Abstract
Traditional opioids have proven analgesic effects in clinical applications but are also associated with side effects, especially hyperalgesia. Reducing the occurrence of hyperalgesia is part of effective clinical pain management. In this study, we investigated the difference between MEL-0614, a novel endomorphin analog that can effectively penetrate the blood–brain barrier, and morphine in inducing hyperalgesia. Under mechanical and thermal stimulation conditions, intravenous administration of morphine led to hyperalgesia even at low concentrations, which was not observed with MEL-0614 even at high concentrations. In a spared nerve injury model, significantly less aggravation of allodynia was caused by an intravenous injection of MEL-0614 compared with that caused by morphine, and the allodynia symptoms occurred later. Notably, MEL-0614 significantly relieved the symptoms of morphine-induced allodynia. The activation of N-methyl-d-aspartic acid receptor and expression of inflammatory mediators differed in spinal microglia after intravenous injections of MEL-0614 and morphine. Intravenous injections of morphine induced increases in the number of microglia and overexpression of inflammatory factors, including tumor necrotic factor and interleukin-1β. Conversely, the effects of MEL-0614 administration did not differ from those of saline, and there was no inflammatory mediator overexpression. Especially in the spared nerve injury model, the cross-administration of morphine and MEL-0614 could reduce the expression of Toll-like receptor 4 and other related genes to different degrees compared with the use of morphine alone. Concurrently, the results could also explain the alleviating effect of MEL-0614 on morphine-induced pain sensitivity in behavioral experiments. Our findings may provide important information regarding the clinical treatment of neuropathic pain in the future.
This is a preview of subscription content, log in via an institution to check access.
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.
Abbreviations
- ANOVA:
-
Analysis of variance
- AUC:
-
Area under the curve
- BBB:
-
Blood–brain barrier
- BDNF:
-
Brain-derived growth factor
- EMs:
-
Endomorphins
- IV:
-
Intravenous
- IL-1β:
-
Interleukin-1β
- NMDA:
-
N-methyl-d-aspartic acid
- P2X7R:
-
P2X receptor 7
- qPCR:
-
Quantitative PCR
- SNI:
-
Spared nerve injury
- TLR4:
-
Toll-like receptor 4
- TNF-α:
-
Tumor necrosis factor-α
- WT:
-
Withdrawal threshold
References
Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, Nassar MA, Dickenson AH, Wood JN (2008) The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321:702–705. https://doi.org/10.1126/science.1156916
Bodnar RJ (2021) Endogenous opiates and behavior: 2019. Peptides 141:170547. https://doi.org/10.1016/j.peptides.2021.170547
Bonin RP, Bories C, De Koninck Y (2014) A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments. Mol Pain 10:26. https://doi.org/10.1186/1744-8069-10-26
Chaves C, Remiao F, Cisternino S, Decleves X (2017) Opioids and the blood–brain barrier: a dynamic interaction with consequences on drug disposition in brain. Curr Neuropharmacol 15:1156–1173. https://doi.org/10.2174/1570159X15666170504095823
Compton PA, Wasser TE, Cheatle MD (2020) Increased experimental pain sensitivity in chronic pain patients who developed opioid use disorder. Clin J Pain 36:667–674. https://doi.org/10.1097/AJP.0000000000000855
Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR, Sotoudeh C, Clark JD, Barres BA, Bohlen CJ, Scherrer G (2017) Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med 23:164–173. https://doi.org/10.1038/nm.4262
Cui JM, Zhao L, Wang ZJ, Ma MT, Wang Y, Luo KY, Wang LQ, Wei S, Zhang XH, Han CZ, Liu X, Wang R (2020) MEL endomorphins act as potent inflammatory analgesics with the inhibition of activated non-neuronal cells and modulation of pro-inflammatory cytokines. Neuropharmacology 168:107992. https://doi.org/10.1016/j.neuropharm.2020.107992
da Cunha Leal P, Clivatti J, Garcia JB, Sakata RK (2010) Opioid-induced hyperalgesia (OIH). Rev Bras Anestesiol 60(639–647):355–639. https://doi.org/10.1016/S0034-7094(10)70080-5
De Marco R, Janecka A (2015) Strategies to improve bioavailability and in vivo efficacy of the endogenous opioid peptides endomorphin-1 and endomorphin-2. Curr Top Med Chem 16:141–155. https://doi.org/10.2174/1568026615666150817103635
Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149–158. https://doi.org/10.1016/S0304-3959(00)00276-1
