Korean J Pain.  2019 Apr;32(2):87-96. 10.3344/kjp.2019.32.2.87.

Effect of sec-O-glucosylhamaudol on mechanical allodynia in a rat model of postoperative pain

• Koh GH
• Song H
• Kim SH
• Yoon MH
• Lim KJ
• Oh SH
• Jung KT

• KMID: 2449821
• DOI: http://doi.org/10.3344/kjp.2019.32.2.87

Abstract

BACKGROUND
This study was performed in order to examine the effect of intrathecal sec-O-glucosylhamaudol (SOG), an extract from the root of the Peucedanum japonicum Thunb., on incisional pain in a rat model.
METHODS
The intrathecal catheter was inserted in male Sprague-Dawley rats (n = 55). The postoperative pain model was made and paw withdrawal thresholds (PWTs) were evaluated. Rats were randomly treated with a vehicle (70% dimethyl sulfoxide) and SOG (10 μg, 30 μg, 100 μg, and 300 μg) intrathecally, and PWT was observed for four hours. Dose-responsiveness and ED50 values were calculated. Naloxone was administered 10 min prior to treatment of SOG 300 μg in order to assess the involvement of SOG with an opioid receptor. The protein levels of the δ-opioid receptor, κ-opioid receptor, and μ-opioid receptor (MOR) were analyzed by Western blotting of the spinal cord.
RESULTS
Intrathecal SOG significantly increased PWT in a dose-dependent manner. Maximum effects were achieved at a dose of 300 μg at 60 min after SOG administration, and the maximal possible effect was 85.35% at that time. The medial effective dose of intrathecal SOG was 191.3 μg (95% confidence interval, 102.3-357.8). The antinociceptive effects of SOG (300 μg) were significantly reverted until 60 min by naloxone. The protein levels of MOR were decreased by administration of SOG.
CONCLUSIONS
Intrathecal SOG showed a significant antinociceptive effect on the postoperative pain model and reverted by naloxone. The expression of MOR were changed by SOG. The effects of SOG seem to involve the MOR.

Keyword

Analgesia; Blotting, western; Dimethyl sulfoxide; Hyperalgesia; Nociceptive pain; Pain, postoperative; Rats; Receptors, opioid; Spinal cord; 11-hydroxy-sec-O-glocosylhamaudol

MeSH Terms

Analgesia
Animals
Blotting, Western
Catheters
Dimethyl Sulfoxide
Humans
Hyperalgesia*
Male
Models, Animal*
Naloxone
Nociceptive Pain
Pain, Postoperative*
Rats*
Rats, Sprague-Dawley
Receptors, Opioid
Spinal Cord
Dimethyl Sulfoxide
Naloxone
Receptors, Opioid

Figure

• 

  Fig. 1 Diagram illustrating the progress of the study protocol throughout the experiment. DMSO: dimethyl sulfoxide.

• 

  Fig. 2 (A) Effects of intrathecal sec-O-glucosylhamaudol (SOG) on paw withdrawal threshold (PWT) after incision. Data are presented as withdrawal thresholds (g). Each value represents the mean ± standard error of mean. (B) Maximal possible effects (MPE) of SOG according to the dose. Data are presented as %MPE. Intrathecal SOG administration showed a significant increase of the PWT and %MPE in a dose-dependent manner. Baseline is the withdrawal threshold measured before paw incision. Control is two hours after paw incision. Vehicle, 70% dimethyl sulfoxide. *P < 0.001 compared to the vehicle.

• 

  Fig. 3 Linear regression of the maximal effects of these individual doses of sec-O-glucosylhamaudol (SOG). The median effective analgesic dose of intrathecal SOG was 191.3 μg (95% confidence interval [CI], 102.3–357.8) with a slope of 50.74 (95% CI, 33.55–67.94).

• 

  Fig. 4 (A) The inhibitory effects of intrathecal naloxone against sec-O-glucosylhamaudol (SOG). Data are presented as withdrawal thresholds (g). Each value represents the mean ± standard error of mean. (B) Maximal possible effects (MPE) of SOG according to the inhibitory effects of intrathecal naloxone. Data are presented as %MPE. Intrathecal administration of naloxone alone showed no antinociceptive effect. Intrathecal administration of naloxone 10 min before the delivery of SOG 300 μg decreased paw withdrawal threshold until 60 min. The %MPE in the administration of naloxone before delivery of SOG 300 μg was decreased until 60 min, which was similar to the %MPE of vehicle or naloxone alone. The inhibitory effect of naloxone against SOG vanished at 120 min. Baseline is the withdrawal threshold measured before paw incision. Control is two hours after paw incision. *P < 0.001 compared to the SOG 300 μg.

