Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens


The benefits of opioid-based treatments to mitigate chronic pain can be hindered by the side effects of opioid-induced hyperalgesia (OIH) that can lead to higher consumption and risk of addiction. The present study advances the understanding of the molecular mechanisms associated with OIH by comparing mice presenting OIH symptoms in response to chronic morphine exposure (OIH treatment) relative to control mice (CON treatment). Using RNA-Seq profiles, gene networks were inferred in the trigeminal ganglia (TG), a central nervous system region associated with pain signaling, and in the nucleus accumbens (NAc), a region associated with reward dependency. The biological process of nucleic acid processing was over-represented among the 122 genes that exhibited a region-dependent treatment effect. Within the 187 genes that exhibited a region-independent treatment effect, circadian rhythm processes were enriched among the genes over-expressed in OIH relative to CON mice. This enrichment was supported by the differential expression of the period circadian clock 2 and 3 genes (Per2 and Per3). Transcriptional regulators in the PAR bZip family that are influenced by the circadian clock and that modulate neurotransmission associated with pain and drug addiction were also over-expressed in OIH relative to CON mice. Also notable was the under-expression in OIH relative to CON mice of the Toll-like receptor, nuclear factor-kappa beta, and interferon gamma genes and enrichment of the adaptive immune processes. The results from the present study offer insights to advance the effective use of opioids for pain management while minimizing hyperalgesia.

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  1. 1.

    Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, Kerns R, Von Korff M et al (2018) Prevalence of chronic pain and high-impact chronic pain among adults—United States, 2016. MMWR Morb Mortal Wkly Rep 67(36):1001–1006. https://doi.org/10.15585/mmwr.mm6736a2

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Breivik H, Eisenberg E, O’Brien T, OPENMinds (2013) The individual and societal burden of chronic pain in Europe: the case for strategic prioritisation and action to improve knowledge and availability of appropriate care. BMC Public Health 13:1229. https://doi.org/10.1186/1471-2458-13-1229

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D (2006) Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 10(4):287–333. https://doi.org/10.1016/j.ejpain.2005.06.009

    PubMed  Article  Google Scholar 

  4. 4.

    Patch Iii RK, Eldrige JS, Moeschler SM, Pingree MJ (2017) Dexmedetomidine as part of a multimodal analgesic treatment regimen for opioid induced hyperalgesia in a patient with significant opioid tolerance. Case Rep Anesthesiol 2017. https://doi.org/10.1155/2017/9876306

  5. 5.

    Hayhurst CJ, Durieux ME (2016) Differential opioid tolerance and opioid-induced hyperalgesia: a clinical reality. Anesthesiology 124(2):483–488. https://doi.org/10.1097/ALN.0000000000000963

    PubMed  Article  Google Scholar 

  6. 6.

    Wanigasekera V, Lee MC, Rogers R, Hu P, Tracey I (2011) Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans. J Neurosci 31(8):2835–2842. https://doi.org/10.1523/JNEUROSCI.5412-10.2011

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Kim SH, Stoicea N, Soghomonyan S, Bergese SD (2015) Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review. Am J Ther 22(3):e62–e74. https://doi.org/10.1097/MJT.0000000000000019

    PubMed  Article  Google Scholar 

  8. 8.

    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

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Johnson EE, Chieng B, Napier I, Connor M (2006) Decreased mu-opioid receptor signalling and a reduction in calcium current density in sensory neurons from chronically morphine-treated mice. Br J Pharmacol 148(7):947–955. https://doi.org/10.1038/sj.bjp.0706820

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Akerman S, Holland PR, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12(10):570–584. https://doi.org/10.1038/nrn3057

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Thalakoti S, Patil VV, Damodaram S, Vause CV, Langford LE, Freeman SE, Durham PL (2007) Neuron–glia signaling in trigeminal ganglion: Implications for migraine pathology. Headache 47(7):1008–1023

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    LaPaglia DM, Sapio MR, Burbelo PD, Thierry-Mieg J, Thierry-Mieg D, Raithel SJ, Ramsden CE, Iadarola MJ et al (2017) RNA-Seq investigations of human post-mortem trigeminal ganglia. Cephalalgia 38:912–932. https://doi.org/10.1177/0333102417720216

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Li JL, Ding YQ, Li YQ, Li JS, Nomura S, Kaneko T, Mizuno N (1998) Immunocytochemical localization of mu-opioid receptor in primary afferent neurons containing substance P or calcitonin gene-related peptide. A light and electron microscope study in the rat. Brain Res 794(2):347–352

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Bellamy J, Bowen EJ, Russo AF, Durham PL (2006) Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosci 23(8):2057–2066

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Burstein R, Jakubowski M (2005) Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol 493(1):9–14

    PubMed  Article  Google Scholar 

  16. 16.

