082). Male and female ICR mice (postnatal 8–20 days) were housed under a 12 h light/dark cycle (light on at 06:00) and were supplied with food and water ad libitum. All mice were capitated between 10:00 and 12:00, and the brains were rapidly dissected and immersed in ice-cold artificial cerebrospinal fluid (ACSF) with the following chemical compounds (in mM): 126 NaCl, 2.5 KCl, 2.4 CaCl2, 1.2 MgCl2, 11 D-glucose, 1.4 NaH2 PO4, and 25 NaHCO3 (pH 7.3–7.4, bubbled with 95% O2 and 5% CO2). The brainstem containing the Vc was fixed to 4% agar by cyanoacrylate and then, excised in ice-cold ACSF using a vibratome (VT1200S, Leica, Nussluch, Eisfeld, Germany). The coronal slices (200 μm in thickness) with the rostral part of Vc were kept in oxygenated ACSF for at least an hour at room temperature before electrophysiological recording.

Whole-cell patch-clamp recording

The coronal slices were relocated to the recording chamber, submerged, and constantly superfused with ACSF at 4–5 ml/min. Slices were observed under an upright microscope (BX51W1, Olympus, Tokyo, Japan) with differential interference contrast optics. The SG neurons of the Vc were identified as a translucent band, just medial to the spinal trigeminal tract traveling along the lateral edge of the brain slices.

Borosilicate glass capillary tubes (PG52151-4, WPI, Sarasota, USA) were pulled on a Flaming Brown puller (P-97, Sutter Instruments Co., Novato, CA) for preparing the patch pipettes. The pipette was filled with high chloride solution containing (in mM): 140 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 4 Mg-ATP, and 10 EGTA (pH = 7.3 with KOH) to amplify the chloride current at the holding potential of − 60 mV. For current pulse experiments, low chloride pipette solution containing (in mM): 130 C6H11 KO7, 10 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 4 Mg-ATP, and 10 EGTA (pH = 7.3 with KOH) was used. The action potentials induced by current injection of +70 pA were counted to compare the number of firings.

The tip resistances of the recording electrodes reached from 4 to 6 MΩ when filled with KCl-based internal solution. Once a gigaohm seal was formed with SG neurons, a slight negative pressure was applied to get the whole-cell mode. Signals were consecutively transferred to an Axopatch 200B (Molecular Devices, CA, USA) for amplifying and an Axon Digidata 1550B (Molecular Devices, CA, USA) for digitizing. Collected data were analyzed with the Axon pClamp 10.6 software (Molecular Devices, CA, USA) and Origin 8 software (OriginLab Corp., Northampton, MA, USA).

Chemicals and statistics

All drugs, including citral, picrotoxin, strychnine, glycine, gamma-aminobutyric acid (GABA), and chemicals for ACSF, were purchased from Sigma-Aldrich (USA), except for 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), D-2-amino-5-phosphonopentanoic acid (AP5), and tetrodotoxin (TTX), which were produced by Tocris Bioscience (Ellisville, MO, USA). Tested drugs were dissolved in ACSF and superfused at known concentrations.

All data were shown as the mean ± standard error of the mean. A paired t-test was used to compare the difference between the two groups. Level of statistical significance was defined as P < 0.05.

  Results Top

In this study, 57 neurons of the Vc from 35 juvenile mice aged 8–20 postnatal days were used for whole-cell patch-clamp recordings, in which 52 neurons were tested under voltage-clamp mode and 5 neurons for current pulse experiments. Mean amplitude of citral (2 mM)-induced inward current was at 62.4 ± 5.43 pA (n = 52).

Nondesensitizing and repeatable responses by citral

In voltage-clamp mode, citral was consecutively applied to examine whether SG neurons were desensitized by the repeatable application. The citral-induced inward currents by the second application were similar in amplitude to those of the first application in 12 neurons tested [Figure 1]a. There was no significant difference in the mean amplitude of citral-induced inward currents between the first (67.3 ± 7.03 pA) and the second (67.9 ± 8.14 pA) applications [n = 12, P > 0.05; [Figure 1]b. Therefore, SG neurons of the Vc are not desensitized by the successively administered citral-induced inward currents.
Figure 1: (a) A representative trace showing the repeatable inward currents by citral (2 mM). (b) Comparison of the mean inward currents between the first and second applications of 2 mM citral (n = 12, paired t-test, P > 0.05). NS: implicates not significant

