Journal of Pharmacy And Bioallied Sciences
Journal of Pharmacy And Bioallied Sciences Login  | Users Online: 936  Print this pageEmail this pageSmall font sizeDefault font sizeIncrease font size 
    Home | About us | Editorial board | Search | Ahead of print | Current Issue | Past Issues | Instructions | Online submission




 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 12  |  Issue : 6  |  Page : 711-717  

Evaluation of antinociceptive profile of chalcone derivative (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DMPF-1) in vivo


1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia; Faculty of Medicine and Health Science, Universiti Sultan Zainal Abidin (UniSZA), Kuala Terengganu, Malaysia
2 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
3 Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
4 Faculty of Industrial Sciences & Technology, University Malaysia Pahang, Gambang, Malaysia

Date of Submission07-Dec-2019
Date of Decision09-Mar-2020
Date of Acceptance30-Mar-2020
Date of Web Publication05-Nov-2020

Correspondence Address:
Dr. Noor Azlina Abu Bakar
Faculty of Medicine, Universiti Sultan Zainal Abidin, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Terengganu.
Malaysia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpbs.JPBS_344_19

Rights and Permissions
   Abstract 

Introduction: Pain is a major global health issue, where its pharmacotherapy prompts unwanted side effects; hence, the development of effective alternative compounds from natural derivatives with lesser side effects is clinically needed. Chalcone; the precursors of flavonoid, and its derivatives have been widely investigated due to its pharmacological properties. Objective: This study addressed the therapeutic effect of 3-(2,5-dimethoxyphenyl)-1-(5-methyl furan-2-yl) prop-2-en-1-one (DMPF-1); synthetic chalcone derivative, on antinociceptive activity in vivoMaterials and Methods: The antinociceptive profile was evaluated using acetic-acid-induced abdominal writhing, hot plate, and formalin-induced paw licking test. Capsaicin, phorbol 12-myristate 12 acetate (PMA), and glutamate-induced paw licking test were carried out to evaluate their potential effects toward different targets. Results: It was shown that the doses of 0.1, 0.5, 1, and 5 mg/kg of DMPF-1 given via intraperitoneal injection showed significant reduction in writhing responses and increased the latency time in hot-plate test where reduced time spent on licking the injected paw in formalin and dose contingency inhibition was observed. The similar results were observed in capsaicin, PMA, and glutamate-induced paw licking test. In addition, the challenge with nonselective opioid receptor antagonist (naloxone) aimed to evaluate the involvement of the opioidergic system, which showed no reversion in analgesic profile in formalin and hot-plate test. Conclusion: Collectively, this study showed that DMPF-1 markedly inhibits both peripheral and central nociception through the mechanism involving an interaction with vanilloid and glutamatergic system regardless of the activation of the opioidergic system.

Keywords: 3-(2,-dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one, abdominal writhing, antinociceptive, chalcone, glutamatergic, hot plate, opioidergic, transient protein vanilloid-1


How to cite this article:
Abu Bakar NA, Sulaiman MR, Lajis N, Akhtar MN, Mohamad AS. Evaluation of antinociceptive profile of chalcone derivative (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DMPF-1) in vivo. J Pharm Bioall Sci 2020;12, Suppl S2:711-7

How to cite this URL:
Abu Bakar NA, Sulaiman MR, Lajis N, Akhtar MN, Mohamad AS. Evaluation of antinociceptive profile of chalcone derivative (3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one (DMPF-1) in vivo. J Pharm Bioall Sci [serial online] 2020 [cited 2020 Nov 24];12, Suppl S2:711-7. Available from: https://www.jpbsonline.org/text.asp?2020/12/6/711/299999




   Introduction Top


Pain is a major global health issue, which requires crucial management to juggle between daily function and enduring pain. However, current available pharmacological treatment that focuses to reduce pain is always associated with unwanted serious side effects that might lead to drug dependency and addiction. Hence, searching for alternative pain medicine with lesser side effects is clinically needed. Natural product and its derivatives are versatile and have been established as a source of therapeutic agent. Knowledge advancement of its multidimensional chemical structure offers a great opportunity to reestablish natural products in drug discovery.