    Chen Y, Yang C, Wang ZJ (2010) Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia. J Neurosci 30(1):38–46. https://doi.org/10.1523/JNEUROSCI.4346-09.2010

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Corder G, Tawfik VL, Wang D, Sypek EI, Low SA, Dickinson JR, Sotoudeh C, Clark JD et al (2017) Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat Med 23(2):164–173. https://doi.org/10.1038/nm.4262

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    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 (89):e51264. https://doi.org/10.3791/51264

  19. 19.

    Liang DY, Shi X, Li X, Li J, Clark JD (2007) The beta2 adrenergic receptor regulates morphine tolerance and physical dependence. Behav Brain Res 181(1):118–126. https://doi.org/10.1016/j.bbr.2007.03.037

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Moye LS, Novack ML, Tipton AF, Krishnan H, Pandey SC, Pradhan AA (2018) The development of a mouse model of mTBI-induced post-traumatic migraine, and identification of the delta opioid receptor as a novel therapeutic target. Cephalalgia. https://doi.org/10.1177/0333102418777507

  21. 21.

    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  Article  Google Scholar 

  22. 22.

    Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA (2016) The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia 36(11):1048–1056. https://doi.org/10.1177/0333102415623070

    PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Moye LS, Pradhan AAA (2017) Animal model of chronic migraine-associated pain. Curr Protoc Neurosci 80:9.60.61–69.60.69. https://doi.org/10.1002/cpns.33

    Article  Google Scholar 

  24. 24.

    Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A (2014) Characterization of a novel model of chronic migraine. PAIN® 155(2):269–274

    CAS  Article  Google Scholar 

  25. 25.

    Jeong H, Moye LS, Southey BR, Hernandez AG, Dripps I, Romanova EV, Rubakhin SS, Sweedler JV et al (2018) Gene network dysregulation in the trigeminal ganglia and nucleus accumbens of a model of chronic migraine-associated hyperalgesia. Front Syst Neurosci 12:63. https://doi.org/10.3389/fnsys.2018.00063

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Andrews S (2010) FastQC: a quality control tool for high throughput sequence data.

    Google Scholar 

  27. 27.

    Pruitt KD, Tatusova T, Maglott DR (2007) NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 35(suppl 1):D61–D65

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Bray NL, Pimentel H, Melsted P, Pachter L (2016) Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol 34(5):525–527

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1):139–140

    CAS  Article  Google Scholar 

  30. 30.

    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol:289–300

  31. 31.

    Caetano-Anollés K, Rhodes JS, Garland T Jr, Perez SD, Hernandez AG, Southey BR, Rodriguez-Zas SL (2016) Cerebellum transcriptome of mice bred for high voluntary activity offers insights into locomotor control and reward-dependent behaviors. PLoS One 11(11):e0167095

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Gonzalez-Pena D, Nixon SE, Southey BR, Lawson MA, McCusker RH, Hernandez AG, Dantzer R, Kelley KW et al (2016) Differential transcriptome networks between IDO1-knockout and wild-type mice in brain microglia and macrophages. PLoS One 11(6):e0157727. https://doi.org/10.1371/journal.pone.0157727

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Gonzalez-Pena D, Nixon SE, O’Connor JC, Southey BR, Lawson MA, McCusker RH, Borras T, Machuca D et al (2016) Microglia transcriptome changes in a model of depressive behavior after immune challenge. PLoS One 11(3):e0150858

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Caetano-Anolles K, Mishra S, Rodriguez-Zas SL (2015) Synergistic and antagonistic interplay between myostatin gene expression and physical activity levels on gene expression patterns in triceps brachii muscles of C57/BL6 mice. PLoS One 10(2):e0116828. https://doi.org/10.1371/journal.pone.0116828

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP (2007) GSEA-P: a desktop application for gene set enrichment analysis. Bioinformatics 23(23):3251–3253

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57

    CAS  Article  Google Scholar 

  37. 37.