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Direct postsynaptic action sof citral on the substantia gelatinosa neurons of the subnucleus caudalis

TTX is a voltage-sensitive sodium channel blocker in sensory neurons, where these channels play a key role in the transmission of pain signals. In this study, TTX was superfused into the bath before citral to examine whether citral acts on SG neurons through action potential mediated presynaptic release.[14] Citral-induced inward currents persisted in the presence of 0.5 μM TTX in six SG neurons [Figure 2]a. The citral-induced inward currents were not significantly different in the absence (76.8 ± 12.0 pA) and in the presence (80.9 ± 11.4 pA) of TTX [n = 6, P > 0.05; [Figure 2]b.
Figure 2: (a) A representative current trace showing no effect by tetrodotoxin (0.5 μM), a voltage-sensitive Na+ channel blocker, on the citral-induced responses. (b) No significant difference was found in the mean citral-induced inward currents between the absence and the presence of tetrodotoxin (n = 6, paired t-test, P > 0.05)

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Furthermore, we tested the action of citral on the SG in the presence of CNQX, a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist and AP5, an NMDA receptor antagonist. CNQX and AP5 did not affect the citral-induced inward currents. In six other neurons, the citral-induced inward currents (68.1 ± 15.6 pA) were approximately similar to those in the presence of 20 μM AP5 and 10 μM CNQX (63.5 ± 19.6 pA, n = 6, P > 0.05; Figures are not shown). These results suggest that citral can directly act on the SG neurons, and citral-induced responses are not mediated by activation of ionotropic glutamate receptors.

Gamma-aminobutyric acid-and glycine-mimetic actions of citral on the substantia gelatinosa neurons of the subnucleus caudalis

In electrophysiology, picrotoxin is commonly used as an example of a noncompetitive GABAA receptors antagonist.[15] In the presence of 50 μM picrotoxin, the citral-induced currents tended to be smaller in extent than those in the absence of this GABAA antagonist in the same neurons [Figure 3]a. The mean inward current induced by citral was diminished from 70.0 ± 19.1 pA to 37.2 ± 9.41 pA [n = 10, *P < 0.05; [Figure 3]b when preapplied with picrotoxin 50 μM. Furthermore, we applied strychnine, a potent competitive glycine receptor antagonist, to see whether these citral-induced currents are mediated by strychnine-sensitive glycine receptors. In the presence of 2 μM strychnine, the citral-induced currents were decreased significantly compared to those in the absence of strychnine [Figure 4]a. The mean inward currents by citral in the absence and the presence of strychnine were 71.6 ± 12.3 pA and 46.4 ± 12.9 pA, respectively [n = 7, **P < 0.01; [Figure 4]b. When strychnine and picrotoxin were applied before citral application, the citral-induced inward currents were almost abolished [Figure 5]a. The mean inward currents induced by citral in the absence and in the presence of strychnine and picrotoxin were 69.9 ± 11.4 pA and 11.5 ± 4.14 pA [n = 5, **P < 0.01; [Figure 5]b, respectively. Taken together, these observations indicate that citral can directly activate GABAA and/or glycine receptors on the SG neurons of the Vc.
Figure 3: (a) A representative current trace showing partial inhibition of citral-induced inward current by picrotoxin (50 μM), a gamma-aminobutyric acid A receptor antagonist. (b) Significant inhibition of mean inward currents by citral in the presence of picrotoxin (n = 10, paired t-test, *P < 0.05)

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Figure 4: (a) A representative current trace showing partial inhibition by strychnine (2 μM), a glycine receptor antagonist, on the citral-induced inward currents. (b) Significant inhibition of mean inward currents by citral in the presence of strychnine (n = 7, paired t-test, **P < 0.01)

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Figure 5: (a) A representative current trace showing almost inhibition by both picrotoxin (50 μM) and strychnine (2 μM) on the citral-induced inward currents. (b) Significant inhibition of mean inward currents by citral in the presence of picrotoxin and strychnine (n = 5, paired t-test, **P < 0.01)

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Effects of citral on the gamma-aminobutyric acid-, glycine- and current-evoked responses

