Skip to main content

Advertisement

SpringerLink
Log in

Endometriosis Is Associated With a Shift in MU Opioid and NMDA Receptor Expression in the Brain Periaqueductal Gray

  • Original Artide
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Studies have examined how endometriosis interacts with the nervous System, but little attention has been paid to opioidergic Systems, which are relevant to pain signaling. We used the autotransplantation rat model of endometriosis and allowed to progress for 60 days. The brain was collected and examined for changes in endogenous Opioid peptides, mu Opioid receptors (MORs), and the N-methyl-D-aspartate subunit receptor (NRI) in the periaqueductal gray (PAG), since both of these receptors can regulate PAG activity. No changes in endogenous Opioid peptides in met- and leu-enkephalin or ß-endorphin levels were observed within the PAG. However, MOR immunoreactivity was significantly decreased in the ventral PAG in the endometriosis group. Endometriosis reduced by 20% the number of neuronal profiles expressing MOR and reduced by 40% the NRI profiles. Our results suggest that endometriosis is associated with subtle variations in opioidergic and glutamatergic activity within the PAG, which may have implications for pain processing.

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

Similar content being viewed by others

References

  1. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.

    CAS  PubMed  Google Scholar 

  2. Moawad NS, Caplin A. Diagnosis, management, and long-term outcomes of rectovaginal endometriosis. Int J Womens Health. 2013;5:753–763.

    PubMed  PubMed Central  Google Scholar 

  3. Rogers PA, D’Hooghe TM, Fazleabas A, et al.. Defining future directions for endometriosis research:Workshop report from the 2011 World Congress of Endometriosis In Montpellier, France. Reprod Sci. 2013;20(5):483–499.

    PubMed  PubMed Central  Google Scholar 

  4. Barnack JL, Chrisler JC. The experience of chronic illness in women:a comparison between women with endometriosis and women with chronic migraine headaches. Women Health. 2007; 46(1):115–133.

    PubMed  Google Scholar 

  5. Fourquet J, Baez L, Figueroa M, Iriarte RI, Flores I. Quantification of the impact of endometriosis Symptoms on health-related quality of life and work productivity. Fertil Steril. 2011;96(1):107–112.

    PubMed  PubMed Central  Google Scholar 

  6. Fourquet J, Gao X, Zavala D, et al.. Patients’ report on how endometriosis affects health, work, and daily life. Fertil Steril. 2010; 93(7):2424–2428.

    PubMed  PubMed Central  Google Scholar 

  7. 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.

    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.

    PubMed  PubMed Central  Google Scholar 

  9. Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007;55(3):377–391.

    CAS  PubMed  Google Scholar 

  10. McAllister SL, Dmitrieva N, Berkley KJ. Sprouted innervation into uterine transplants contributes to the development of hyper-algesia in a rat model of endometriosis. PLoS One. 2012;7(2):e31758.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  12. Cuevas M, Flores I, Thompson KJ, Ramos-Ortolaza DL, Torres-Reveron A, Appleyard CB. Stress exacerbates endometriosis manifestations and inflammatory parameters in an animal model. Reprod Sci. 2012;19(8):851–862.

    PubMed  PubMed Central  Google Scholar 

  13. Bandler R, Shipley MT. Columnar Organization in the midbrain periaqueductal gray:modules for emotional expression? Trends Neurosci. 1994;17(9):379–389.

    CAS  PubMed  Google Scholar 

  14. Vianna DM, Borelli KG, Ferreira-Netto C, Macedo CE, Brandao ML. Fos-like immunoreactive neurons following electrical Stimulation of the dorsal periaqueductal gray at freezing and escape thresholds. Brain Res Bull. 2003;62(3):179–189.

    CAS  PubMed  Google Scholar 

  15. Yu R, Gollub RL, Spaeth R, Napadow V, Wasan A, Kong J. Disrupted functional Connectivity of the periaqueductal gray in chronic low back pain. Neuroimage Clin. 2014;6:100–108.

    PubMed  PubMed Central  Google Scholar 

  16. Mainero C, Louapre C. Migraine and inhibitory System-I can’t hold it! Curr Pain Headache Rep. 2014;18(7):426.

    PubMed  Google Scholar 

  17. Chadha HK, Armstrong JE, Mo wer GD, Hubscher CH. Effects of surgical induction of endometriosis on response properties of pre-optic area neurons in rats. Brain Res. 2008;1246:101–110.

