Skip to main content

Advertisement

SpringerLink
Log in

Analgesic potency of intrathecally administered punicalagin in rat neuropathic and inflammatory pain models

  • Note
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Punicalagin, a natural polyphenolic compound classified as an ellagitannin, is a major ingredient of pomegranate (Punica granatum L.). Punicalagin has potent antioxidant and anti-inflammatory effects. Although the antinociceptive effects of orally administered pomegranate extracts have been reported, little is known about the effect of punicalagin on nociceptive transmission in the central nervous system. We examined whether punicalagin ameliorates neuropathic pain and inflammatory pain in the spinal cord. Male Sprague–Dawley rats were subjected to chronic constriction injury (CCI) of the sciatic nerve, and an intrathecal catheter was implanted for drug administration. The electronic von Frey test and cold-plate test were performed in CCI rats to evaluate mechanical and cold hyperalgesia in neuropathic pain, and the formalin test was performed in normal rats to evaluate acute and persistent inflammatory pain. An open-field test was conducted to explore whether punicalagin affects locomotor activity in CCI rats. Punicalagin administered intrathecally attenuated mechanical and cold hyperalgesia to the same degree as gabapentin in CCI rats and reduced pain-related behaviors in both the early and late phases in formalin-injected rats. Punicalagin did not affect motor function. These results suggest that punicalagin exerts an antinociceptive effect in the spinal cord without motor deficit, thus showing therapeutic potential for neuropathic pain and inflammatory pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Fischer UA, Carle R, Kammerer DR (2011) Identification and quantification of phenolic compounds from pomegranate (Punica granatum L.) peel, mesocarp, aril and differently produced juices by HPLC-DAD-ESI/MS(n). Food Chem 127:807–821

    CAS  PubMed  Google Scholar 

  2. Almowallad S, Huwait E, Al-Massabi R, Saddeek S, Gauthaman K, Prola A (2020) Punicalagin regulates key processes associated with atherosclerosis in THP-1 cellular model. Pharmaceuticals (Basel) 13:372

    CAS  Google Scholar 

  3. Kim YE, Hwang CJ, Lee HP, Kim CS, Son DJ, Ham YW, Hellström M, Han SB, Kim HS, Park EK, Hong JT (2017) Inhibitory effect of punicalagin on lipopolysaccharide-induced neuroinflammation, oxidative stress and memory impairment via inhibition of nuclear factor-kappaB. Neuropharmacology 117:21–32

    CAS  PubMed  Google Scholar 

  4. Álvarez-Martínez FJ, Rodríguez JC, Borrás-Rocher F, Barrajón-Catalán E, Micol V (2021) The antimicrobial capacity of Cistus salviifolius and Punica granatum plant extracts against clinical pathogens is related to their polyphenolic composition. Sci Rep 11:588

    PubMed  PubMed Central  Google Scholar 

  5. Zhang F, Wu K, Wu X, Xin C, Zhou M, Lei J, Chen J (2020) Punicalagin alleviates brain injury and inflammatory responses, and regulates HO-1/Nrf-2/ARE signaling in rats after experimental intracerebral haemorrhage. Trop J Pharm Res 19:727–737

    CAS  Google Scholar 

  6. Yaidikar L, Byna B, Thakur SR (2014) Neuroprotective effect of punicalagin against cerebral ischemia reperfusion-induced oxidative brain injury in rats. J Stroke Cerebrovasc Dis 23:2869–2878

    PubMed  Google Scholar 

  7. Jain V, Pareek A, Bhardwaj YR, Singh N (2013) Attenuating effect of standardized fruit extract of Punica granatum L in rat model of tibial and sural nerve transection induced neuropathic pain. BMC Complement Altern Med 13:274

    PubMed  PubMed Central  Google Scholar 

  8. Saad LB, Hwi KK, Quah T (2014) Evaluation of the antinociceptive effect of the ethanolic extract of Punica granatum. Afr J Tradit Complement Altern Med 11:228–233

    PubMed  PubMed Central  Google Scholar 

  9. Alles SRA, Smith PA (2018) Etiology and pharmacology of neuropathic pain. Pharmacol Rev 70:315–347

    CAS  PubMed  Google Scholar 

  10. Peirs C, Williams SP, Zhao X, Walsh CE, Gedeon JY, Cagle NE, Goldring AC, Hioki H, Liu Z, Marell PS, Seal RP (2015) Dorsal horn circuits for persistent mechanical pain. Neuron 87:797–812

