Skip to main content

Chronic nanocurcumin treatment ameliorates pain-related behavior, improves spatial memory, and reduces hippocampal levels of IL-1β and TNFα in the chronic constriction injury model of neuropathic pain

Psychopharmacology volume 238, pages 877–886 (2021)Cite this article

Abstract

Background

Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity.

Methods

Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1β, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA).

Results

Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1β (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats.

Conclusion

Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1β and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

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

Abbreviations

ABC:

Avidin-biotin-peroxidase complex

CCI:

Chronic constriction injury

ELISA:

Enzyme-linked immunosorbent assay

IL-1β:

Interleukin 1 beta

MWM:

Morris water maze

TBS:

Tris-buffered saline

TMB:

3,3,5,5-tetramethylbenzidine

TNF-α:

Tumor necrosis factor alpha

References

  • Agrawal M, Saraf S, Saraf S, Antimisiaris SG, Chougule MB, Shoyele SA, Alexander A (2018) Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Control Release 281:139–177

    CAS  PubMed  Google Scholar 

  • Austin PJ, Wu A, Moalem-Taylor G (2012) Chronic constriction of the sciatic nerve and pain hypersensitivity testing in rats. J Vis Exp 61

  • Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33(1):87–107

    PubMed  Google Scholar 

  • Bian Y, Pan Z, Hou Z, Huang C, Li W, Zhao B (2012) Learning, memory, and glial cell changes following recovery from chronic unpredictable stress. Brain Res Bull 88(5):471–476

    PubMed  Google Scholar 

  • Bilbao A, Falfán-Melgoza C, Leixner S, Becker R, Singaravelu SK, Sack M, Sartorius A, Spanagel R, Weber-Fahr W (2018) Longitudinal structural and functional brain network alterations in a mouse model of neuropathic pain. Neuroscience 387:104–115

    CAS  PubMed  Google Scholar 

  • Boadas-Vaello P, Homs J, Reina F, Carrera A, Verdú E (2017) Neuroplasticity of supraspinal structures associated with pathological pain. Anat Rec (Hoboken) 300(8):1481–1501

    Google Scholar 

  • Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    CAS  PubMed  Google Scholar 

  • Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN (2017) Neuropathic pain. Nature reviews Disease primers 3:17002–17002

    PubMed  PubMed Central  Google Scholar 

  • Flora G, Gupta D, Tiwari A (2013) Preventive efficacy of bulk and nanocurcumin against lead-induced oxidative stress in mice. Biol Trace Elem Res 152(1):31–40

    CAS  PubMed  Google Scholar 

  • Galvez-Sánchez CM, Duschek S, Del Paso GAR (2019) Psychological impact of fibromyalgia: current perspectives. Psychol Res Behav Manag 12:117–127

    PubMed  PubMed Central  Google Scholar 

  • Gerard E, Spengler RN, Bonoiu AC, Mahajan SD, Davidson BA, Ding H, Kumar R, Prasad PN, Knight PR, Ignatowski TA (2015) Chronic constriction injury-induced nociception is relieved by nanomedicine-mediated decrease of rat hippocampal tumor necrosis factor. Pain 156(7):1320–1333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gui WS, Wei X, Mai CL, Murugan M, Wu LJ, Xin WJ, Zhou LJ, Liu XG (2016a) Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain 12:174480691664678

    Google Scholar 

  • Gui WS, Wei X, Mai CL, Murugan M, Wu LJ, Xin WJ, Zhou LJ, Liu XG (2016b) Interleukin-1beta overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain 12:174480691664678

    Google Scholar 

  • Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32(1):77–88

    CAS  PubMed  Google Scholar 

  • Jayarajan P, Nirogi R, Shinde A, Goura V, Babu VA, Yathavakilla S, Bhyrapuneni G (2015) 5-HT6 receptor antagonist attenuates the memory deficits associated with neuropathic pain and improves the efficacy of gabapentinoids. Pharmacol Rep 67(5):934–942

    CAS  PubMed  Google Scholar 

  • Jia T et al (2017) Nanoparticle-encapsulated curcumin inhibits diabetic neuropathic pain involving the P2Y12 receptor in the dorsal root ganglia. Front Neurosci 11:755

    PubMed  Google Scholar 

  • Keay KA, Monassi CR, Levison DB, Bandler R (2004) Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain? Neurosci Lett 361(1–3):188–191

    CAS  PubMed  Google Scholar 

  • Khangura RK, Bali A, Kaur G, Singh N, Jaggi AS (2017) Neuropathic pain attenuating effects of perampanel in an experimental model of chronic constriction injury in rats. Biomed Pharmacother 94:557–563

