Skip to main content

Advertisement

SpringerLink
Log in

Toll-like Receptor 2-Melatonin Feedback Loop Regulates the Activation of Spinal NLRP3 Inflammasome in Morphine-Tolerant Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Background and Purpose: Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. Methods: Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. Key Results: Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. Conclusion: In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance.

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

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Fields HL (2011) The doctor’s dilemma: opiate analgesics and chronic pain. Neuron 69(4):591–594. https://doi.org/10.1016/j.neuron.2011.02.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Abdel-Zaher AO, Mostafa MG, Farghaly HS, Hamdy MM, Abdel-Hady RH (2013) Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid. Behav Brain Res 247:17–26. https://doi.org/10.1016/j.bbr.2013.02.034

    Article  PubMed  CAS  Google Scholar 

  3. Kong H, Jiang CY, Hu L, Teng P, Zhang Y, Pan XX, Sun XD, Liu WT (2019) Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance. J Mol Cell Biol 11(12):1056–1068. https://doi.org/10.1093/jmcb/mjz002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Dang VC, Christie MJ (2012) Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol 165(6):1704–1716. https://doi.org/10.1111/j.1476-5381.2011.01482.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Chao PK, Chang HF, Ou LC, Chuang JY, Lee PT, Chang WT, Chen SC, Ueng SH, Hsu JT, Tao PL, Law PY, Loh HH, Yeh SH (2019) Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice. Sci Rep 9(1):2405. https://doi.org/10.1038/s41598-019-39555-x

    Article  PubMed  PubMed Central  Google Scholar 

  6. Eidson LN, Murphy AZ (2019) Inflammatory mediators of opioid tolerance: implications for dependency and addiction. Peptides 115:51–58. https://doi.org/10.1016/j.peptides.2019.01.003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR (2004) A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24(33):7353–7365. https://doi.org/10.1523/JNEUROSCI.1850-04.2004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zhang H, Li F, Li WW, Stary C, Clark JD, Xu S, Xiong X (2016) The inflammasome as a target for pain therapy. Br J Anaesth 117(6):693–707. https://doi.org/10.1093/bja/aew376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Heneka MT, McManus RM, Latz E (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19(10):610–621. https://doi.org/10.1038/s41583-018-0055-7

    Article  PubMed  CAS  Google Scholar 

  10. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426. https://doi.org/10.1016/s1097-2765(02)00599-3

    Article  PubMed  CAS  Google Scholar 

  11. Kim JJ, Jo EK (2013) NLRP3 inflammasome and host protection against bacterial infection. J Korean Med Sci 28(10):1415–1423. https://doi.org/10.3346/jkms.2013.28.10.1415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Wang H, Huang M, Wang W, Zhang Y, Ma X, Luo L, Xu X, Xu L, Shi H, Xu Y, Wang A, Xu T (2021) Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance. Pharmacol Res 165:105482. https://doi.org/10.1016/j.phrs.2021.105482

    Article  PubMed  CAS  Google Scholar 

  13. Cai Y, Kong H, Pan YB, Jiang L, Pan XX, Hu L, Qian YN, Jiang CY, Liu WT (2016) Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. J Neuroinflammation 13(1):53. https://doi.org/10.1186/s12974-016-0520-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Zhang HM, Zhang Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57(2):131–146. https://doi.org/10.1111/jpi.12162

    Article  PubMed  CAS  Google Scholar 

  15. Zisapel N (2018) New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol 175(16):3190–3199. https://doi.org/10.1111/bph.14116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hardeland R (2018) Melatonin and inflammation-story of a double-edged blade. J Pineal Res 65(4):e12525. https://doi.org/10.1111/jpi.12525

    Article  PubMed  CAS  Google Scholar 

  17. Yuan H, Wu G, Zhai X, Lu B, Meng B, Chen J (2019) Melatonin and rapamycin attenuate Isoflurane-Induced Cognitive Impairment through Inhibition of Neuroinflammation by suppressing the mTOR Signaling in the Hippocampus of aged mice. Front Aging Neurosci 11:314. https://doi.org/10.3389/fnagi.2019.00314

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Arioz BI, Tastan B, Tarakcioglu E, Tufekci KU, Olcum M, Ersoy N, Bagriyanik A, Genc K, Genc S (2019) Melatonin attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway. Front Immunol 10:1511. https://doi.org/10.3389/fimmu.2019.01511

