Mechanism of antinociceptive action of syringic acid

Abstract

Syringic acid presents various biological properties such as antioxidant, anti-inflammatory, anticancer, and other activities. The present experiment aimed to investigate the effect of the oral administration of syringic acid (10, 50, and 100 mg/kg) on its possible nociceptive response using hot-plate and tail-flick assay in the Balb-C mice model. The mice were pre-treated with 5 mg/kg atropine 15 min before, 1mg/kg mecamylamine 20 min before, 1mg/kg ketanserin 30 min before, 1 mg/kg ondansetron 30 min before, 1mg/kg yohimbine 30 min before, 1 mg/kg prazosin 30 min before and 5 mg/kg naloxone 15min before the administration of the Syringic acid. Dose-dependent antinociceptive activity of syringic acid was reported for 50 and 100 mg/kg doses in tail-flick and hot-plate assays, respectively. In further, mecamylamine, yohimbine, and naloxone significantly reversed syringic acid-induced response to thermal stimuli in tail-flick and hot-plate assays, respectively. From the data, it was confirmed that syringic acid presents central antinociceptive effects which may be coordinated by supraspinal/spinal mediated cholinergic, opioidergic, and adrenergic, inflection.

Keywords

• Antinociception
• muscarinic receptors
• opioidergic receptors
• α2-adrenoceptors
• syringic acid.

References

1. [1] Sneddon LU. Evolution of Nociception and Pain: Evidence From Fish Models. Philos. Trans R Soc B Biol Sci. 2019; 374: 20190290. [CrossRef]
2. [2] Sneddon LU, Elwood RW, Adamo SA, Leach MC. Defining and Assessing Animal Pain. Anim Behav. 2014; 97: 201–212. [CrossRef]
3. [3] van Rensburg R, Reuter H. An Overview of Analgesics: NSAIDs, Paracetamol, and Topical Analgesics Part 1. South African Fam Pract. 2019; 61: S4–S10. [CrossRef]
4. [4] Cregg R, Russo G, Gubbay A, Branford R, Sato H. Pharmacogenetics of Analgesic Drugs. Br J Pain. 2013; 7(4): 189–208. [CrossRef]
5. [5] Power I. An Update on Analgesics. Br J Anaesth. 2011; 107: 19–24. [CrossRef]
6. [6] Peterson NC, Nunamaker EA, Turner PV. To Treat or Not to Treat: The Effects of Pain on Experimental Parameters. Comp Med. 2017; 67: 469–482.
7. [7] Hooijmans CR, Draper D, Ergün M, Scheffe GJ. The Effect of Analgesics on Stimulus Evoked Pain-like Behaviour in Animal Models for Chemotherapy Induced Peripheral Neuropathy- A Meta-Analysis. Sci Rep. 2019; 9: 17549. [CrossRef]
8. [8] Suokas AK, Sagar DR, Mapp PI, Chapman V, Walsh DA. Design, Study Quality and Evidence of Analgesic Efficacy in Studies of Drugs in Models of OA Pain: A Systematic Review And A Meta-Analysis. Osteoarthr Cartil. 2014; 22(9): 1207–1223. [CrossRef]

