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Spinal Glial Adaptations Occur in a Minimally Invasive Mouse Model of Endometriosis: Potential Implications for Lesion Etiology and Persistent Pelvic Pain

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Abstract

Glial adaptations within the central nervous system are well known to modulate central sensitization and pain. Recently, it has been suggested that activity of glial-related proinflammatory cytokines may potentiate peripheral inflammation, via central neurogenic processes. However, a role for altered glial function has not yet been investigated in the context of endometriosis, a chronic inflammatory condition in women associated with peripheral lesions, often manifesting with persistent pelvic pain. Using a minimally invasive mouse model of endometriosis, we investigated associations between peripheral endometriosis-like lesions and adaptations in central glial reactivity. Spinal cords (T13-S1) from female C57BL/6 mice with endometriosis-like lesions (ENDO) were imaged via fluorescent immunohistochemistry for the expression of glial fibrillary acidic protein (GFAP; astrocytes) and CD11b (microglia) in the dorsal horn (n = 5). Heightened variability (P =.02) as well as an overall increase (P =.04) in the mean area of GFAP immunoreactivity was found in ENDO versus saline-injected control animals. Interestingly, spinal levels showing the greatest alterations in GFAP immunoreactivity appeared to correlate with the spatial location of lesions within the abdominopelvic cavity. A subtle but significant increase in the mean area of CD11b immunostaining was also observed in ENDO mice compared to controls (P =.02). This is the first study to describe adaptations in nonneuronal, immune-like cells of the central nervous system attributed to the presence of endometriosis-like lesions.

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References

  1. Johnson NP, Hummelshoj L, Adamson GD, et al. World Endometriosis Society Consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315–324.

    Article  PubMed  Google Scholar 

  2. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327–346.

    Article  PubMed  Google Scholar 

  3. Hansen KE, Kesmodel US, Baldursson EB, Kold M, Forman A. Visceral syndrome in endometriosis patients. Eur J Obstet Gynecol Reprod Biol. 2014;179:198–203.

    Article  PubMed  Google Scholar 

  4. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11(6):595–606.

    Article  CAS  PubMed  Google Scholar 

  5. He W, Liu X, Zhang Y, Guo SW. Generalized hyperalgesia in women with endometriosis and its resolution following a successful surgery. Reprod Sci. 2010;17(12):1099–1111.

    Article  PubMed  Google Scholar 

  6. Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003;4(7):372–380.

    Article  PubMed  Google Scholar 

  7. Laursen BS, Bajaj P, Olesen AS, Delmar C, Arendt-Nielsen L. Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain. Eur J Pain. 2005;9(3):267–275.

    Article  PubMed  Google Scholar 

  8. As-Sanie S, Harris RE, Napadow V, et al. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain. 2012;153(5):1006–1014.

    Article  PubMed  PubMed Central  Google Scholar 

  9. As-Sanie S, Kim J, Schmidt-Wilcke T, et al. Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. J Pain. 2016;17(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  10. Liaw WJ, Stephens RL Jr, Binns BC, et al. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain. 2005;115(1–2):60–70.

    Article  CAS  PubMed  Google Scholar 

  11. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–1318.

    Article  CAS  PubMed  Google Scholar 

  12. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10(1):23–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154(suppl 1):S10–S28.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dodds KN, Beckett EA, Evans SF, Grace PM, Watkins LR, Hutchinson MR. Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain. Transl Psychiatry. 2016;6(9):e888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Old EA, Clark AK, Malcangio M. The role of glia in the spinal cord in neuropathic and inflammatory pain. In: Schaible H-G, ed. Pain Control. Berlin, Heidelberg: Springer; 2015:145–170.

    Chapter  Google Scholar 

  16. Kannampalli P, Pochiraju S, Bruckert M, Shaker R, Banerjee B, Sengupta JN. Analgesic effect of minocycline in rat model of inflammation-induced visceral pain. Eur J Pharmacol. 2014;727:87–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Feng QX, Wang W, Feng XY, et al. Astrocytic activation in thoracic spinal cord contributes to persistent pain in rat model of chronic pancreatitis. Neuroscience. 2010;167(2):501–509.

    Article  CAS  PubMed  Google Scholar 

  18. Qian NS, Liao YH, Feng QX, Tang Y, Dou KF, Tao KS. Spinal toll like receptor 3 is involved in chronic pancreatitis-induced mechanical allodynia of rat. Mol Pain. 2011;7(1):15.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu B, Su M, Tang S, et al. Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis. Mol Pain. 2016;12:doi:https://doi.org/10.1177/1744806916674479

  20. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20(5):737–747.

    Article  PubMed  Google Scholar 

  21. Boettger MK, Weber K, Grossmann D, et al. Spinal tumor necrosis factor α neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor α during induction and maintenance of peripheral inflammation. Arthritis Rheum. 2010;62(5):1308–1318.