• 

  Fig. 5 Protein levels of (A) δ-opioid receptor (DOR), (B) κ-opioid receptor (KOR), and (C) μ-opioid receptor (MOR) in the spinal cord of rats. The protein levels of DOR and KOR showed no significant differences among the groups. Expression of MOR protein was increased by paw incision, and decreased by administration of sec-O-glucosylhamaudol (SOG). Data represent protein levels normalized to β-actin expression. Each value represents mean ± standard error of mean of five rats. Group 1, naïve group; Group 2, control group (2 h after incision of left hind paw); Group 3, 1 h after vehicle administration (70% dimethyl sulfoxide); Group 4, 1 h after SOG 300 μg administration. *P < 0.05, compared with naïve group.

Reference

1. Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007; 21:185–211. DOI: 10.2165/00023210-200721030-00002. PMID: 17338592.

2. Kang S, Brennan TJ. Mechanisms of postoperative pain. Anesth Pain Med. 2016; 11:236–48. DOI: 10.17085/apm.2016.11.3.236.

3. Shin DJ, Yoon MH, Lee HG, Kim WM, Park BY, Kim YO, et al. The effect of treatment with intrathecal ginsenosides in a rat model of postoperative pain. Korean J Pain. 2007; 20:100–5. DOI: 10.3344/kjp.2007.20.2.100.

4. Kim IJ, Park CH, Lee SH, Yoon MH. The role of spinal adrenergic receptors on the antinociception of ginsenosides in a rat postoperative pain model. Korean J Anesthesiol. 2013; 65:55–60. DOI: 10.4097/kjae.2013.65.1.55. PMID: 23904940. PMCID: 3726848.

5. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology. 1987; 66:729–36. DOI: 10.1097/00000542-198706000-00004. PMID: 3296854.

6. Pogatzki-Zahn EM, Segelcke D, Schug SA. Postoperative pain-from mechanisms to treatment. Pain Rep. 2017; 2:e588. DOI: 10.1097/PR9.0000000000000588. PMID: 29392204. PMCID: PMC5770176.

7. McCurdy CR, Scully SS. Analgesic substances derived from natural products (natureceuticals). Life Sci. 2005; 78:476–84. DOI: 10.1016/j.lfs.2005.09.006. PMID: 16216276.

8. Ikeshiro Y, Mase I, Tomia Y. Dihydropyranocoumarins from roots of Peucedanum japonicum. Phytochemistry. 1992; 31:4303–6. DOI: 10.1016/0031-9422(92)80463-O.

9. Chen IS, Chang CT, Sheen WS, Teng CM, Tsai IL, Duh CY, et al. Coumarins and antiplatelet aggregation constituents from Formosan Peucedanum japonicum. Phytochemistry. 1996; 41:525–30. DOI: 10.1016/0031-9422(95)00625-7. PMID: 8821432.

10. Hisamoto M, Kikuzaki H, Ohigashi H, Nakatani N. Antioxidant compounds from the leaves of Peucedanum japonicum thunb. J Agric Food Chem. 2003; 51:5255–61. DOI: 10.1021/jf0262458. PMID: 12926867.

11. Zimecki M, Artym J, Cisowski W, Mazol I, WIodarczyk M, Gleńsk M. Immunomodulatory and anti-inflammatory activity of selected osthole derivatives. Z Naturforsch C. 2009; 64:361–8. DOI: 10.1515/znc-2009-5-610. PMID: 19678539.

12. Zheng MS, Jin WY, Son KH, Chang HW, Kim HP, Bae KH, et al. The constituents isolated from Peucedanum japonicum Thunb. and their Cyclooxygenase (COX) inhibitory activity. Korean J Med Crop Sci. 2005; 13:75–9.

13. Okuyama E, Hasegawa T, Matsushita T, Fujimoto H, Ishibashi M, Yamazaki M. Analgesic components of saposhnikovia root (Saposhnikovia divaricata). Chem Pharm Bull (Tokyo). 2001; 49:154–60. DOI: 10.1248/cpb.49.154. PMID: 11217101.

14. Kim SH, Jong HS, Yoon MH, Oh SH, Jung KT. Antinociceptive effect of intrathecal sec-O-glucosylhamaudol on the formalin-induced pain in rats. Korean J Pain. 2017; 30:98–103. DOI: 10.3344/kjp.2017.30.2.98. PMID: 28416993. PMCID: 5392663.

15. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983; 16:109–10. DOI: 10.1016/0304-3959(83)90201-4. PMID: 6877845.

16. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976; 17:1031–6. DOI: 10.1016/0031-9384(76)90029-9. PMID: 14677603.

17. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain. 1996; 64:493–501. DOI: 10.1016/0304-3959(95)01441-1. PMID: 8783314.

18. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994; 53:55–63. DOI: 10.1016/0165-0270(94)90144-9. PMID: 7990513.

19. Tallarida RJ, Murray RB. Manual of pharmacologic calculations with computer programs. 2nd ed. New York: Springer-Verlag;1987. p. 1–95.

20. Garimella V, Cellini C. Postoperative pain control. Clin Colon Rectal Surg. 2013; 26:191–6. DOI: 10.1055/s-0033-1351138. PMID: 24436674. PMCID: 3747287.

21. Woolf CJ, Chong MS. Preemptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg. 1993; 77:362–79. DOI: 10.1213/00000539-199377020-00026. PMID: 8346839.

22. Law PY, Reggio PH, Loh HH. Opioid receptors: toward separation of analgesic from undesirable effects. Trends Biochem Sci. 2013; 38:275–82. DOI: 10.1016/j.tibs.2013.03.003. PMID: 23598157. PMCID: 3665630.

23. Xiao X, Wang X, Gui X, Chen L, Huang B. Natural flavonoids as promising analgesic candidates: asystematic review. Chem Biodivers. 2016; 13:1427–40. DOI: 10.1002/cbdv.201600060. PMID: 27449823.

24. Khadem S, Marles RJ. Chromone and flavonoid alkaloids: occurrence and bioactivity. Molecules. 2011; 17:191–206. DOI: 10.3390/molecules17010191. PMID: 22202807. PMCID: 6268529.

25. Colak T, Akca T, Dirlik M, Kanik A, Dag A, Aydin S. Micronized flavonoids in pain control after hemorrhoidectomy: a prospective randomized controlled study. Surg Today. 2003; 33:828–32. DOI: 10.1007/s00595-003-2604-5. PMID: 14605954.

26. Silva CF, Pinto DC, Silva AM. Chromones: a promising ring system for new anti-inflammatory drugs. ChemMedChem. 2016; 11:2252–60. DOI: 10.1002/cmdc.201600359. PMID: 27630077.

27. Sarkhail P. Traditional uses, phytochemistry and pharmacological properties of the genus Peucedanum: a review. J Ethnopharmacol. 2014; 156:235–70. DOI: 10.1016/j.jep.2014.08.034. PMID: 25193684.

28. Sasaki H, Taguchi H, Endo T, Yosioka I. The constituents of Ledebouriella seseloides WOLFF. I. Structures of three new chromones. Chem Pharm Bull (Tokyo). 1982; 30:3555–62. DOI: 10.1248/cpb.30.3555.

29. Gautam R, Jachak SM, Kumar V, Mohan CG. Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents. Bioorg Med Chem Lett. 2011; 21:1612–6. DOI: 10.1016/j.bmcl.2011.01.116. PMID: 21345672.

30. Chun JM, Kim HS, Lee AY, Kim SH, Kim HK. Antiinflammatory and antiosteoarthritis effects of saposhnikovia divaricata ethanol extract: in vitro and in vivo studies. Evid Based Complement Alternat Med. 2016; 2016:1984238. DOI: 10.1155/2016/1984238.

31. de Oliveira JO Junior, de Freitas MF, Bullara de Andrade C, Chacur M, Ashmawi HA. Local analgesic effect of tramadol is mediated by opioid receptors in late postoperative pain after plantar incision in rats. J Pain Res. 2016; 9:797–802. DOI: 10.2147/JPR.S117674. PMID: 27799813. PMCID: PMC5074711.

32. Berger V, Alloui A, Kemeny JL, Dubray C, Eschalier A, Lavarenne J. Evidence for a role for bulbospinal pathways in the spinal antinociceptive effect of systemically administered vapreotide in normal rats. Fundam Clin Pharmacol. 1998; 12:200–4. DOI: 10.1111/j.1472-8206.1998.tb00942.x. PMID: 9565775.

33. Katavic PL, Lamb K, Navarro H, Prisinzano TE. Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships. J Nat Prod. 2007; 70:1278–82. DOI: 10.1021/np070194x. PMID: 17685652. PMCID: 2265593.

34. Higgs J, Wasowski C, Loscalzo LM, Marder M. In vitro binding affinities of a series of flavonoids for μ-opioid receptors. Antinociceptive effect of the synthetic flavonoid 3,3-dibromoflavanone in mice. Neuropharmacology. 2013; 72:9–19. DOI: 10.1016/j.neuropharm.2013.04.020. PMID: 23624290.

35. Colucci M, Maione F, Bonito MC, Piscopo A, Di Giannuario A, Pieretti S. New insights of dimethyl sulphoxide effects (DMSO) on experimental in vivo models of nociception and inflammation. Pharmacol Res. 2008; 57:419–25. DOI: 10.1016/j.phrs.2008.04.004. PMID: 18508278.