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Google Scholar 

  12. Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107

    PubMed  Google Scholar 

  13. Yaksh TL, Rudy TA (1976) Chronic catheterization of the spinal subarachnoid space. Physiol Behav 17:1031–1036

    CAS  PubMed  Google Scholar 

  14. Rauck R, Coffey RJ, Schultz DM, Wallace MS, Webster LR, McCarville SE, Grigsby EJ, Page LM (2013) Intrathecal gabapentin to treat chronic intractable noncancer pain. Anesthesiology 119:675–686

    PubMed  Google Scholar 

  15. Bannister K, Qu C, Navratilova E, Oyarzo J, Xie JY, King T, Dickenson AH, Porreca F (2017) Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. Pain 158:2386–2395

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hara K, Haranishi Y, Kataoka K, Takahashi Y, Terada T, Nakamura M, Sata T (2014) Chlorogenic acid administered intrathecally alleviates mechanical and cold hyperalgesia in a rat neuropathic pain model. Eur J Pharmacol 723:459–464

    CAS  PubMed  Google Scholar 

  17. Hara K, Haranishi Y, Terada T (2020) Intrathecally administered perampanel alleviates neuropathic and inflammatory pain in rats. Eur J Pharmacol. https://doi.org/10.1016/j.ejphar.2020.172949

    Article  PubMed  Google Scholar 

  18. Finnerup NB, Sindrup SH, Jensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–581

    PubMed  Google Scholar 

  19. Lim EY, Kim YT (2016) Food-derived natural compounds for pain relief in neuropathic pain. Biomed Res Int 2016:7917528

    PubMed  PubMed Central  Google Scholar 

  20. Kroth A, Santos MDCQ, da Silva TCB, Santos Silveira EM, Partata WA (2021) Aqueous leaf extract from Luehea divaricata Mart. modulates oxidative stress markers in the spinal cord of rats with neuropathic pain. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2020.113674

    Article  PubMed  Google Scholar 

  21. Zhao B, Pan Y, Wang Z, Tan Y, Song X (2016) Intrathecal administration of tempol reduces chronic constriction injury-induced neuropathic pain in rats by increasing SOD activity and inhibiting NGF expression. Cell Mol Neurobiol 36:893–906

    CAS  PubMed  Google Scholar 

  22. DeLeo JA, Colburn RW, Rickman AJ (1997) Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res 759:50–57

    CAS  PubMed  Google Scholar 

  23. Nong X, Lan Y (2018) Picroside II attenuates CCI-induced neuropathic pain in rats by inhibiting spinal reactive astrocyte-mediated neuroinflammation through the NF-κB pathway. Neurochem Res 43:1058–1066

    CAS  PubMed  Google Scholar 

  24. Sommer C, Lindenlaub T, Teuteberg P, Schäfers M, Hartung T, Toyka KV (2001) Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res 913:86–89

    CAS  PubMed  Google Scholar 

  25. Schäfers M, Brinkhoff J, Neukirchen S, Marziniak M, Sommer C (2001) Combined epineurial therapy with neutralizing antibodies to tumor necrosis factor-alpha and interleukin-1 receptor has an additive effect in reducing neuropathic pain in mice. Neurosci Lett 310:113–116

    PubMed  Google Scholar 

  26. Moalem G, Tracey DJ (2006) Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 51:240–264

    CAS  PubMed  Google Scholar 

  27. Nazıroğlu M, Öz A, Yıldızhan K (2020) Selenium and neurological diseases: focus on peripheral pain and TRP channels. Curr Neuropharmacol 18:501–517

    PubMed  PubMed Central  Google Scholar 

  28. Niederberger E, Geisslinger G (2008) The IKK-NF-κB pathway: a source for novel molecular drug targets in pain therapy? FASEB J 22:3432–3442

    CAS  PubMed  Google Scholar 

  29. Olajide OA, Kumar A, Velagapudi R, Okorji UP, Fiebich BL (2014) Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia. Mol Nutr Food Res 58:1843–1851

    CAS  PubMed  Google Scholar 

  30. Vetter G, Geisslinger G, Tegeder I (2001) Release of glutamate, nitric oxide and prostaglandin E2 and metabolic activity in the spinal cord of rats following peripheral nociceptive stimulation. Pain 92:213–218