    Serao NV, Delfino KR, Southey BR, Beever JE, Rodriguez-Zas SL (2011) Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival. BMC Med Genet 4:49. https://doi.org/10.1186/1755-8794-4-49

    CAS  Article  Google Scholar 

  38. 38.

    Delfino KR, Serao NV, Southey BR, Rodriguez-Zas SL (2011) Therapy-, gender- and race-specific microRNA markers, target genes and networks related to glioblastoma recurrence and survival. Cancer Genomics Proteomics 8(4):173–183

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Delfino KR, Rodriguez-Zas SL (2013) Transcription factor-microRNA-target gene networks associated with ovarian cancer survival and recurrence. PLoS One 8(3):e58608. https://doi.org/10.1371/journal.pone.0058608

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Martin A, Ochagavia M, Rabasa L, Miranda J, Fernandez-de-Cossio J, Bringas R (2010) BisoGenet: a new tool for gene network building, visualization and analysis. BMC Bioinf 11(1):1–9. https://doi.org/10.1186/1471-2105-11-91

    CAS  Article  Google Scholar 

  41. 41.

    Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504. https://doi.org/10.1101/gr.1239303

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Salwinski L, Miller CS, Smith AJ, Pettit FK, Bowie JU, Eisenberg D (2004) The database of interacting proteins: 2004 update. Nucleic Acids Res 32(Database issue):D449–D451. https://doi.org/10.1093/nar/gkh086

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Alfarano C, Andrade CE, Anthony K, Bahroos N, Bajec M, Bantoft K, Betel D, Bobechko B et al (2005) The biomolecular interaction network database and related tools 2005 update. Nucleic Acids Res 33(Database issue):D418–D424. https://doi.org/10.1093/nar/gki051

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M (2006) BioGRID: a general repository for interaction datasets. Nucleic Acids Res 34(Database issue):D535–D539. https://doi.org/10.1093/nar/gkj109

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Licata L, Briganti L, Peluso D, Perfetto L, Iannuccelli M, Galeota E, Sacco F, Palma A et al (2012) MINT, the molecular interaction database: 2012 update. Nucleic Acids Res 40(Database issue):D857–D861. https://doi.org/10.1093/nar/gkr930

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Kerrien S, Alam-Faruque Y, Aranda B, Bancarz I, Bridge A, Derow C, Dimmer E, Feuermann M et al (2007) IntAct—open source resource for molecular interaction data. Nucleic Acids Res 35(Database):D561–D565. https://doi.org/10.1093/nar/gkl958

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Mishra GR, Suresh M, Kumaran K, Kannabiran N, Suresh S, Bala P, Shivakumar K, Anuradha N et al (2006) Human protein reference database—2006 update. Nucleic Acids Res 34(Database issue):D411–D414. https://doi.org/10.1093/nar/gkj141

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Janky R, Verfaillie A, Imrichova H, Van de Sande B, Standaert L, Christiaens V, Hulselmans G, Herten K et al (2014) iRegulon: from a gene list to a gene regulatory network using large motif and track collections. PLoS Comput Biol 10(7):e1003731. https://doi.org/10.1371/journal.pcbi.1003731

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD (2008) Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision. Mol Pain 4:7. https://doi.org/10.1186/1744-8069-4-7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Sarlani E, Balciunas BA, Grace EG (2005) Orofacial pain—part I: assessment and management of musculoskeletal and neuropathic causes. AACN Clin Issues 16(3):333–346

    PubMed  Article  Google Scholar 

  51. 51.

    Grueter BA, Rothwell PE, Malenka RC (2012) Integrating synaptic plasticity and striatal circuit function in addiction. Curr Opin Neurobiol 22(3):545–551. https://doi.org/10.1016/j.conb.2011.09.009

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Gear RW, Levine JD (2011) Nucleus accumbens facilitates nociception. Exp Neurol 229(2):502–506. https://doi.org/10.1016/j.expneurol.2011.03.021

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Cook-Sather SD, Li J, Goebel TK, Sussman EM, Rehman MA, Hakonarson H (2014) TAOK3, a novel genome-wide association study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population. Pain 155(9):1773–1783. https://doi.org/10.1016/j.pain.2014.05.032

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Crowder RJ, Enomoto H, Yang M, Johnson EM Jr, Milbrandt J (2004) Dok-6, a novel p62 Dok family member, promotes Ret-mediated neurite outgrowth. J Biol Chem 279(40):42072–42081. https://doi.org/10.1074/jbc.M403726200

  55. 55.