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Wu HM, Zhao CC, Xie QM, Xu J, Fei GH (2020) TLR2-Melatonin feedback Loop regulates the activation of NLRP3 inflammasome in Murine allergic airway inflammation. Front Immunol 11:172. https://doi.org/10.3389/fimmu.2020.00172

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Schilling S, Chausse B, Dikmen HO, Almouhanna F, Hollnagel JO, Lewen A, Kann O (2021) TLR2- and TLR3-activated microglia induce different levels of neuronal network dysfunction in a context-dependent manner. Brain Behav Immun 96:80–91. https://doi.org/10.1016/j.bbi.2021.05.013

    Article  PubMed  CAS  Google Scholar 

  21. Gill R, Tsung A, Billiar T (2010) Linking oxidative stress to inflammation: toll-like receptors. Free Radic Biol Med 48(9):1121–1132. https://doi.org/10.1016/j.freeradbiomed.2010.01.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kopiasz L, Dziendzikowska K, Gajewska M, Oczkowski M, Majchrzak-Kuligowska K, Krolikowski T, Gromadzka-Ostrowska J (2021) Effects of Dietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs and Dectin-1 Signaling Pathways-Crohn’s Disease Model Study. Nutrients 13(2). https://doi.org/10.3390/nu13020321

  23. Milanesi S, Verzola D, Cappadona F, Bonino B, Murugavel A, Pontremoli R, Garibotto G, Viazzi F (2019) Uric acid and angiotensin II additively promote inflammation and oxidative stress in human proximal tubule cells by activation of toll-like receptor 4. J Cell Physiol 234(7):10868–10876. https://doi.org/10.1002/jcp.27929

    Article  PubMed  CAS  Google Scholar 

  24. Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T, Wang F, Oh SB, Ji RR (2015) Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med 21(11):1326–1331. https://doi.org/10.1038/nm.3978

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Lacagnina MJ, Watkins LR, Grace PM (2018) Toll-like receptors and their role in persistent pain. Pharmacol Ther 184:145–158. https://doi.org/10.1016/j.pharmthera.2017.10.006

    Article  PubMed  CAS  Google Scholar 

  26. Chen J, Wang G, Sun T, Ma C, Huo X, Kong Y (2021) Involvement of TCF7L2 in generation of morphine-induced antinociceptive tolerance and hyperalgesia by modulating TLR4/ NF-kappaB/NLRP3 in microglia. Toxicol Appl Pharmacol 416:115458. https://doi.org/10.1016/j.taap.2021.115458

    Article  PubMed  CAS  Google Scholar 

  27. Qu J, Tao XY, Teng P, Zhang Y, Guo CL, Hu L, Qian YN, Jiang CY, Liu WT (2017) Blocking ATP-sensitive potassium channel alleviates morphine tolerance by inhibiting HSP70-TLR4-NLRP3-mediated neuroinflammation. J Neuroinflammation 14(1):228. https://doi.org/10.1186/s12974-017-0997-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924. https://doi.org/10.4049/jimmunol.173.6.3916

    Article  PubMed  CAS  Google Scholar 

  29. Fan L, Xu C, Ge Q, Lin Y, Wong CC, Qi Y, Ye B, Lian Q, Zhuo W, Si J, Chen S, Wang L (2021) Muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-Mediated M1-Like TAMs. Cancer Immunol Res 9(10):1111–1124. https://doi.org/10.1158/2326-6066.CIR-20-1019

    Article  PubMed  CAS  Google Scholar 

  30. Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, Chen PX, Feng JQ (2008) A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 22(1):114–123. https://doi.org/10.1016/j.bbi.2007.07.014

    Article  PubMed  CAS  Google Scholar 

  31. Lin SH, Huang YN, Kao JH, Tien LT, Tsai RY, Wong CS (2016) Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression. Life Sci 152:38–43. https://doi.org/10.1016/j.lfs.2016.03.032

    Article  PubMed  CAS  Google Scholar 

  32. Lin F, Shan W, Zheng Y, Pan L, Zuo Z (2021) Toll-like receptor 2 activation and up-regulation by high mobility group box-1 contribute to post-operative neuroinflammation and cognitive dysfunction in mice. J Neurochem 158(2):328–341. https://doi.org/10.1111/jnc.15368