    CAS  PubMed  Google Scholar 

  • Liu S, Li Q, Zhang MT, Mao-Ying QL, Hu LY, Wu GC, Mi WL, Wang YQ (2016) Curcumin ameliorates neuropathic pain by down-regulating spinal IL-1β via suppressing astroglial NALP1 inflammasome and JAK2-STAT3 signalling. Sci Rep 6:28956–28956

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Zhou LJ, Wang J, Li D, Ren WJ, Peng J, Wei X, Xu T, Xin WJ, Pang RP, Li YY, Qin ZH, Murugan M, Mattson MP, Wu LJ, Liu XG (2017) TNF-α differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci 37(4):871–881

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mai CL et al (2019) Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury. Mol Pain 15:1744806919826789

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mirzaie Z, Ansari M, Kordestani SS, Rezaei MH, Mozafari M (2019) Preparation and characterization of curcumin-loaded polymeric nanomicelles to interference with amyloidogenesis through glycation method. Biotechnol Appl Biochem 66(4):537–544

    CAS  PubMed  Google Scholar 

  • Nasirinezhad F, Saffarpour S (2009) Involvement of NMDA receptors in antinociceptive effect of ascorbic acid in a neuropathic pain model. RJMS 15(0):193–204

    Google Scholar 

  • Qian Y et al (2019) The role of CaMKII in neuropathic pain and fear memory in chronic constriction injury in rats. Int J Neurosci 129(2):146–154

    PubMed  Google Scholar 

  • Rahn EJ, Guzman-Karlsson MC, David Sweatt J (2013) Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem 105:133–150

    PubMed  PubMed Central  Google Scholar 

  • Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Kandimalla R, Kuruva CS (2016) Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer’s disease. J Investig Med 64(8):1220–1234

    PubMed  PubMed Central  Google Scholar 

  • Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Tonk S, Kuruva CS, Bhatti JS, Kandimalla R, Vijayan M, Kumar S, Wang R, Pradeepkiran JA, Ogunmokun G, Thamarai K, Quesada K, Boles A, Reddy AP (2018) Protective effects of Indian spice curcumin against amyloid-β in Alzheimer’s disease. J Alzheimers Dis 61(3):843–866

    PubMed  PubMed Central  Google Scholar 

  • Ren WJ, Liu Y, Zhou LJ, Li W, Zhong Y, Pang RP, Xin WJ, Wei XH, Wang J, Zhu HQ, Wu CY, Qin ZH, Liu G, Liu XG (2011) Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-α in rodents. Neuropsychopharmacology 36(5):979–992

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenberger DC et al (2020) Challenges of neuropathic pain: focus on diabetic neuropathy. Journal of neural transmission (Vienna, Austria: 1996) 127(4):589–624

    Google Scholar 

  • Saffarpour S, Shaabani M, Naghdi N, Farahmandfar M, Janzadeh A, Nasirinezhad F (2017) In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain. Physiol Behav 175:97–103

    CAS  PubMed  Google Scholar 

  • Scholz J, Finnerup NB, Attal N, Aziz Q, Baron R, Bennett MI, Benoliel R, Cohen M, Cruccu G, Davis KD, Evers S, First M, Giamberardino MA, Hansson P, Kaasa S, Korwisi B, Kosek E, Lavandʼhomme P, Nicholas M, Nurmikko T, Perrot S, Raja SN, Rice ASC, Rowbotham MC, Schug S, Simpson DM, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ, Barke A, Rief W, Treede RD (2019) The IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain 160(1):53–59

    PubMed  PubMed Central  Google Scholar 

  • Sepideh S, Farinaz N (2020) The CA1 hippocampal serotonin alterations involved in anxiety-like behavior induced by sciatic nerve injury in rats. Scand J Pain (0):000010151520200037

  • Sommer C, Leinders M, Üçeyler N (2018) Inflammation in the pathophysiology of neuropathic pain. Pain 159(3):595–602

    CAS  PubMed  Google Scholar 

  • Sumitani M, Sakai T, Matsuda Y, Abe H, Yamaguchi S, Hosokawa T, Fukui S (2018) Executive summary of the clinical guidelines of pharmacotherapy for neuropathic pain: second edition by the Japanese Society of Pain Clinicians. J Anesth 32(3):463–478

    PubMed  PubMed Central  Google Scholar 

  • Tomas Pereira I, Burwell RD (2015) Using the spatial learning index to evaluate performance on the water maze. Behav Neurosci 129(4):533–539