Chalcones are simple but contain highly biological active forms of naturally or synthetic class of compounds, which comprise two aromatic rings linked by three carbon α,β-unsaturated system.[1] These compounds possess several biological activities including anti-inflammatory, antileishmanial, anti-invasive, antituberculosis, antifungal, antimalarial, antitumor, antimicrobial, antinociceptives, and anticancer. Our group is working on chalcone and its derivatives since last decade to find a reasonable compound against various diseases, especially cancer on nociception.[2],[3],[4],[5]

DMPF-1 [3-(2,5-dimethoxyphenyl)-1-(5-methyl furan-2-yl) prop-2-en-1-one] is one of the synthetic chalcone derivatives, shown to be a potential anti-inflammatory agent as its mediates inhibition in the synthesis of various pro-inflammatory mediators, such as prostaglandins (PG), nitric oxide (NO), and inhibits cyclooxygenase (COX) pathways.[1] Furthermore, it is also capable to inhibit the nuclear translocation and suppression of nuclear factor kappa B (NF-kB), which explains its anti-inflammatory action.[6] This finding was supported by other in vitro studies using interferon-c/lipopolysaccharide (IFN-c/LPS)-activated RAW 264.7 macrophages cells showing that chalcones bearing furanyl group revealed remarkable anti-inflammatory activity via inhibition of NO and prostaglandin E2 (PGE2) production.[7]

Concerning the ability of pro-inflammatory mediators in sensitizing and modulating nociception via intracellular signaling pathway in the peripheral terminals, which leads to the changes in function and expression of receptor molecules, inhibition of this mediator was postulated to suppress nociception. However, the effect of DMPF-1 on antinociceptive activity has never been studied. Inhibition of the pro-inflammatory mediators was hypothesized to suppress nociception either by direct or indirect action of these mediators on the nociceptors. Therefore, the aims of this study were to evaluate the pharmacological activity of DMPF-1 compound on its antinociceptive action on induction with inflammatory mediators and to assess its potential mechanisms on different biological receptors involved using acute pain animal models.


   Materials and Methods Top


Drugs and reagents

Glacial acetic acid (Scharlau Chemie S.A., Barcelona, Spain), formalin (HmbG Chemical, Germany), naloxone, acetylsalicylic acid (ASA), morphine, capsazepine, capsaicin, and glutamate (Sigma Chemical, St. Louis, MO, USA) were used. All drugs were dissolved in saline (0.9%; NaCl); DMPF-1 compound was dissolved in a vehicle (ethanol, Tween 20 [Sigma Chemical] and distilled water; 5:5:90 [v/v] fraction). The DMPF-1 doses used (0.1, 0.5, 1, and 5 mg/kg) were chosen based on a pilot experiment, and volume administered was 10 mL/kg body weight.

Animals

Adult male ICR albino mice (20–25 g, n = 6 for each group) were used. These animals were kept in constant temperature 24 ± 1°C, 12 h with free access to food and water ad libitum. The experiments followed the rules of ethical guideline for evaluation of pain on conscious animals[3] with approval by Animal Care and Use Committee, Universiti Putra Malaysia, Serdang, Selangor.

Synthesis of (E)-3-(2,5 dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one

DMPF-1 was synthesized by Claisen–Schmidt condensation reaction as discussed in our previous publication [Figure 1]A.[8] The compound was purified by column chromatography using silica gel mesh size (200–400 mesh, Merck) and elution with petroleum ether and ethyl acetate. Yield: 58%; yellow crystals, infrared (CHCl3)υ: 2946 (C–H stretch), 1652 (C = O), 1600 (C = C), 1515 (C = C), 1269 (C–O aromatic), 1074 cm–1; proton nuclear magnetic resonance (1H nuclear magnetic resonance (NMR)) (500 MHz, CDCl3):δ 2.38 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.38 (d, J = 3.0 Hz, 1H, H-4 furanyl), 6.97 (br, s, 2H, H-3 and H-4 phenyl), 7.42 (s, 1H, H-6 phenyl), 7.60 (d, J = 16.0 Hz, 1H, H-α), 7.70 (d, J = 3.0 Hz, 1H, H-3 furanyl), and 8.01 (d, J = 16.0 Hz, 1H, H-β). 13C NMR (125 MHz, dimethyl sulfoxide [DMSO]): δ: 176.7, 159.3, 154.0, 153.3, 152.6, 137.0, 124.2, 122.6, 121.9, 118.5, 113.7, 113.4, 109.9, 56.7, 56.3, and 14.5. electron ionization mass spectral m/z (rel. int.) calcd for C16H16O4 (M+, %): 272 (M+ –43), 257, 241, 191, 137, and 81.
Figure 1: (A) Chemical structure of 3-(2,5 dimethoxyphenyl)-1-(5-methyl furan-2-yl) prop-2-en-1-one (DMPF-1), effect of DMPF-1 compound in (B) acetic-acid-induced abdominal writhing test, (C) phase 1 formalin-, (D) phase 2 formalin-, (E) capsaicin- (F) phorbol 12-myristate 12 acetate (PMA)-, and (G) glutamate-induced paw licking test. Every column signifies mean ± standard error mean (SEM). Asterisks (*) represent the significant difference at P < 0.05 as compared to the vehicle-treated group