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Liu D, Zhou Y, Peng Y, Su P, Li Z, Xu Q, Tu Y, Tian X, Yang H, Wu Z, Mei W, Gao F (2018) Endoplasmic reticulum stress in spinal cord contributes to the development of Morphine Tolerance. Front Mol Neurosci 11:72. https://doi.org/10.3389/fnmol.2018.00072

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Jurga AM, Rojewska E, Piotrowska A, Makuch W, Pilat D, Przewlocka B, Mika J (2016) Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model, Neural Plast (2016) 5238730.https://doi.org/10.1155/2016/5238730

  35. Yang H, Wu L, Deng H, Chen Y, Zhou H, Liu M, Wang S, Zheng L, Zhu L, Lv X (2020) Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-kappaB signaling pathway in spinal microglia. J Neuroinflammation 17(1):154. https://doi.org/10.1186/s12974-020-1731-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Wang X, Tian S, Wang H, Liu P, Zheng H, Wu L, Liu Q, Wu W (2020) Botulinum toxin type a alleviates neuropathic pain and suppresses inflammatory cytokines release from microglia by targeting TLR2/MyD88 and SNAP23. Cell Biosci 10(1):141. https://doi.org/10.1186/s13578-020-00501-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Zhang L, Meng J, Ban Y, Jalodia R, Chupikova I, Fernandez I, Brito N, Sharma U, Abreu MT, Ramakrishnan S, Roy S (2019) Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome. Proc Natl Acad Sci U S A 116(27):13523–13532. https://doi.org/10.1073/pnas.1901182116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Thomas JHL, Lui L, Abell A, Tieu W, Somogyi AA, Bajic JE, Hutchinson MR (2022) Toll-like receptors change morphine-induced antinociception, tolerance and dependence: studies using male and female TLR and signalling gene KO mice. Brain Behav Immun 102:71–85. https://doi.org/10.1016/j.bbi.2022.02.001

    Article  PubMed  CAS  Google Scholar 

  39. Kwilasz AJ, Todd LS, Duran-Malle JC, Schrama AEW, Mitten EH, Larson TA, Clements MA, Harris KM, Litwiler ST, Wang X, Van Dam AM, Maier SF, Rice KC, Watkins LR, Barrientos RM (2021) Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone. Behav Brain Res 396:112896. https://doi.org/10.1016/j.bbr.2020.112896

    Article  PubMed  CAS  Google Scholar 

  40. Wang L, Yang HY, Zang CX, Shang JM, Liu H, Zhang ZH, Yuan FY, Ju C, Li FY, Bao XQ, Zhang D (2021) TLR2 potentiates SR-Marco-Mediated neuroinflammation by interacting with the SRCR Domain. Mol Neurobiol 58(11):5743–5755. https://doi.org/10.1007/s12035-021-02463-1

    Article  PubMed  CAS  Google Scholar 

  41. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ (2013) Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65(1):223–254. https://doi.org/10.1124/pr.112.005942

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Gurley C, Nichols J, Liu S, Phulwani NK, Esen N, Kielian T (2008) Microglia and astrocyte activation by toll-like receptor ligands: modulation by PPAR-gamma agonists. PPAR Res 2008:453120. https://doi.org/10.1155/2008/453120

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gong X, Chen Y, Chang J, Huang Y, Cai M, Zhang M (2018) Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury. J Neuroinflammation 15(1):262. https://doi.org/10.1186/s12974-018-1301-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Inta D, Lang UE, Borgwardt S, Meyer-Lindenberg A, Gass P (2017) Microglia activation and Schizophrenia: Lessons from the Effects of Minocycline on postnatal neurogenesis, neuronal survival and synaptic pruning. Schizophr Bull 43(3):493–496. https://doi.org/10.1093/schbul/sbw088

    Article  PubMed  Google Scholar 

  45. Liu Q, Su LY, Sun C, Jiao L, Miao Y, Xu M, Luo R, Zuo X, Zhou R, Zheng P, Xiong W, Xue T, Yao YG (2020) Melatonin alleviates morphine analgesic tolerance in mice by decreasing NLRP3 inflammasome activation. Redox Biol 34:101560. https://doi.org/10.1016/j.redox.2020.101560

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Derangula K, Javalgekar M, Kumar Arruri V, Gundu C, Kumar Kalvala A, Kumar A (2022) Probucol attenuates NF-kappaB/NLRP3 signalling and augments Nrf-2 mediated antioxidant defence in nerve injury induced neuropathic pain. Int Immunopharmacol 102:108397. https://doi.org/10.1016/j.intimp.2021.108397