    PubMed  Google Scholar 

  • Tyrtyshnaia A, Manzhulo I, Kipryushina Y, Ermolenko E (2019) Neuroinflammation and adult hippocampal neurogenesis in neuropathic pain and alkyl glycerol ethers treatment in aged mice. Int J Mol Med 43(5):2153–2163

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vo T, Rice AS, Dworkin RH (2009) Non-steroidal anti-inflammatory drugs for neuropathic pain: how do we explain continued widespread use? Pain 143(3):169–171

    PubMed  Google Scholar 

  • Wang XM, Zhang GF, Jia M, Xie ZM, Yang JJ, Shen JC, Zhou ZQ (2019) Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4. Psychopharmacology 236(7):1999–2014

    CAS  PubMed  Google Scholar 

  • Wright ME, Rizzolo D (2017) An update on the pharmacologic management and treatment of neuropathic pain. Jaapa 30(3):13–17

    PubMed  Google Scholar 

  • Xie W, Xie W, Kang Z, Jiang C, Liu N (2019) Administration of curcumin alleviates neuropathic pain in a rat model of brachial plexus avulsion. Pharmacology 103(5–6):324–332

    CAS  PubMed  Google Scholar 

  • Yalcin I, Barthas F, Barrot M (2014) Emotional consequences of neuropathic pain: insight from preclinical studies. Neurosci Biobehav Rev 47:154–164

    PubMed  Google Scholar 

  • Yavarpour-Bali H, Ghasemi-Kasman M, Pirzadeh M (2019) Curcumin-loaded nanoparticles: a novel therapeutic strategy in treatment of central nervous system disorders. Int J Nanomedicine 14:4449–4460

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Ding X, Wu Z, Wang M, Tian M (2018) Curcumin alleviates pain and improves cognitive impairment in a rat model of cobra venom-induced trigeminal neuralgia. J Pain Res 11:1095–1104

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Wang C, Zhang JF, Liu L, Liu AM, Ma Q, Zhou WH, Xu Y (2014) Chronic curcumin treatment normalizes depression-like behaviors in mice with mononeuropathy: involvement of supraspinal serotonergic system and GABAA receptor. Psychopharmacology 231(10):2171–2187

    CAS  PubMed  Google Scholar 

  • Zhao S, Yang J, Han X, Gong Y, Rao S, Wu B, Yi Z, Zou L, Jia T, Li L, Yuan H, Shi L, Zhang C, Gao Y, Li G, Liu S, Xu H, Liu H, Liang S (2017) Effects of nanoparticle-encapsulated curcumin on HIV-gp120-associated neuropathic pain induced by the P2X3 receptor in dorsal root ganglia. Brain Res Bull 135:53–61

    CAS  PubMed  Google Scholar 

  • Zhu Q et al (2014a) Antinociceptive effects of curcumin in a rat model of postoperative pain. Sci Rep 4:4932–4932

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu X, Li Q, Chang R, Yang D, Song Z, Guo Q, Huang C (2014b) Curcumin alleviates neuropathic pain by inhibiting p300/CBP histone acetyltransferase activity-regulated expression of BDNF and cox-2 in a rat model. PLoS One 9(3):e91303

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors appreciate Mr. A. Razhaghdoust who presented the nanocurcumin from Exire Nano Sina Co. as a generous gift to them.

Funding

This experiment received grant from the Physiology Research Center of Iran University of Medical Science (Grant number: 97-4-32-13617).

Author information

Affiliations

  1. Physiology Research Center, Department of Physiology, Iran University of Medical Sciences, Tehran, Islamic Republic of Iran

    Sepideh Saffarpour, Behnaz Rahimi, Fatemeh Ramezani & Farinaz Nasirinezhad

  2. Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran

    Sepideh Saffarpour

  3. Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran

    Atousa Janzadeh

Authors
  1. Sepideh Saffarpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atousa Janzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Behnaz Rahimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fatemeh Ramezani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Farinaz Nasirinezhad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Farinaz Nasirinezhad.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Highlights

The goal of this study was to investigate the effects of chronic nanocurcumin treatment on neuropathic pain-related behaviors and spatial learning and memory performance in the CCI model of rats and illuminate the relative IL-1β and TNF-α level alteration in the hippocampus.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saffarpour, S., Janzadeh, A., Rahimi, B. et al. Chronic nanocurcumin treatment ameliorates pain-related behavior, improves spatial memory, and reduces hippocampal levels of IL-1β and TNFα in the chronic constriction injury model of neuropathic pain. Psychopharmacology 238, 877–886 (2021). https://doi.org/10.1007/s00213-020-05739-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-020-05739-x

Keywords

  • Neuropathic pain
  • Nanocurcumin
  • Spatial memory, Hippocampus
  • IL-1β,TNF-α