GABA and glycine have important roles in a variety of physiological functions, especially in modulating pain transmission, not only in normal but also pathological situations. In this study, citral was experienced in the impact on the GABA and glycine responses to determine the correlation between citral and GABA/glycine at the receptor level. First, GABA or glycine and citral were successively applied into the bath, and then, GABA/glycine and citral were co-applied to check the differences in the mean inward currents induced in each case [Figure 6]a and [Figure 6]b, respectively]. In this experiment, when citral and GABA were co-treated, the mean inward current (105 ± 19.7 pA) was similar to the sum [92.9 ± 11.5 pA, n = 7, P > 0.05; [Figure 6]c of the each mean inward currents by GABA (48.6 ± 8.11 pA) and citral (44.3 ± 7.70 pA). These results show that the combination of citral and GABA produces an additive effect on the SG neurons of the Vc in mice. However, as shown in [Figure 6]b, there was a potentiation between glycine and citral when two drugs were simultaneously applied. The mean inward current induced by glycine and citral co-application (183 ± 32.0 pA) was much bigger than the sum of those in the presence of only glycine and citral [98.4 ± 5.21 pA; n = 6, *P < 0.05; [Figure 6]c.
Figure 6: (a) A representative current trace showing the additive effect between gamma-aminobutyric acid and citral. (b) A representative current trace showing the potentiation effect between glycine and citral. (c) No significant difference was found between IGABA + citral and IGABA + Icitral (n = 7, Paired t-test, P > 0.05) but a significant increase in Iglycine + citral to compare with Iglycine + Icitral (n = 6, paired t-test, *P < 0.05)

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To examine the effect of citral on the intrinsic firing activity of the neurons, we next used the pulse experiments in current-clamp mode. In this study, the firing rate was measured from the action potentials by positive current injection of +70 pA. As shown in [Figure 7]a, the action potentials appearing in control were mostly abolished in the presence of citral, and then partially recovered after 15-min washout of citral. The frequency of spikes generated by a +70 pA injection was dropped from 24.8 ± 5.62 Hz to 0.80 ± 0.20 Hz when citral was applied into the bath [n = 5, *P < 0.05; [Figure 7]b. This result indicates that citral has an inhibitory effect on the SG neurons of the Vc.
Figure 7: (a) Representative current traces showing in the current-clamp mode with the +70 pA-injection. (b) Blocking effect of citral (2 mM) on the firing activities of the substantia gelatinosa neurons (n = 5, paired t-test, *P < 0.05)

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  Discussion Top

In this study, we found that the citral-induced inward currents persisted in the presence of TTX, CNQX, and AP5, but were suppressed in the presence of strychnine and picrotoxin under a high chloride pipette solution, suggesting that citral has GABA- and/or glycine-mimetic actions through direct effect on GABAA and/or glycine receptors. Furthermore, citral showed its potentiation effect with glycine, additive one with GABA, and depressive action on the neuronal excitability on the SG neurons of the Vc. These results can provide an evidence that citral has GABA-, glycine-mimetic actions.

The function of the CNS is regulated by the balanced interplay between excitatory and inhibitory neurons. Besides GABA and glycine are predominant inhibitory, glutamate is the crucial excitatory neurotransmitter in the mammalian CNS.[16] One-third of the synapses in the brain use GABA, which reduces neuronal excitability as their neurotransmitters.[17] Two general classes of GABA receptors include GABAA and GABAB receptors. GABAA receptors are a ligand-gated ion-channel complex that is activated by GABA and the agonist muscimol and increases chloride-ion conductance. This ion channel is also blocked by bicuculline and coupled to the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites.[18],[19],[20] Glycine receptor mainly mediates fast inhibitory neurotransmission in the CNS and controls various motor and sensory functions, including nociception.[16] Similar to GABAA receptors, once agonist binds to the glycine receptors, the glycine receptors integral anion channel opens and hyperpolarizes the postsynaptic cell through influx chloride inducing neuronal firing inhibition.[16] The importance of GABA and glycine in nociception was shown by blocking GABAergic and/or glycinergic neurotransmission, which regulates inhibitory postsynaptic potential to decrease nociceptive impulse.[16],[21] In the neuropathic pain states, it is evidenced that there is a GABAergic inhibition reduction in the superficial dorsal.[22] Furthermore, during chronic inflammatory pain, glycinergic transmission is suppressed in the spinal lamina I neurons by a presynaptic mechanism.[23]