    Article  CAS  PubMed  Google Scholar 

  22. Bressan E, Mitkovski M, Tonussi CR. LPS-induced knee-joint reactive arthritis and spinal cord glial activation were reduced after intrathecal thalidomide injection in rats. Life Sci. 2010;87(15):481–489.

    Article  CAS  PubMed  Google Scholar 

  23. Luo JG, Zhao XL, Xu WC, et al. Activation of spinal NF-κB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis. Arthritis Rheumatol. 2014;66(4):896–906.

    Article  CAS  PubMed  Google Scholar 

  24. Boyle DL, Jones TL, Hammaker D, et al. Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med. 2006;3(9):e338.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Willis WD Jr. Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res. 1999;124(4):395–421.

    Article  CAS  PubMed  Google Scholar 

  26. Gong K, Yue Y, Zou X, Li D, Lin Q. Minocycline inhibits the enhancement of antidromic primary afferent stimulation-evoked vasodilation following intradermal capsaicin injection. Neurosci Lett. 2010;482(2):177–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Majima T, Funahashi Y, Kawamorita N, et al. Role of microglia in the spinal cord in colon-to-bladder neural crosstalk in a rat model of colitis. Neurourol Urodyn. 2018.

  28. Laux-Biehlmann A, d’Hooghe T, Zollner TM. Menstruation pulls the trigger for inflammation and pain in endometriosis. Trends Pharmacol Sci. 2015;36(5):270–276.

    Article  CAS  PubMed  Google Scholar 

  29. McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015;26(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  30. Dodds KN, Staikopoulos V, Beckett EA. Uterine contractility in the nonpregnant mouse: changes during the estrous cycle and effects of chloride channel blockade. Biol Reprod. 2015;92(6):141.

    Article  PubMed  CAS  Google Scholar 

  31. Dodds KN, Beckett EAH, Evans SF, Hutchinson MR. Lesion development is modulated by the natural estrus cycle and mouse strain in a minimally-invasive model of endometriosis. Biol Reprod. 2017;97(6):810–821.

    Article  PubMed  Google Scholar 

  32. Loram LC, Sholar PW, Taylor FR, et al. Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats. Psychoneuroendocrinology. 2012;37(10):1688–1699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hains LE, Loram LC, Weiseler JL, et al. Pain intensity and duration can be enhanced by prior challenge: initial evidence suggestive of a role of microglial priming. J Pain. 2010;11(10):1004–1014.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lewis SS, Hutchinson MR, Frick MM, et al. Select steroid hormone glucuronide metabolites can cause Toll-like receptor 4 activation and enhanced pain. Brain Behav Immun. 2015;44:128–136.

    Article  CAS  PubMed  Google Scholar 

  35. Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007;14(4):241–260.

    Article  PubMed  Google Scholar 

  36. Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–682.

    Article  CAS  PubMed  Google Scholar 

  37. Sengul G, Watson C. Spinal cord. In: Watson C, Paxinos G, Puelles L, eds. The Mouse Nervous System. 1st ed. San Diego, CA: Academic Press; 2012:424–458.

    Chapter  Google Scholar 

  38. Somigliana E, Vigano P, Rossi G, Carinelli S, Vignali M, Panina-Bordignon P. Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum Reprod. 1999;14(12):2944–2950.

    Article  CAS  PubMed  Google Scholar 

  39. Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci. 2003;23(7):2899–2910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xin WJ, Weng HR, Dougherty PM. Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol Pain. 2009;5:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Chen Z, Muscoli C, Doyle T, et al. NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing. Pain. 2010;149(1):100–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yan X, Weng HR. Endogenous interleukin-1beta in neuropathic rats enhances glutamate release from the primary afferents in the spinal dorsal horn through coupling with presynaptic N-methyl-d-aspartic acid receptors. J Biol Chem. 2013;288(42):30544–30557.

    Article  CAS  PubMed  Google Scholar 

  43. Clark AK, Gruber-Schoffnegger D, Drdla-Schutting R, Gerhold KJ, Malcangio M, Sandkuhler J. Selective activation of microglia facilitates synaptic strength. J Neurosci. 2015;35(11):4552–4570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gruber-Schoffnegger D, Drdla-Schutting R, Hönigsperger C, Wunderbaldinger G, Gassner M, Sandkühler J. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells. J Neurosci. 2013;33(15):6540–6551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Choi JI, Svensson CI, Koehrn FJ, Bhuskute A, Sorkin LS. Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. Pain. 2010;149(2):243–253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang RX, Li A, Liu B, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008;135(3):232–239.