Click here to view


Acetic-acid-induced abdominal writhing test

The acetic-acid-induced abdominal writhing test was performed as described previously.[9] The groups of mice (n = 6) were pretreated with DMPF-1 (0.1–5 mg/kg), vehicle (10 mL/kg), and ASA (100 mg/kg) intraperitoneally 30 min before 0.6% intraperitoneal acetic acid injection and they were placed individually in glass observation chambers. The number of writhing episodes was recorded cumulatively between 5 and 30 min postinjection.

Formalin-induced paw licking test

The method used similarly as described previously.[10] Briefly 20 μL of 2.5% formaldehyde solution was administered intraplantar (i.p.) to the left hind paw of a pretreated group of mice (n = 6) 30 min with DMPF-1 (0.1–5 mg/kg, respectively), vehicle (10 mL/kg), ASA (100 mg/kg i.p.), and morphine (5 mg/kg subcutaneous (s.c.)). Time spent on licking or biting the injected paws was recorded in two phases: neurogenic phase (0–5 min) and inflammatory phase (15–30 min).

Hot-plate test

This test was performed using the method described.[11] The groups of preselected mice (n = 6) with latency of 6–8s were pretreated 30 min with DMPF-1 (0.1–5 mg/kg, respectively, i.p.), vehicle (10 mL/kg i.p.), and morphine (5 mg/kg s.c.) before placing the animals on the hot-plate apparatus (Ugo Basile, model- 7189, Gemonio (VA), Italy), 52.5°C ± 0.2°C. The latency time between placing and observed thermonocifensive reactions such as paw licking or shaking, jumping, or an attempt to escape was recorded every 30-min interval for 210 min. The cutoff time on the heated surface was 20s to avoid further tissue injuries.

Evaluation of opioid receptor’s involvement

In evaluation of opioidergic system involvement, separated groups of mice were pretreated with naloxone (5 mg/kg i.p.) 15 min before administering of DMPF-1 (1 mg/kg i.p.) 30 min. Hot-plate test was applied. Morphine (5 mg/kg s.c.) was used as a reference drug.[10]

Antinociceptive evaluation against capsaicin-, phorbol 12-myristate 12 acetate-, and glutamate- induced nociception

The evaluation of the DMPF-1 antinociceptive mechanism was carried out according to the procedures described.[12] The capability of DMPF-1 to antagonize the effect of the phlogistic agents 30 min after assessing the administration of DMPF-1 (0.1–5 mg/kg i.p., respectively). Vehicle (10 mL/kg), capsazepine (0.17 µmol/kg i.p.; capsaicin positive control), and ASA (100 mg/kg i.p.; PMA and glutamate positive control) were used as control group.

Statistical analysis

The statistical significance of differences between groups was assessed using one-way analysis of variance (ANOVA) with Tukey’s, Dunnet’s, and Bonferroni’s post hoc tests using Prism 4.0 software (GraphPad Software, San Diego, California); a value of P < 0.05 was considered significant for all cases. The percentage of inhibition was calculated using the following formula: ([mean of control group – mean of the test group]/[mean of control group]) × 100.