    Maynard KB, Smith SA, Davis AC, Trivette A, Seipelt-Thiemann RL (2014) Evolutionary analysis of the mammalian M1 aminopeptidases reveals conserved exon structure and gene death. Gene 552(1):126–132. https://doi.org/10.1016/j.gene.2014.09.025

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Osada T, Ikegami S, Takiguchi-Hayashi K, Yamazaki Y, Katoh-Fukui Y, Higashinakagawa T, Sakaki Y et al (1999) Increased anxiety and impaired pain response in puromycin-sensitive aminopeptidase gene-deficient mice obtained by a mouse gene-trap method. J Neurosci 19(14):6068–6078

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Li W, Shi L, You Y, Gong Y, Yin B, Yuan J, Peng X (2010) Downstream of tyrosine kinase/docking protein 6, as a novel substrate of tropomyosin-related kinase C receptor, is involved in neurotrophin 3-mediated neurite outgrowth in mouse cortex neurons. BMC Biol 8:86. https://doi.org/10.1186/1741-7007-8-86

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Tanioka T, Hattori A, Masuda S, Nomura Y, Nakayama H, Mizutani S, Tsujimoto M (2003) Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases. J Biol Chem 278(34):32275–32283. https://doi.org/10.1074/jbc.M305076200

  59. 59.

    Paek J, Kalocsay M, Staus DP, Wingler L, Pascolutti R, Paulo JA, Gygi SP, Kruse AC (2017) Multidimensional tracking of GPCR signaling via peroxidase-catalyzed proximity labeling. Cell 169(2):338–349 e311. https://doi.org/10.1016/j.cell.2017.03.028

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Vo L, Hood S, Drummond PD (2016) Involvement of opioid receptors and alpha2-adrenoceptors in inhibitory pain modulation processes: a double-blind placebo-controlled crossover study. J Pain 17(11):1164–1173. https://doi.org/10.1016/j.jpain.2016.07.004

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Ofte HK, Berg DH, Bekkelund SI, Alstadhaug KB (2013) Insomnia and periodicity of headache in an arctic cluster headache population. Headache 53(10):1602–1612. https://doi.org/10.1111/head.12241

    PubMed  Article  Google Scholar 

  62. 62.

    Bering T, Carstensen MB, Wortwein G, Weikop P, Rath MF (2017) The circadian oscillator of the cerebral cortex: molecular, biochemical and behavioral effects of deleting the Arntl clock gene in cortical neurons. Cereb Cortex. https://doi.org/10.1093/cercor/bhw406

  63. 63.

    Dorsey SG, Leitch CC, Renn CL, Lessans S, Smith BA, Wang XM, Dionne RA (2009) Genome-wide screen identifies drug-induced regulation of the gene giant axonal neuropathy (Gan) in a mouse model of antiretroviral-induced painful peripheral neuropathy. Biol Res Nurs 11(1):7–16. https://doi.org/10.1177/1099800409332726

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Yang Y, Zhang Y, Li XH, Li Y, Qian R, Li J, Xu SL (2015) Involvements of galanin and its receptors in antinociception in nucleus accumbens of rats with inflammatory pain. Neurosci Res 97:20–25. https://doi.org/10.1016/j.neures.2015.03.006

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Grace PM, Maier SF, Watkins LR (2015) Opioid-induced central immune signaling: Implications for opioid analgesia. Headache 55(4):475–489. https://doi.org/10.1111/head.12552

    PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Nousiainen HO, Quintero IB, Myöhänen TT, Voikar V, Mijatovic J, Segerstråle M, Herrala AM, Kulesskaya N et al (2014) Mice deficient in transmembrane prostatic acid phosphatase display increased GABAergic transmission and neurological alterations. PLoS One 9(5):e97851. https://doi.org/10.1371/journal.pone.0097851

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Wang C, Gu L, Ruan Y, Gegen T, Yu L, Zhu C, Yang Y, Zhou Y et al (2018) Pirt together with TRPV1 is involved in the regulation of neuropathic pain. Neural Plast 2018. https://doi.org/10.1155/2018/4861491

  68. 68.

    Capasso KE, Manners MT, Quershi RA, Tian Y, Gao R, Hu H, Barrett JE, Sacan A et al (2015) Effect of histone deacetylase inhibitor JNJ-26481585 in pain. J Mol Neurosci 55(3):570–578. https://doi.org/10.1007/s12031-014-0391-7

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Hong QX, Xu SY, Dai SH, Zhao WX (2016) Expression profiling of spinal genes in peripheral neuropathy model rats with type 2 diabetes mellitus. Int J Clin Exp Med 9(3):6376–6384

    CAS  Google Scholar 

  70. 70.