Elhabazi K, Ayachi S, Ilien B, Simonin F (2014) Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities. J Vis Exp. https://doi.org/10.3791/51264
Fletcher D, Martinez V (2014) Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 112:991–1004. https://doi.org/10.1093/bja/aeu137
Gong K, Bhargava A, Jasmin L (2016) GluN2B N-methyl-d-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats: implication for opiate-induced hyperalgesia. Pain 157:147–158. https://doi.org/10.1097/j.pain.0000000000000342
Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, Fabisiak TJ, Anderson ND, Cheng K, Greene LI, Berkelhammer D, Zhang Y, Ellis AL, Yin HH, Campeau S, Rice KC, Roth BL, Maier SF, Watkins LR (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci USA 113:E3441-3450. https://doi.org/10.1073/pnas.1602070113
Gu X, Wu X, Liu Y, Cui S, Ma Z (2009) Tyrosine phosphorylation of the N-methyl-d-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine. Mol Pain 5:76. https://doi.org/10.1186/1744-8069-5-76
Gu ZH, Wang B, Kou ZZ, Bai Y, Chen T, Dong YL, Li H, Li YQ (2017) Endomorphins: promising endogenous opioid peptides for the development of novel analgesics. Neurosignals 25:98–116. https://doi.org/10.1159/000484909
Hahnenkamp K, Nollet J, Van Aken HK, Buerkle H, Halene T, Schauerte S, Hahnenkamp A, Hollmann MW, Strumper D, Durieux ME, Hoenemann CW (2004) Remifentanil directly activates human N-methyl-d-aspartate receptors expressed in Xenopus laevis oocytes. Anesthesiology 100:1531–1537. https://doi.org/10.1097/00000542-200406000-00028
Huang M, Luo L, Zhang Y, Wang W, Dong J, Du W, Jiang W, Xu T (2019) Metabotropic glutamate receptor 5 signalling induced NMDA receptor subunits alterations during the development of morphine-induced antinociceptive tolerance in mouse cortex. Biomed Pharmacother 110:717–726. https://doi.org/10.1016/j.biopha.2018.12.042
Inoue K, Tsuda M (2018) Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19:138–152. https://doi.org/10.1038/nrn.2018.2
Jensen TS, Finnerup NB (2014) Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol 13:924–935. https://doi.org/10.1016/S1474-4422(14)70102-4
Juni A, Cai M, Stankova M, Waxman AR, Arout C, Klein G, Dahan A, Hruby VJ, Mogil JS, Kest B (2010) Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor. Anesthesiology 112:181–188. https://doi.org/10.1097/ALN.0b013e3181c53849
Khan F, Mehan A (2021) Addressing opioid tolerance and opioid-induced hypersensitivity: recent developments and future therapeutic strategies. Pharmacol Res Perspect 9:e00789. https://doi.org/10.1002/prp2.789
Kim SH, Stoicea N, Soghomonyan S, Bergese SD (2015) Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review. Am J Ther 22:e62-74. https://doi.org/10.1097/MJT.0000000000000019
Kohno K, Tsuda M (2021) Role of microglia and P2X4 receptors in chronic pain. Pain Rep 6:e864. https://doi.org/10.1097/PR9.0000000000000864
Koller G, Schwarzer A, Halfter K, Soyka M (2019) Pain management in opioid maintenance treatment. Expert Opin Pharmacother 20:1993–2005. https://doi.org/10.1080/14656566.2019.1652270
Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L (2011) A comprehensive review of opioid-induced hyperalgesia. Pain Physician 14:145–161
Liu X, Wang Y, Xing Y, Yu J, Ji H, Kai M, Wang Z, Wang D, Zhang Y, Zhao D, Wang R (2013) Design, synthesis, and pharmacological characterization of novel endomorphin-1 analogues as extremely potent mu-opioid agonists. J Med Chem 56:3102–3114. https://doi.org/10.1021/jm400195y
Loram LC, Grace PM, Strand KA, Taylor FR, Ellis A, Berkelhammer D, Bowlin M, Skarda B, Maier SF, Watkins LR (2012) Prior exposure to repeated morphine potentiates mechanical allodynia induced by peripheral inflammation and neuropathy. Brain Behav Immun 26:1256–1264. https://doi.org/10.1016/j.bbi.2012.08.003
Ma M, Wang Z, Wang J, Wei S, Cui J, Wang Y, Luo K, Zhao L, Liu X, Wang R (2020) Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors. J Neurochem 155:662–678. https://doi.org/10.1111/jnc.15127
MacDonald DI, Wood JN, Emery EC (2020) Molecular mechanisms of cold pain. Neurobiol Pain 7:100044. https://doi.org/10.1016/j.ynpai.2020.100044
Malcangio M (2017) Spinal mechanisms of neuropathic pain: is there a P2X4-BDNF controversy? Neurobiol Pain 1:1–5. https://doi.org/10.1016/j.ynpai.2017.04.001
Mercadante S, Arcuri E, Santoni A (2019) Opioid-induced tolerance and hyperalgesia. CNS Drugs 33:943–955. https://doi.org/10.1007/s40263-019-00660-0