9. [9] Frias B, Merighi A. Capsaicin, Nociception and Pain. Molecules. 2016; 21(6): 797. [CrossRef] [10] Dubin AE, Patapoutian A. Nociceptors: The Sensors of The Pain Pathway. J Clin Invest. 2010; 120(11): 3760–3772. [CrossRef]
10. [11] Price DD, Dubner R. Mechanisms of First and Second Pain in The Peripheral and Central Nervous Systems. J Invest Dermatol. 1977; 69: 167–171. [CrossRef]
11. [12] Mitsi V, Zachariou V. Modulation of Pain, Nociception, and Analgesia by The Brain Reward Center. Neuroscience. 2016; 338: 81–92. [CrossRef]
12. [13] Falk S, Dickenson AH. Pain and Nociception: Mechanisms of Cancer-Induced Bone Pain. J Clin Oncol. 2014; 32: 1647–1654. [CrossRef]
13. [14] Tracey WD Jr. Nociception. Curr Biol. 2017; 27(4): R129-R133. [CrossRef]
14. [15] Srinivasulu C, Ramgopal M, Ramanjaneyulu G, Anuradha CM, Kumar CS. Syringic acid (SA) ‒ A Review of Its Occurrence, Biosynthesis, Pharmacological and Industrial Importance. Biomed Pharmacother. 2018; 108: 547–557. [CrossRef]
15. [16] Ramachandran V, Raja B. Protective Effects of Syringic Acid Against Acetaminophen-Induced Hepatic Damage in Albino Rats. J Basic Clin Physiol Pharmacol. 2010; 21: 369–386. [CrossRef]
16. [17] Ren J, Yang M, Xu F, Chen J, Ma S. Acceleration of Wound Healing Activity with Syringic Acid in Streptozotocin Induced Diabetic Rats. Life Sci. 2019; 233: 116728. [CrossRef]
17. [18] Gias ZT, Afsana F, Debnath P, Alam MS, Ena TN, Hossain MH, et al. A Mechanistic Approach to HPLC Analysis, Antinociceptive, Anti-inflammatory and Postoperative Analgesic Activities of Panch Phoron in Mice. BMC Complement Med Ther. 2020; 20: 102. [CrossRef]
18. [19] Bouhlali EDT, Hmidani A, Bourkhis B, Khouya T, Ramchoun M, Filali-Zegzouti Y, et al. Phenolic Profile and Anti-inflammatory Activity of Four Moroccan Date (Phoenix Dactylifera L.) Seed Varieties. Heliyon. 2020; 6: e03436.[CrossRef]
19. [20] Cikman O, Soylemez O, Ozkan OF, Kiraz HA, Sayar I, Ademoglu S, et al. Antioxidant Activity of Syringic Acid Prevents Oxidative Stress in L-arginine-Induced Acute Pancreatitis: An Experimental Study on Rats. Int Surg. 2015;100: 891–896. [CrossRef]
20. [21] Choi J, Shin K-M, Park H-J, Jung H-J, Kim H-J, Lee YS, et al. Anti-Inflammatory and Antinociceptive Effects of Sinapyl Alcohol and its Glucoside Syringin. Planta Med. 2004; 70: 1027–1032. [CrossRef]
21. [22] Giorno TBS, Moreira IGDS, Rezende CM, Fernandes PD. New β N-octadecanoyl-5-hydroxytryptamide: Antinociceptive Effect and Possible Mechanism of Action in Mice. Sci Rep. 2018; 8: 10027. [CrossRef]
22. [23] Mirza AC, Panchal SS. Safety Evaluation of Syringic Acid: Subacute Oral Toxicity Studies in Wistar Rats. Heliyon. 2019; 5: e02129. [CrossRef]
23. [24] Oliveira PA, Capim SL, Gonçalves GM, Laureano-Melo R, Côrtes WDS, Vasconcellos MLAA, et al. Pharmacological Evaluation Underlying The Antinociceptive Activity of Two New Hybrids NSAIDs Tetrahydropyran Derivatives. Fundam Clin Pharmacol. 2020; 34: 321–335. [CrossRef]
24. [25] Fiorino DF, Garcia-Guzman M. Muscarinic Pain Pharmacology: Realizing The Promise of Novel Analgesics by Overcoming Old Challenges. Handb Exp Pharmacol. 2012; 208: 191-221. [CrossRef]
25. [26] Vincler M. Neuronal Nicotinic Receptors as Targets for Novel Analgesics. Expert Opin Investig Drugs.2005; 14(10): 1191-1198. [CrossRef] [27] Sudo RT, Hayashida K, Santos AN, Kawatani M, Monteiro CE, Moreira RD, et al. Novel Agonist of α 4 β 2 * Neuronal Nicotinic Receptor with Antinociceptive Efficacy in Rodent Models of Acute and Chronic Pain. J Pain Res. 2018; 11: 2453-2462. [CrossRef]
26. [28] Woodcock J, Witter J, Dionne RA. Stimulating The Development of Mechanism-Based, Individualized Pain Therapies. Nat Rev Drug Discov. 2007; 6: 703–710. [CrossRef]