   Result Top


Acetic-acid-induced abdominal writhing test

DMPF-1 compound at doses 0.1, 0.5, 1, and 5 mg/kg i.p. caused a significant abdominal writhing reduction as compared to control group [Figure 1B] with percentage of reduction 36.27%, 59.72%, 93.68%, and 98.15%, respectively. DMPF-1 treatment at dose of 0.5 mg/kg produced comparable effect with ASA at dose 100 mg/kg.

Formalin-induced paw licking test

DMPF-1 produced a significant inhibition in formalin-induced nociception in both phases with 61.6% and 88.2%, respectively, at dose 5 mg/kg [Figure 1C and D].

Hot-plate test

Mice treated with DMPF-1 (1 and 5 mg/kg) and morphine (5 mg/kg) significantly decreased the withdrawal latencies in hot-plate test starting at 30 min onward as compared to the control group as depicted in [Table 1].
Table 1: The effect of 3-(2,5-dimethoxyphenyl)-1-(5-methyl furan-2-yl) prop-2-en-1-one (DMPF-1) compound on opioid receptor involvement using hot plate test

Click here to view


Evaluation of opioid receptor’s involvement

Pretreatment of mice with naloxone (5 mg/kg i.p.) showed no significant reduction in the antinociceptive profile of DMPF-1 in the hot-plate test [Table 1].

Antinociceptive effect of DMPF-1 against capsaicin-, phorbol 12-myristate 12 acetate-, and glutamate-induced nociception

DMPF-1 pretreatment caused a significant inhibition in capsaicin-induced nociception. The compound at a dose of 5 mg/kg produced 78.8% inhibition, respectively, as compared to its competitive antagonist, capsazepine with 36.4% inhibition [Figure 1E]. A similar reduction response was seen in PMA- and glutamate-induced nociception with 91.04% and 53%, respectively, at a similar dose [Figure 1F and G]. DMPF-1 at a dose of 5 mg/kg produces a higher reduction in nocifensive response than the standard drug ASA.


   Discussion Top


This study has shown the peripheral and central antinociceptive profile of DMPF-1 as this compound attenuated the chemical and thermal-induced nociception.[13] From the finding, it is postulated that DMPF-1 inhibit the release of various mediators that is capable of influencing nociception including COX and lipoxygenase (LOX) upon acetic acid administration.[13] Local i.p. induction of the formalin produced a biphasic nociceptive response. The first phase indicates neurogenic phase due to the direct activation of the nociceptor by the chemical; meanwhile, the second phase is an inflammatory phase due to the release of tissue by-products and various inflammatory mediators including PG, histamine, bradykinin, cytokines, substance P, and 5-hydroxytryptamine on stimulation with the noxious stimuli.[14] Taking this into account, the formalin test is proficient at distinguishing the possible antinociceptive mechanism of DMPF-1. Meanwhile, the hot-plate test is used in screening centrally acting drugs. From the experiment, DMPF-1 supplementation had increased the latency response, which suggests the involvement of the central system.

Naloxone antagonism assay was conducted to evaluate the possible participation of the opioidergic system of this compound in modulating nociception.[13] Various analgesics exert their effects via an opioid system such as morphine, which is often associated with sedative and tolerance. Naloxone is a well-known antagonist that occupies opioid receptors to perform its action. In this study, the antinociceptive activity of DMPF-1 was not altered by naloxone pretreatment in the hot-plate test, which indicates that DMPF-1 is not likely to mediate its analgesic activity via opioid receptors antagonism.

A recent report stated the role of transient protein vanilloid-1 (TRPV1) receptor in nociception,[15] which can be activated by capsaicin, heat >42°C, and pH <6.5.[16] The binding of capsaicin to the TRPV1 receptor triggers the release of various mediators such as neuropeptides, pro-inflammatory mediators, NO, and excitatory amino acids at the free nerves ending.[15] Studies have shown that capsaicin also induces nociception via the reduction of the threshold level and increases the sensitivity of certain receptors.[17] In this study, a capsaicin-induced paw licking test was conducted to determine the involvement of TRPV1 receptor in DMPF-1-induced antinociception. In this experiment, the introduction of DMPF-1 produced a significant reduction in nociception caused by capsaicin i.p. injection. Thus, these data proposed that DMPF-1 elicited neurogenic antinociception through the binding with the TRPV1 receptor, which then inhibited the activation of this receptor on stimulation with capsaicin.