The findings of this study indicate that citral-induced repeatable inward currents at the holding potential of −60 mV in voltage-clamp mode. When a GABAA or glycine receptor is activated in the whole-cell mode, the direction of chloride ion movement depends on the intracellular and extracellular chloride concentration gradient. In this study, we used a high chloride pipette solution to amplify the chloride current at the holding potential of −60 mV. Hence, citral-induced inward currents should result from the outflow of chloride ions by activation of GABAA and/or glycine receptors. Conversely, if the intracellular chloride-ion concentration was similar to the normal condition, citral would have induced outward currents in the same condition.

Citral, a monoterpenoid, is naturally extracted from some plants, such as lemon myrtle or lemongrass. From ancient times, citral has been applied not only in perfumery, cuisines, and pesticides but also in medicine. However, to elucidate the anecdotal and uncontrolled evidence is difficult for the millennia of its use. The essential oil from lemongrass, which comprises 75%–85% citral,[7] has been proved to have an anxiolytic-like effect mediated by the GABA receptor-benzodiazepine complex.[24] Furthermore, the citral-based semicarbazones has been used as an anticonvulsant drug by facilitating GABAergic neurotransmission.[25] In this study, though the GABA- and/or glycine-mimetic effect of citral has been elucidated, as far as we know, the action of citral involving the glycinergic neurotransmission has not been reported evidently.

The connectivity of a neuronal network which based on the firing activity of neurons has a fundamental effect on its functionality and role. While glutamate is the main excitatory transmitter which targets neurons more likely to fire an action potential, GABA and glycine have been reported to highly effect in modulating the firing rate which decreased when an inhibitory neurotransmitter was introduced.[26] In this study, citral was confirmed its properties as inhibitory GABA and/or glycine mimetic actions by blocking the firing activities.

It has been commonly accepted that the sensory inputs from the dental and craniofacial regions are primarily relayed on the spinal trigeminal nucleus, in which Vc processed orofacial nociceptive input.[3],[4] The SG neurons, a collection of cells in the gray area of the spinal cord, are believed to directly receive input from dorsal nerve fibers, especially those from pain.[27] The SG neurons of the Vc transition zone play a key role in integrating nociceptive orofacial information, processing deep-tissue pain, and developing persistent orofacial pain.[4],[27] Citral, with low molecular-weight compounds and high lipid solubility, can overcome the blood-brain barrier [25],[28] and can act on the CNS by regulating the function of various receptors.[9],[29] There are multiple lines of evidence on the nociceptive modulation ability of this monoterpenoid. Citral has been documented as a potential treatment for inflammatory and neuropathic pain. In the different mice experimental models of acute and chronic pain, citral pretreatment can inhibit formalin-induced licking, not only in neurogenic but also in inflammatory phases.[12] Otherwise, citral has been examined for antinociceptive and anti-inflammatory effects through acetic-acid and formalin tests in rodents. This examination indicated that citral possesses convincing central and peripheral antinociceptive activity as well as an anti-inflammatory property.[13]

The concentration of citral used in this study (2 mM) seems somewhat high. However, 1–1.5 mM of citral was also applied in other similar whole-cell patch-clamp experiments,[9],[28] and the toxic potential of citral seems to be negative. For example, the acute toxicity of citral in rodents is likely low, since the oral or derma median lethal-dose values of this chemical were more than 1000 mg/kg.[7] About repeated-dose oral toxicity, several studies in mice and rats indicate no adverse effect of citral at less than 1000 mg/kg for 14 days–13 weeks exposure.[7]

  Conclusion Top

Taken together, these results demonstrate that citral has glycine- and/or GABA-mimetic actions and suggest that citral might be a potential target for orofacial pain modulation by activation of inhibitory neurotransmission on the SG area of the Vc. Results from this study will set a fundamental step, open a new research direction for further study to confirm the effect of this terpenoid on orofacial pain management.

Financial support and sponsorship

This research was supported by Basic Research Program through the National Research Foundation of Korea (NRF) funded by Ministry of Education (2016R1D1A3B03932241) and Ministry of Science, ICT and Future Planning (2015R1C1A1A02036793).

Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

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[Pubmed] | [DOI]


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