    Article  PubMed  CAS  Google Scholar 

  47. Ahmed S, Kwatra M, Ranjan Panda S, Murty USN, Naidu VGM (2021) Andrographolide suppresses NLRP3 inflammasome activation in microglia through induction of parkin-mediated mitophagy in in-vitro and in-vivo models of Parkinson disease. Brain Behav Immun 91:142–158. https://doi.org/10.1016/j.bbi.2020.09.017

    Article  PubMed  CAS  Google Scholar 

  48. Tian L, Yan J, Li K, Zhang W, Lin B, Lai W, Bian L, Liu H, Xi Z, Liu X (2021) Ozone exposure promotes pyroptosis in rat lungs via the TLR2/4-NF-kappaB-NLRP3 signaling pathway. Toxicology 450:152668. https://doi.org/10.1016/j.tox.2020.152668

    Article  PubMed  CAS  Google Scholar 

  49. Duffy EB, Periasamy S, Hunt D, Drake JR, Harton JA (2016) FcgammaR mediates TLR2- and syk-dependent NLRP3 inflammasome activation by inactivated Francisella tularensis LVS immune complexes. J Leukoc Biol 100(6):1335–1347. https://doi.org/10.1189/jlb.2A1215-555RR

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Wen YR, Tan PH, Cheng JK, Liu YC, Ji RR (2011) Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc 110(8):487–494. https://doi.org/10.1016/S0929-6646(11)60074-0

    Article  PubMed  PubMed Central  Google Scholar 

  51. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM (2020) Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules 10(9). https://doi.org/10.3390/biom10091211

  52. Gonzalez-Gonzalez A, Garcia Nieto E, Gonzalez A, Sanchez-Fernandez C, Alonso-Gonzalez C, Menendez-Menendez J, Gomez-Arozamena J, Cos S (2019) Martinez-Campa, Melatonin Modulation of Radiation and Chemotherapeutics-induced changes on differentiation of breast fibroblasts. Int J Mol Sci 20(16). https://doi.org/10.3390/ijms20163935

  53. Liu W, Yu M, Xie D, Wang L, Ye C, Zhu Q, Liu F, Yang L (2020) Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Res Ther 11(1):259. https://doi.org/10.1186/s13287-020-01756-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Song L, Wu C, Zuo Y (2015) Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-D-aspartate receptors. BMC Anesthesiol 15:12. https://doi.org/10.1186/1471-2253-15-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Luo J, Song J, Zhang H, Zhang F, Liu H, Li L, Zhang Z, Chen L, Zhang M, Lin D, Lin M, Zhou R (2018) Melatonin mediated Foxp3-downregulation decreases cytokines production via the TLR2 and TLR4 pathways in H. pylori infected mice. Int Immunopharmacol 64:116–122. https://doi.org/10.1016/j.intimp.2018.08.034

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

We would like to thank the National Natural Science Foundation of China (Grant no. 81974168) for their support in this research.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China

    Xiaoling Peng, Jihong Wang, Zheng Li, Xiaoqian Jia, Anqi Zhang, Jie Ju & Feng Gao

  2. Department for Translational Anaesthesiology and Intensive Care Medicine, Medical Faculty University of Augsburg, 86156, Augsburg, Germany

    Volker Eulenburg

Authors
  1. Xiaoling Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jihong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoqian Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anqi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Volker Eulenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Feng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xiaoling Peng wrote the main manuscript text. Jihong Wang and Zheng Li prepared Figs. 1 and 2. Xiaoqian Jia, Anqi Zhang and Jie Ju prepared Figs. 3, 4 and 5. Volker Eulenburg and Feng Gao revised and edited the manuscript.

Corresponding authors

Correspondence to Volker Eulenburg or Feng Gao.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Conflict of Interest

The authors declare that they have no conflict of financial interest or benefit. Informed consent was obtained from all individual participants included in the study.

Ethical Approval

The animal research was approved by the Animal Experimental Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Ethics Approval Number: TJH-202007007).

Additional information

Publisher’s Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peng, X., Wang, J., Li, Z. et al. Toll-like Receptor 2-Melatonin Feedback Loop Regulates the Activation of Spinal NLRP3 Inflammasome in Morphine-Tolerant Rats. Neurochem Res 48, 3597–3609 (2023). https://doi.org/10.1007/s11064-023-03998-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-023-03998-6

Keywords

Search

Navigation