In sequence, protein kinase C (PKC) is another mediator that directly phosphorylates the activation of TRPV1 receptor where challenging the TRPV1 receptor agonist with PKC inhibitor had abolished its phosphorylation.[18] Because of that, the study on the participation of this mediator by DMPF-1 was conveyed. As the pretreatment of DMPF-1 had attenuated the behavioral response of the mice injected with PMA, it is suggested that DMPF-1 mediates its action on PKC with subsequence blocking of the TRPV1 receptor. It also postulated to increase the threshold level of certain receptors together in decreasing the membrane permeability followed by inhibition of impulse transmission.

Previous reports stated that PKC was also a phosphorylated glutamatergic receptor: AMPA directly and N-methyl-D-aspartate (NMDA) receptor indirectly.[19] Glutamate mediates its action on ionotropic receptors at three different levels that are peripheral, spinal, and supraspinal[20] and activates the metabotropic receptors via second messenger system.[21] As glutamate receptors give a big contribution to the pain pathway, modulation of its receptors becomes a therapeutic target in neuropathic pain, inflammation, and joint pain.[22] Therefore, the involvement of the glutamatergic system in DMPF-1 action was evaluated. Our finding verified that DMPF-1 effectively attenuates glutamate-induced nociception, thus occupying this receptor in mediating its analgesic activity.

Moreover, glutamate-induced nociception and paw edema were greatly influenced by the presence of NO where activation of the NMDA receptor was shown to increase calcium influx, thus rising the intracellular concentration.[23] This situation indirectly influences NO synthase to convert L-arginine to NO and L-citrulline.[12] Our finding was in parallel with the study, which showed that chalcone inhibits the production of NO in murine macrophage cell line RAW 264.7.[7] Thus, this suggests that DMPF-1 reduces NO production through interaction with the glutamatergic system.


   Conclusion Top


In summary, this study revealed that DMPF-1 is capable as an antinociceptive and anti-inflammatory agent. Various complex pathways took part in DMPF-1antinociception such as TRPV-1, glutamatergic, and PKC system, excluding the opioid system.

Acknowledgement

We thank the Faculty of Medicine and Health Sciences, Universiti Putra Malaysia for providing the facilities in doing this research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Gonçalves CJ, Lenoir AS, Padaratz P, Corrêa R, Niero R, Cechinel-Filho V, et al. Benzofuranones as potential antinociceptive agents: structure-activity relationships. Eur J Med Chem 2012;56:120-6.  Back to cited text no. 1
    
2.
Abu Bakar A, Akhtar MN, Ali NM, Yeap SK, Quah CK, Loh W-S, et al. Design, synthesis and docking studies of flavokawain B type chalcones and their cytotoxic effects on MCF-7 and MDA-MB-231 cell lines. Molecules 2018;23:616.  Back to cited text no. 2
    
3.
Abu N, Ho WY, Yeap SK, Akhtar MN, Abdullah MP, Omar AR, et al. The flavokawains: uprising medicinal chalcones. Cancer Cell Int 2013;13:102.  Back to cited text no. 3
    
4.
Abu N, Mohamed NE, Yeap SK, Lim KL, Akhtar MN, Zulfadli AJ, et al. In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice. Drug Des Devel Ther 2015;9:1401-17.  Back to cited text no. 4
    
5.
Abu N, Akhtar MN, Yeap SK, Lim KL, Ho WY, Abdullah MP, et al. Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases in vitro. BMC Complement Altern Med 2016;16:86.  Back to cited text no. 5
    
6.
Rajajendram R, Tham CL, Akhtar MN, Sulaiman MR, Israf DA Inhibition of epithelial CC-family chemokine synthesis by the synthetic chalcone DMPF-1 via disruption of NF-κb nuclear translocation and suppression of experimental asthma in mice. Mediators Inflamm 2015;2015:176926.  Back to cited text no. 6
    
7.
Tham CL, Liew CY, Lam KW, Mohamad AS, Kim MK, Cheah YK, et al. A synthetic curcuminoid derivative inhibits nitric oxide and proinflammatory cytokine synthesis. Eur J Pharmacol 2010;628:247-54.  Back to cited text no. 7
    