    Article  CAS  PubMed  Google Scholar 

  47. Weng HR, Chen JH, Cata JP. Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience. 2006;138(4):1351–1360.

    Article  CAS  PubMed  Google Scholar 

  48. Jiang E, Yan X, Weng H-R. Glial glutamate transporter and glutamine synthetase regulate GABAergic synaptic strength in the spinal dorsal horn. J Neurochem. 2012;121(4):526–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Torres-Reverón A, Palermo K, Hernández-López A, et al. Endometriosis is associated with a shift in MU opioid and NMDA receptor expression in the brain periaqueductal gray. Reprod Sci. 2016;23(9):1158–1167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Zhang LP, Chen Y, Clark BP, Sher E, Westlund KN. The role of type 1 metabotropic glutamate receptors in the generation of dorsal root reflexes induced by acute arthritis or the spinal infusion of 4-aminopyridine in the anesthetized rat. J Pain. 2000;1(2):151–161.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Bradesi S, Golovatscka V, Ennes HS, et al. Role of astrocytes and altered regulation of spinal glutamatergic neurotransmission in stress-induced visceral hyperalgesia in rats. Am J Physiol Gastrointest Liver Physiol. 2011;301(3):G580–G589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int. 2004;45(2):397–407.

    Article  CAS  PubMed  Google Scholar 

  53. Zhang J, De Koninck Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem. 2006;97(3):772–783.

    Article  CAS  PubMed  Google Scholar 

  54. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mogil JS, Chanda ML. The case for the inclusion of female subjects in basic science studies of pain. Pain. 2005;117(1–2):1–5.

    Article  PubMed  Google Scholar 

  56. Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13(12):859–866.

    Article  CAS  PubMed  Google Scholar 

  57. Sorge RE, Mapplebeck JC, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18(8):1081–1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stokes JA, Cheung J, Eddinger K, Corr M, Yaksh TL. Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J Neuroinflamm. 2013;10:148.

    Article  CAS  Google Scholar 

  59. Chen G, Luo X, Qadri MY, Berta T, Ji RR. Sex-dependent glial signaling in pathological pain: distinct roles of spinal microglia and astrocytes. Neurosci Bull. 2018;34(1):98–108.

    Article  CAS  PubMed  Google Scholar 

  60. Schrepf A, Bradley CS, O’Donnell M, et al. Toll-like receptor 4 and comorbid pain in interstitial cystitis/bladder pain syndrome: a multidisciplinary approach to the study of chronic pelvic pain research network study. Brain Behav Immun. 2015;49:66–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Saraswat L, Ayansina D, Cooper KG, Bhattacharya S, Horne AW, Bhattacharya S. Impact of endometriosis on risk of further gynaecological surgery and cancer: a national cohort study. BJOG. 2018;125(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  62. Cervero F, Laird JM. Visceral pain. Lancet. 1999;353(9170):2145–2148.

    Article  CAS  PubMed  Google Scholar 

  63. Mirkin D, Murphy-Barron C, Iwasaki K. Actuarial analysis of private payer administrative claims data for women with endometriosis. J Manag Care Pharm. 2007;13(3):262–272.

    Article  PubMed  Google Scholar 

  64. Malykhina AP. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. 2007;149(3):660–672.

    Article  CAS  PubMed  Google Scholar 

  65. Peng HY, Chang HM, Lee SD, et al. TRPV1 mediates the uterine capsaicin- induced NMDA NR2B-dependent cross-organ reflex sensitization in anesthetized rats. Am J Physiol Renal Physiol. 2008;295(5): F1324–F1335.

    Article  CAS  PubMed  Google Scholar 

  66. Wang Y, Zhang M, Xie F, et al. Upregulation of alpha(2)delta-1 calcium channel subunit in the spinal cord contributes to pelvic organ cross-sensitization in a rat model of experimentally-induced endometriosis. Neurochem Res. 2015;40(6):1267–1273.

    Article  CAS  PubMed  Google Scholar 

  67. Chen Z, Xie F, Bao M, et al. Activation of p38 MAPK in the rostral ventromedial medulla by visceral noxious inputs transmitted via the dorsal columns may contribute to pelvic organ cross-sensitization in rats with endometriosis. Neuroscience. 2015;291:272–278.

    Article  CAS  PubMed  Google Scholar 

  68. McAllister SL, McGinty SL, Resuehr D, et al. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain. 2009;147:255–264.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Discipline of Physiology, Adelaide Medical School, University of Adelaide, Frome Road, Adelaide, 5005, South Australia, Australia

    Kelsi N. Dodds BHlthSc Hons., Elizabeth A. H. Beckett PhD & Mark R. Hutchinson PhD

  2. Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia

    Susan F. Evans MBBS

  3. Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, South Australia, Australia

    Mark R. Hutchinson PhD

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  1. Kelsi N. Dodds BHlthSc Hons.
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Correspondence to Kelsi N. Dodds BHlthSc Hons..

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Dodds, K.N., Beckett, E.A.H., Evans, S.F. et al. Spinal Glial Adaptations Occur in a Minimally Invasive Mouse Model of Endometriosis: Potential Implications for Lesion Etiology and Persistent Pelvic Pain. Reprod. Sci. 26, 357–369 (2019). https://doi.org/10.1177/1933719118773405

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