    Nagy V, Cole T, Van Campenhout C, Khoung TM, Leung C, Vermeiren S, Novatchkova M, Wenzel D et al (2015) The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception. Cell Cycle 14(12):1799–1808. https://doi.org/10.1080/15384101.2015.1036209

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Ray P, Torck A, Quigley L, Wangzhou A, Neiman M, Rao C, Lam T, Kim JY et al (2018) Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research. Pain 159(7):1325–1345. https://doi.org/10.1097/j.pain.0000000000001217

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Buchman VL, Adu J, Pinon LG, Ninkina NN, Davies AM (1998) Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat Neurosci 1(2):101–103. https://doi.org/10.1038/349

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Miyamoto T, Morita K, Takemoto D, Takeuchi K, Kitano Y, Miyakawa T, Nakayama K, Okamura Y et al (2005) Tight junctions in Schwann cells of peripheral myelinated axons: a lesson from claudin-19-deficient mice. J Cell Biol 169(3):527–538. https://doi.org/10.1083/jcb.200501154

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Dacci P, Taroni F, Bella ED, Milani M, Pareyson D, Morbin M, Lauria G (2012) Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy. J Peripher Nerv Syst 17(4):422–425. https://doi.org/10.1111/j.1529-8027.2012.00443.x

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Gillespie CS, Sherman DL, Fleetwood-Walker SM, Cottrell DF, Tait S, Garry EM, Wallace VC, Ure J et al (2000) Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 26(2):523–531

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    McClintick JN, McBride WJ, Bell RL, Ding ZM, Liu Y, Xuei X, Edenberg HJ (2016) Gene expression changes in glutamate and GABA-A receptors, neuropeptides, ion channels, and cholesterol synthesis in the periaqueductal gray following binge-like alcohol drinking by adolescent alcohol-preferring (P) rats. Alcohol Clin Exp Res 40(5):955–968. https://doi.org/10.1111/acer.13056

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Chen SP, Zhou YQ, Liu DQ, Zhang W, Manyande A, Guan XH, Tian YK, Ye DW et al (2017) PI3K/Akt pathway: a potential therapeutic target for chronic pain. Curr Pharm Des 23(12):1860–1868. https://doi.org/10.2174/1381612823666170210150147

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Nehme B, Henry M, Mouginot D, Drolet G (2012) The expression pattern of the Na(+) sensor, Na(X) in the hydromineral homeostatic network: a comparative study between the rat and mouse. Front Neuroanat 6:26. https://doi.org/10.3389/fnana.2012.00026

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Ke CB, He WS, Li CJ, Shi D, Gao F, Tian YK (2012) Enhanced SCN7A/Nax expression contributes to bone cancer pain by increasing excitability of neurons in dorsal root ganglion. Neuroscience 227:80–89. https://doi.org/10.1016/j.neuroscience.2012.09.046

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Maruyama K (2012) Integrins and nitric oxide in the regulation of glia cells: potential roles in pathological pain. J Anesth Clin Res S7 (01). doi:https://doi.org/10.4172/2155-6148.s7-008

  81. 81.

    Sapio MR, Goswami SC, Gross JR, Mannes AJ, Iadarola MJ (2016) Transcriptomic analyses of genes and tissues in inherited sensory neuropathies. Exp Neurol 283(Pt A):375–395. https://doi.org/10.1016/j.expneurol.2016.06.023

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Schurks M (2010) Genetics of cluster headache. Curr Pain Headache Rep 14(2):132–139. https://doi.org/10.1007/s11916-010-0096-8

    PubMed  Article  Google Scholar 

  83. 83.

    Harris RA, Harris LS, Dunn A (1975) Effect of narcotic drugs on ribonucleic-acid and nucleotide-metabolism in mouse-brain. J Pharmacol Exp Ther 192(2):280–287

    CAS  PubMed  Google Scholar 

  84. 84.

    Tsai RY, Shen CH, Feng YP, Chien CC, Lee SO, Tsai WY, Lin YS, Wong CS (2012) Ultra-low-dose naloxone enhances the antinociceptive effect of morphine in PTX-treated rats: regulation on global histone methylation. Acta Anaesthesiol Taiwanica 50(3):106–111. https://doi.org/10.1016/j.aat.2012.08.003

    Article  Google Scholar 

  85. 85.