Przewlocki R, Labuz D, Mika J, Przewlocka B, Tomboly C, Toth G (1999) Pain inhibition by endomorphins. Ann N Y Acad Sci 897:154–164. https://doi.org/10.1111/j.1749-6632.1999.tb07887.x
Richner M, Bjerrum OJ, Nykjaer A, Vaegter CB (2011) The spared nerve injury (SNI) model of induced mechanical allodynia in mice. J Vis Exp. https://doi.org/10.3791/3092
Rivat C, Richebe P, Laboureyras E, Laulin JP, Havouis R, Noble F, Moulinoux JP, Simonnet G (2008) Polyamine deficient diet to relieve pain hypersensitivity. Pain 137:125–137. https://doi.org/10.1016/j.pain.2007.08.021
Roeckel LA, Le Coz GM, Gaveriaux-Ruff C, Simonin F (2016) Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338:160–182. https://doi.org/10.1016/j.neuroscience.2016.06.029
Silverman SM (2009) Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician 12:679–684
Starnowska-Sokol J, Przewlocka B (2020) Multifunctional opioid-derived hybrids in neuropathic pain: preclinical evidence, ideas and challenges. Molecules. https://doi.org/10.3390/molecules25235520
Tumati S, Largent-Milnes TM, Keresztes A, Ren J, Roeske WR, Vanderah TW, Varga EV (2012) Repeated morphine treatment-mediated hyperalgesia, allodynia and spinal glial activation are blocked by co-administration of a selective cannabinoid receptor type-2 agonist. J Neuroimmunol 244:23–31. https://doi.org/10.1016/j.jneuroim.2011.12.021
van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N (2014) Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155:654–662. https://doi.org/10.1016/j.pain.2013.11.013
Varamini P, Toth I (2013) Lipid- and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain. Front Pharmacol 4:155. https://doi.org/10.3389/fphar.2013.00155
Wang Y, Liu X, Wang D, Yang J, Zhao L, Yu J, Wang R (2015) Endomorphin-1 analogues (MELs) penetrate the blood–brain barrier and exhibit good analgesic effects with minimal side effects. Neuropharmacology 97:312–321. https://doi.org/10.1016/j.neuropharm.2015.06.010
Wei S, Han CZ, Wang J, Li K, Ru QM, Wang Y, Ma MT, Wang LQ, Liu X, Wang R (2021) Repeated endomorphin analogue MEL-0614 reduces tolerance and improves chronic postoperative pain without modulating the P2X7R signaling pathway. ACS Chem Neurosci 12:3124–3139. https://doi.org/10.1021/acschemneuro.1c00418
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 110:487–494. https://doi.org/10.1016/S0929-6646(11)60074-0
Yi P, Pryzbylkowski P (2015) Opioid induced hyperalgesia. Pain Med. https://doi.org/10.1111/pme.12914
Zadina JE, Hackler L, Ge LJ, Kastin AJ (1997) A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386:499–502. https://doi.org/10.1038/386499a0
Zhang Y, Ahmed S, Vo T, St Hilaire K, Houghton M, Cohen AS, Mao J, Chen L (2015) Increased pain sensitivity in chronic pain subjects on opioid therapy: a cross-sectional study using quantitative sensory testing. Pain Med 16:911–922. https://doi.org/10.1111/pme.12606
Zhou J, Zhao L, Wei S, Wang Y, Zhang X, Ma M, Wang K, Liu X, Wang R (2021) Contribution of the mu opioid receptor and enkephalin to the antinociceptive actions of endomorphin-1 analogs with unnatural amino acid modifications in the spinal cord. Peptides 141:170543. https://doi.org/10.1016/j.peptides.2021.170543
Acknowledgements
The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (21432003, 21402076 and 81502904), the Program for Chang-Jiang Scholars (IRT_15R27), the Natural Science Foundation of Gansu Province (20JR5RA285, 18JR2RA031), and the Fundamental Research Funds for the Central Universities (561221002, lzujbky-2018-Kb11).
Author information
Authors and Affiliations
Contributions
RW, YW and XL designed the experiments. YW and MM wrote the manuscript. MM, JW, CH, KL, QR, and NL performed experiments. MM calculated the date and prepared the figures. All authors reviewed the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no potential conflict of interests.
Ethical Approval
The experiments conducted in this study met the ethical and moral requirements. To reduce the suffering of animals, each mouse was used only once. All experiments in this study were approved by the ethics committee of Lanzhou University (License Number: SYXK Gan 2009-0005).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Wang, Y., Ma, Mt., Wang, J. et al. Peripheral Administration of an Opioid Peptide Analog Ameliorates Morphine-Produced Hyperalgesia in a Spared Nerve Injury Model. Int J Pept Res Ther 28, 12 (2022). https://doi.org/10.1007/s10989-021-10319-4
Accepted:
Published:
DOI: https://doi.org/10.1007/s10989-021-10319-4