27. [29] Llorca-Torralba M, Borges G, Neto F, Mico JA, Berrocoso E. Noradrenergic Locus Coeruleus Pathways in Pain Modulation. Neuroscience. 2016; 338: 93–113. [CrossRef]
28. [30] Tanabe M, Takasu K, Kasuya N, Shimizu S, Honda M, Ono H. Role of Descending Noradrenergic System and Spinal α2-adrenergic Receptors in The Effects of Gabapentin on Thermal and Mechanical Nociception After Partial Nerve Injury in The Mouse. Br J Pharmacol. 2005; 144: 703–714. [CrossRef]
29. [31] Gutierrez T, Nackley AG, Neely MH, Freeman KG, Edwards GL, Hohmann AG. Effects of Neurotoxic Destruction of Descending Noradrenergic Pathways on Cannabinoid Antinociception in Models of Acute and Tonic Nociception. Brain Res. 2003; 987: 176–185. [CrossRef]
30. [32] Abubakar A, Nazifi AB, Odoma S, Shehu S, Danjuma NM. Antinociceptive Activity of Methanol Extract of Chlorophytum Alismifolium Tubers in Murine Model of Pain: Possible Involvement of α2-adrenergic Receptor and KATP Channels. J Tradit Complement Med. 2020; 10: 1–6. [CrossRef]
31. [33] Romero TRL, Pacheco DDF, Duarte IDG. Xylazine Induced Central Antinociception Mediated by Endogenous Opioids and μ-opioid Receptor, But Not δ-or κ-opioid Receptors. Brain Res. 2013; 1506: 58–63. [CrossRef]
32. [34] Pavlovic ZW, Bodnar RJ. Opioid Supraspinal Analgesic Synergy Between The Amygdala and Periaqueductal Gray in Rats. Brain Res. 1998; 779: 158–169. [CrossRef]
33. [35] Dalmagro AP, Camargo A, Severo Rodrigues AL, Zeni ALB. Involvement of PI3K/Akt/GSK-3β Signaling Pathway in The Antidepressant-like and Neuroprotective Effects of Morus Nigra and Its Major Phenolic, Syringic acid. Chem Biol Interact. 2019; 314: 108843. [CrossRef]
34. [36] Martini LH, Jung F, Soares FA, Rotta LN, Vendite DA, Frizzo ME, et al. Naturally Occurring Compounds Affect Glutamatergic Neurotransmission in Rat Brain. Neurochem Res. 2007; 32: 1950–1956. [CrossRef]
35. [37] 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. [CrossRef]
36. [38] Dalmagro AP, Camargo A, Zeni ALB. Morus Nigra and Its Major Phenolic, Syringic Acid, Have Antidepressant-Like and Neuroprotective Effects In Mice. Metab Brain Dis. 2017; 32: 1963–1973. [CrossRef]
37. [39] Ogut E, Akcay G, Yildirim FB, Derin N, Aslan M. The Influence of Syringic Acid Treatment on Total Dopamine Levels of The Hippocampus and on Cognitive Behavioral Skills. Int J Neurosci. 2020; 17: 1–9. [CrossRef]
38. [40] Rezaee L, Alizadeh AM, Haghparast A. Role of Hippocampal Dopamine Receptors in The Antinociceptive Responses Induced by Chemical Stimulation of The Lateral Hypothalamus in Animal Model of Acute Pain. Brain Res. 2020; 1734: 146759. [CrossRef]
39. [41] Ahmed F, Shahid IZ, Biswas UK, Roy BA, Das AK, Choudhuri MSK. Anti-inflammatory, Antinociceptive, and Neuropharmacological Activities of Clerodendron Viscosum. Pharm Biol. 2007; 45: 587–593. [CrossRef]
40. [42] Bektaş N, Arslan R. The Centrally-Mediated Mechanisms of Action of Ferulic Acid–Induced Antinociception. Marmara Pharm J. 2016; 20: 303–310.
41. [43] Arslan R, Bektas N. Evaluation of the Centrally-Acting Mechanisms of Some Non-Steroidal Anti-inflammatory Drugs. Am J Pharm Heal Res. 2015; 3: 191–202.
42. [44] Arslan R, Aydin S, Nemutlu Samur D, Bektas N. The Possible Mechanisms of Protocatechuic Acid-induced Central Analgesia. Saudi Pharm J. 2018; 26: 541–545. [CrossRef]
43. [45] De Caro C, Raucci F, Saviano A, Cristiano C, Casillo GM, Di Lorenzo R, et al. Pharmacological and Molecular Docking Assessment of Cryptotanshinone as Natural-Derived Analgesic Compound. Biomed Pharmacother. 2020; 126: 110042. [CrossRef]