    Altier N, Stewart J (1998) Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. J Pharmacol Exp Ther 285(1):208–215

    CAS  PubMed  Google Scholar 

  86. 86.

    Smith HS (2008) Combination opioid analgesics. Pain Physician 11(2):201–214

    PubMed  Google Scholar 

  87. 87.

    Ito T, Ohtori S, Hata K, Inoue G, Moriya H, Takahashi K, Yamashita T (2007) Rho kinase inhibitor improves motor dysfunction and hypoalgesia in a rat model of lumbar spinal canal stenosis. Spine (Phila Pa 1976) 32(19):2070–2075. https://doi.org/10.1097/BRS.0b013e318145a502

    Article  Google Scholar 

  88. 88.

    Majdalawieh A, Zhang L, Ro HS (2007) Adipocyte enhancer-binding protein-1 promotes macrophage inflammatory responsiveness by up-regulating NF-kappaB via IkappaBalpha negative regulation. Mol Biol Cell 18(3):930–942. https://doi.org/10.1091/mbc.E06-03-0217

  89. 89.

    Bai L, Zhai C, Han K, Li Z, Qian J, Jing Y, Zhang W, Xu JT (2014) Toll-like receptor 4-mediated nuclear factor-kappaB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats. Neurosci Bull 30(6):936–948. https://doi.org/10.1007/s12264-014-1483-7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Simmler LD, Anacker AMJ, Levin MH, Vaswani NM, Gresch PJ, Nackenoff AG, Anastasio NC, Stutz SJ et al (2017) Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. Br J Pharmacol 174(16):2716–2738. https://doi.org/10.1111/bph.13899

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Gaiteri C, Sibille E (2011) Differentially expressed genes in major depression reside on the periphery of resilient gene coexpression networks. Front Neurosci 5:95. https://doi.org/10.3389/fnins.2011.00095

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Li SX, Liu LJ, Jiang WG, Sun LL, Zhou SJ, Le Foll B, Zhang XY, Kosten TR et al (2010) Circadian alteration in neurobiology during protracted opiate withdrawal in rats. J Neurochem 115(2):353–362. https://doi.org/10.1111/j.1471-4159.2010.06941.x

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Vansteensel MJ, Magnone MC, van Oosterhout F, Baeriswyl S, Albrecht U, Albus H, Dahan A, Meijer JH (2005) The opioid fentanyl affects light input, electrical activity and per gene expression in the hamster suprachiasmatic nuclei. Eur J Neurosci 21(11):2958–2966. https://doi.org/10.1111/j.1460-9568.2005.04131.x

    PubMed  Article  Google Scholar 

  94. 94.

    Segal JP, Tresidder KA, Bhatt C, Gilron I, Ghasemlou N (2018) Circadian control of pain and neuroinflammation. J Neurosci Res 96(6):1002–1020. https://doi.org/10.1002/jnr.24150

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Proudnikov D, Yuferov V, Randesi M, Kreek MJ (2013) Genetics of opioid addiction. In: Biological research on addiction: comprehensive addictive behaviors and disorders, vol 2, pp. 509–521. https://doi.org/10.1016/B978-0-12-398335-0.00050-9

    Chapter  Google Scholar 

  96. 96.

    Burish MJ, Chen Z, Yoo SH (2019) Emerging relevance of circadian rhythms in headaches and neuropathic pain. Acta Physiol (Oxf) 225(1):e13161. https://doi.org/10.1111/apha.13161

    CAS  Article  Google Scholar 

  97. 97.

    Guillaumond F, Dardente H, Giguere V, Cermakian N (2005) Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J Biol Rhythm 20(5):391–403. https://doi.org/10.1177/0748730405277232

    CAS  Article  Google Scholar 

  98. 98.

    Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K (2002) Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419(6909):841–844. https://doi.org/10.1038/nature01123

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Gachon F (2007) Physiological function of PARbZip circadian clock-controlled transcription factors. Ann Med 39(8):562–571. https://doi.org/10.1080/07853890701491034

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Krueger SK, Williams DE (2005) Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 106(3):357–387. https://doi.org/10.1016/j.pharmthera.2005.01.001

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Watkins LR, Hutchinson MR, Rice KC, Maier SF (2009) The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci 30(11):581–591. https://doi.org/10.1016/j.tips.2009.08.002

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Sandstrom ME, Madden LA, Taylor L, Siegler JC, Lovell RJ, Midgley A, McNaughton L (2009) Variation in basal heat shock protein 70 is correlated to core temperature in human subjects. Amino Acids 37(2):279–284. https://doi.org/10.1007/s00726-008-0144-4

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Koks S, Fernandes C, Kurrikoff K, Vasar E, Schalkwyk LC (2008) Gene expression profiling reveals upregulation of Tlr4 receptors in Cckb receptor deficient mice. Behav Brain Res 188(1):62–70. https://doi.org/10.1016/j.bbr.2007.10.020

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Ko MH, Hsieh YL, Hsieh ST, Tseng TJ (2015) Nerve demyelination increases metabotropic glutamate receptor subtype 5 expression in peripheral painful mononeuropathy. Int J Mol Sci 16(3):4642–4665. https://doi.org/10.3390/ijms16034642

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Pringsheim T (2002) Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 29(1):33–40

    PubMed  Article  Google Scholar 

  106. 106.

    Plein LM, Rittner HL (2018) Opioids and the immune system—friend or foe. Br J Pharmacol 175(14):2717–2725. https://doi.org/10.1111/bph.13750

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    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

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Hasegawa-Moriyama M, Kurimoto T, Nakama M, Godai K, Kojima M, Kuwaki T, Kanmura Y (2013) Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages. Pain 154(8):1402–1412. https://doi.org/10.1016/j.pain.2013.04.039

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Petrosino S, Palazzo E, de Novellis V, Bisogno T, Rossi F, Maione S, Di Marzo V (2007) Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 52(2):415–422. https://doi.org/10.1016/j.neuropharm.2006.08.011

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Kostadinova R, Wahli W, Michalik L (2005) PPARs in diseases: control mechanisms of inflammation. Curr Med Chem 12(25):2995–3009

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    D’Agostino G, La Rana G, Russo R, Sasso O, Iacono A, Esposito E, Mattace Raso G, Cuzzocrea S et al (2009) Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-kappaB nuclear signalling in dorsal root ganglia. Eur J Pharmacol 613(1–3):54–59. https://doi.org/10.1016/j.ejphar.2009.04.022

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Goswami SC, Thierry-Mieg D, Thierry-Mieg J, Mishra S, Hoon MA, Mannes AJ, Iadarola MJ (2014) Itch-associated peptides: RNA-Seq and bioinformatic analysis of natriuretic precursor peptide B and gastrin releasing peptide in dorsal root and trigeminal ganglia, and the spinal cord. Mol Pain 10:44. https://doi.org/10.1186/1744-8069-10-44

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Flegel C, Schobel N, Altmuller J, Becker C, Tannapfel A, Hatt H, Gisselmann G (2015) RNA-Seq analysis of human trigeminal and dorsal root ganglia with a focus on chemoreceptors. PLoS One 10(6):e0128951. https://doi.org/10.1371/journal.pone.0128951

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Lopes DM, Denk F, McMahon SB (2017) The molecular fingerprint of dorsal root and trigeminal ganglion neurons. Front Mol Neurosci 10:304. https://doi.org/10.3389/fnmol.2017.00304

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Nguyen MQ, Wu Y, Bonilla LS, von Buchholtz LJ, Ryba NJP (2017) Diversity amongst trigeminal neurons revealed by high throughput single cell sequencing. PLoS One 12(9):e0185543. https://doi.org/10.1371/journal.pone.0185543

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Delbes AS, Castel J, Denis RGP, Morel C, Quinones M, Everard A, Cani PD, Massiera F et al (2018) Prebiotics supplementation impact on the reinforcing and motivational aspect of feeding. Front Endocrinol (Lausanne) 9:273. https://doi.org/10.3389/fendo.2018.00273

    Article  Google Scholar 

  117. 117.

    van den Heuvel JK, Furman K, Gumbs MC, Eggels L, Opland DM, Land BB, Kolk SM, Narayanan NS et al (2015) Neuropeptide Y activity in the nucleus accumbens modulates feeding behavior and neuronal activity. Biol Psychiatry 77(7):633–641. https://doi.org/10.1016/j.biopsych.2014.06.008

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Chen H, Liu Z, Gong S, Wu X, Taylor WL, Williams RW, Matta SG, Sharp BM (2011) Genome-wide gene expression profiling of nucleus accumbens neurons projecting to ventral pallidum using both microarray and transcriptome sequencing. Front Neurosci 5:98. https://doi.org/10.3389/fnins.2011.00098

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L (2011) A comprehensive review of opioid-induced hyperalgesia. Pain Physician 14(2):145–161

    PubMed  Google Scholar 

  120. 120.