8.
Ismail NI, Ming-Tatt L, Lajis N, Akhtar MN, Akira A, Perimal EK, et al. Antinociceptive effect of 3-(2, 3-Dimethoxyphenyl)-1-(5-methylfuran-2-yl) prop-2-en-1-one in mice models of induced nociception. Molecules 2016;21:1077.  Back to cited text no. 8
    
9.
Sulaiman MR, Tengku Mohamad TA, Shaik Mossadeq WM, Moin S, Yusof M, Mokhtar AF, et al. Antinociceptive activity of the essential oil of Zingiber zerumbet. Planta Med 2010;76:107-12.  Back to cited text no. 9
    
10.
Sulaiman MR, Zakaria ZA, Adilius M, Mohamad AS, Ismail M, Israf DA Antinociceptive and anti-inflammatory effects of the ethanol extract of Alpinia conchigera griff. Leaves in various animal models. Methods Find Exp Clin Pharmacol 2009;31:241-7.  Back to cited text no. 10
    
11.
Ankier SI New hot plate tests to quantify antinociceptive and narcotic antagonist activities. Eur J Pharmacol 1974;27:1-4.  Back to cited text no. 11
    
12.
Zakaria ZA, Abdul Rahim MH, Roosli RAJ, Mohd Sani MH, Omar MH, Mohd Tohid SF, et al. Antinociceptive activity of methanolic extract of clinacanthus nutans leaves: possible mechanisms of action involved. Pain Res Manag 2018;2018:9536406.  Back to cited text no. 12
    
13.
Zakaria ZA, Mohamad AS, Chear CT, Wong YY, Israf DA, Sulaiman MR Antiinflammatory and antinociceptive activities of zingiber zerumbet methanol extract in experimental model systems. Med Princ Pract 2010;19:287-94.  Back to cited text no. 13
    
14.
Tjølsen A, Berge OG, Hunskaar S, Rosland JH, Hole K The formalin test: an evaluation of the method. Pain 1992;51:5-17.  Back to cited text no. 14
    
15.
Ikeda Y, Ueno A, Naraba H, Oh-ishi S Involvement of vanilloid receptor VR1 and prostanoids in the acid-induced writhing responses of mice. Life Sci 2001;69:2911-9.  Back to cited text no. 15
    
16.
Tominaga M, Caterina MJ Thermosensation and pain. J Neurobiol 2004;61:3-12.  Back to cited text no. 16
    
17.
Szallasi A, Blumberg PM Mechanisms and therapeutic potential of vanilloids (capsaicin-like molecules). Adv Pharmacol 1993;24:123-55.  Back to cited text no. 17
    
18.
Siebel JS, Beirith A, Calixto JB Evidence for the involvement of metabotropic glutamatergic, neurokinin 1 receptor pathways and protein kinase C in the antinociceptive effect of dipyrone in mice. Brain Res 2004;1003:61-7.  Back to cited text no. 18
    
19.
Kohno T, Wang H, Amaya F, Brenner GJ, Cheng JK, Ji RR, et al. Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity. J Neurosci 2008;28:4533-40.  Back to cited text no. 19
    
20.
Quintans-Júnior LJ, Melo MS, De Sousa DP, Araujo AA, Onofre AC, Gelain DP, et al. Antinociceptive effects of citronellal in formalin-, capsaicin-, and glutamate-induced orofacial nociception in rodents and its action on nerve excitability. J Orofac Pain 2010;24:305-12.  Back to cited text no. 20
    
21.
Goudet C, Magnaghi V, Landry M, Nagy F, Gereau RW 4th, Pin JP Metabotropic receptors for glutamate and GABA in pain. Brain Res Rev 2009;60:43-56.  Back to cited text no. 21
    
22.
Bleakman D, Alt A, Nisenbaum ES Glutamate receptors and pain. Semin Cell Dev Biol 2006;17:592-604.  Back to cited text no. 22
    
23.
Beirith A, Santos AR, Calixto JB Mechanisms underlying the nociception and paw oedema caused by injection of glutamate into the mouse paw. Brain Res 2002;924:219-28.  Back to cited text no. 23
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Materials and Me...
   Result
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed123    
    Printed4    
    Emailed0    
    PDF Downloaded2    
    Comments [Add]    

Recommend this journal