    CAS  PubMed  Google Scholar 

  31. Coderre TJ, Fundytus ME, McKenna JE, Dalal S, Melzack R (1993) The formalin test: a validation of the weighted-scores method of behavioural pain rating. Pain 54:43–50

    PubMed  Google Scholar 

  32. Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D (2006) Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem 54:980–985

    CAS  PubMed  Google Scholar 

  33. Zeilhofer HU (2005) The glycinergic control of spinal pain processing. Cell Mol Life Sci 62:2027–2035

    CAS  PubMed  Google Scholar 

  34. Ji G, Zhou S, Kochukov MY, Westlund KN, Carlton SM (2007) Plasticity in intact A delta- and C-fibers contributes to cold hypersensitivity in neuropathic rats. Neuroscience 150:182–193

    CAS  PubMed  Google Scholar 

  35. Koltzenburg M, Torebjörk HE, Wahren LK (1994) Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 117:579–591

    PubMed  Google Scholar 

  36. Lynch JW (2004) Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 84:1051–1095

    CAS  PubMed  Google Scholar 

  37. Betley JN, Wright CV, Kawaguchi Y, Erdélyi F, Szabó G, Jessell TM, Kaltschmidt JA (2009) Stringent specificity in the construction of a GABAergic presynaptic inhibitory circuit. Cell 139:161–174

    CAS  PubMed  PubMed Central  Google Scholar 

  38. D’Amico JM, Butler AA, Héroux ME, Cotel F, Perrier JM, Butler JE, Gandevia SC, Taylor JL (2017) Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone. J Physiol 595:1763–1773

    PubMed  Google Scholar 

  39. Haranishi Y, Hara K, Terada T, Nakamura S, Sata T (2010) The antinociceptive effect of intrathecal administration of glycine transporter-2 inhibitor ALX1393 in a rat acute pain model. Anesth Analg 110:615–621

    CAS  PubMed  Google Scholar 

  40. Haranishi Y, Hara K, Terada T (2020) Antihyperalgesic effects of intrathecal perospirone in a rat model of neuropathic pain. Pharmacol Biochem Behav. https://doi.org/10.1016/j.pbb.2020.172964

    Article  PubMed  Google Scholar 

  41. Kovács Z, Czurkó A, Kékesi KA, Juhász G (2011) The effect of intraperitoneally administered dimethyl sulfoxide on absence-like epileptic activity of freely moving WAG/Rij rats. J Neurosci Methods 197:133–136

    PubMed  Google Scholar 

  42. Farkas E, Institóris A, Domoki F, Mihály A, Luiten PG, Bari F (2004) Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res 1008:252–260

    CAS  PubMed  Google Scholar 

  43. Shimizu S, Simon RP, Graham SH (1997) Dimethylsulfoxide (DMSO) treatment reduces infarction volume after permanent focal cerebral ischemia in rats. Neurosci Lett 239:125–127

    CAS  PubMed  Google Scholar 

  44. Zhang C, Deng Y, Dai H, Zhou W, Tian J, Bing G, Zhao L (2017) Effects of dimethyl sulfoxide on the morphology and viability of primary cultured neurons and astrocytes. Brain Res Bull 128:34–39

    CAS  PubMed  Google Scholar 

  45. Yuan C, Gao J, Guo J, Bai L, Marshall C, Cai Z, Wang L, Xiao M (2014) Dimethyl sulfoxide damages mitochondrial integrity and membrane potential in cultured astrocytes. PLoS ONE. https://doi.org/10.1371/journal.pone.0107447

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by JSPS KAKENHI Grant Number JP18K08838 and JP21K08960 (to K.H.).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan

    Yasunori Haranishi & Tadanori Terada

  2. Division of Anesthesia, Kawashima Orthopaedic Hospital, 17 Miyabu, Nakatsu, 871-0012, Japan

    Yasunori Haranishi

  3. Division of Operative Medicine, Hospital of the University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8556, Japan

    Koji Hara

Authors
  1. Yasunori Haranishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koji Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tadanori Terada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koji Hara.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haranishi, Y., Hara, K. & Terada, T. Analgesic potency of intrathecally administered punicalagin in rat neuropathic and inflammatory pain models. J Nat Med 76, 314–320 (2022). https://doi.org/10.1007/s11418-021-01576-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-021-01576-0

Keywords

Search

Navigation