    Zhou J, Fan Y, Chen H (2017) Analyses of long non-coding RNA and mRNA profiles in the spinal cord of rats using RNA sequencing during the progression of neuropathic pain in an SNI model. RNA Biol 14(12):1810–1826. https://doi.org/10.1080/15476286.2017.1371400

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Hur J, Sullivan KA, Pande M, Hong Y, Sima AA, Jagadish HV, Kretzler M, Feldman EL (2011) The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain 134(Pt 11):3222–3235. https://doi.org/10.1093/brain/awr228

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Xiao X, Zuo X, Davis AA, McMillan DR, Curry BB, Richardson JA, Benjamin IJ (1999) HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice. EMBO J 18(21):5943–5952. https://doi.org/10.1093/emboj/18.21.5943

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Wessells J, Baer M, Young HA, Claudio E, Brown K, Siebenlist U, Johnson PF (2004) BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. J Biol Chem 279(48):49995–50003. https://doi.org/10.1074/jbc.M404246200

  124. 124.

    Wu HY, Mao XF, Tang XQ, Ali U, Apryani E, Liu H, Li XY, Wang YX (2018) Spinal interleukin-10 produces antinociception in neuropathy through microglial beta-endorphin expression, separated from antineuroinflammation. Brain Behav Immun 73:504–519. https://doi.org/10.1016/j.bbi.2018.06.015

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Shao J, Wang J, Huang J, Liu C, Pan Y, Guo Q, Zou W (2018) Identification of lncRNA expression profiles and ceRNA analysis in the spinal cord of morphine-tolerant rats. Mol Brain 11(1):21. https://doi.org/10.1186/s13041-018-0365-8

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Gomez R, Kohler DM, Brackley AD, Henry MA, Jeske NA (2018) Serum response factor mediates nociceptor inflammatory pain plasticity. Pain Rep 3(3):e658. https://doi.org/10.1097/PR9.0000000000000658

    PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Groth RD, Mermelstein PG (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci 23(22):8125–8134

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Jourdan D, Boghossian S, Alloui A, Veyrat-Durebex C, Coudore MA, Eschalier A, Alliot J (2000) Age-related changes in nociception and effect of morphine in the Lou rat. Eur J Pain 4(3):291–300. https://doi.org/10.1053/eujp.2000.0188

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Goldberg JS (2013) Chronic opioid therapy and opioid tolerance: a new hypothesis. Pain Res Treat 2013:1–6. https://doi.org/10.1155/2013/407504

    CAS  Article  Google Scholar 

  130. 130.

    Ferrini F, Trang T, Mattioli TA, Laffray S, Del’Guidice T, Lorenzo LE, Castonguay A, Doyon N et al (2013) Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(−) homeostasis. Nat Neurosci 16(2):183–192. https://doi.org/10.1038/nn.3295

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Bruehl S, Apkarian AV, Ballantyne JC, Berger A, Borsook D, Chen WG, Farrar JT, Haythornthwaite JA et al (2013) Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges. J Pain 14(2):103–113. https://doi.org/10.1016/j.jpain.2012.10.016

    PubMed  PubMed Central  Article  Google Scholar 

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We would like to thank Dr. Dennis Grayson for helpful discussion regarding experimental procedures and manuscript preparation. We are also grateful to Ying Chen for helping us with the RNA isolation and Hyeonsoo Jeong for preliminary data evaluation. Laura Moye is a member of the UIC Graduate Program in Neuroscience.


This study was funded by the National Institute of Health (grant numbers P30 DA018310-14 (SRZ, BS, JS), and DA031243 (AP)), the Department of Defense (grant number PR100085 (AP)), and US Department of Agriculture NIFA ILLU-538-909.

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Zhang, P., Moye, L.S., Southey, B.R. et al. Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens. Mol Neurobiol 56, 7929–7949 (2019). https://doi.org/10.1007/s12035-019-01650-5

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  • Opioid-induced hyperalgesia
  • Morphine
  • RNA-Seq
  • Circadian rhythm
  • Adaptive immune response