    CAS  PubMed  Google Scholar 

  18. Bach FW, Yaksh TL. Release into ventriculo-cisternal perfusate of beta-endorphin- and Met-enkephalin-immunoreactivity:effects of electrical Stimulation in the arcuate nucleus and periaqueductal gray of the rat. Brain Res. 1995;690(2):167–176.

    CAS  PubMed  Google Scholar 

  19. Bach FW, Yaksh TL. Release of beta-endorphin immunoreactiv-ity from brain by activation of a hypothalamic N-methyl-D-aspartate receptor. Neuroscience. 1995;65(3):775–783.

    CAS  PubMed  Google Scholar 

  20. Terashvili M, Tseng LF, Wu HE, et al.. Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of beta-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray. J Pharmacol Exp Ther. 2008;326(2):614–622.

    CAS  PubMed  Google Scholar 

  21. Moss MS, Basbaum AI. The fine structure of the caudal periaqueductal gray of the cat:morphology and synaptic Organization of normal and immunoreactive enkephalin-labeled profiles. Brain Res. 1983;289(1-2):27–43.

    CAS  PubMed  Google Scholar 

  22. Finley JC, Lindstrom P, Petrusz P. Immunocytochemical loca-lization of beta-endorphin-containing neurons in the rat brain. Neuroendocrinology. 1981;33(1):28–42.

    PubMed  Google Scholar 

  23. Finley JC, Maderdrut JL, Petrusz P. The immunocytochemical localization of enkephalin in the central nervous System of the rat. J Comp Neurol. 1981;198(4):541–565.

    CAS  PubMed  Google Scholar 

  24. Vercellini P, Sacerdote P, Panerai AE, Manfredi B, Bocciolone L, Crosignani G. Mononuclear cell beta-endorphin concentration in women with and without endometriosis. Obstet Gynecol. 1992; 79(5 pt l):743–746.

    CAS  PubMed  Google Scholar 

  25. Rodriguez-Munoz M, Sanchez-Blazquez P, Vicente-Sanchez A, Berrocoso E, Garzon J. The mu-opioid receptor and the NMDA receptor associate in PAG neurons:implications in pain control. Neuropsychopharmacology. 2012;37(2):338–349.

    CAS  PubMed  Google Scholar 

  26. Commons KG, van Bockstaele EJ, Pfaff DW. Frequent colocali-zation of mu Opioid and NMDA-type glutamate receptors at post-synaptic sites in periaqueductal gray neurons. J Comp Neurol. 1999;408(4):549–559.

    CAS  PubMed  Google Scholar 

  27. Ghelardini C, Galeotti N, Vivoli E, et al.. Molecular interaction in the mouse PAG between NMDA and Opioid receptors in morphine-induced acute thermal nociception. J Neurochem. 2008;105(1):91–100.

    CAS  PubMed  Google Scholar 

  28. Appleyard CB, Cruz ML, Hernandez S, Thompson KJ, Bayona M, Flores I. Stress management affects outcomes in the pathophysiol-ogy of an endometriosis model. Reprod Sci. 2015;22(4):431–441.

    CAS  PubMed  Google Scholar 

  29. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44(5):684–694.

    CAS  PubMed  Google Scholar 

  30. Appleyard CB, Cruz ML, Rivera E, Hernandez GA, Flores I. Experimental endometriosis in the rat is correlated with colonic motor funetion alterations but not with bacterial load. Reprod Sci. 2007;14(8):815–824.

    PubMed  Google Scholar 

  31. Ocio EM, Vilanova D, Atadja P, et al.. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010;95(5):794–803.

    CAS  PubMed  Google Scholar 

  32. Milner TA, Drake CT. Ultrastructural evidence for presynaptic mu Opioid receptor modulation of synaptic plasticity in NMDA-receptor-containing dendrites in the dentate gyrus. Brain Res Bull. 2001;54(2):131–140.

    CAS  PubMed  Google Scholar 

  33. Roh DH, Seo HS, Yoon SY, et al.. Activation of spinal alpha-2 adrenoceptors, but not mu-opioid receptors, reduces the intrathe-cal N-methyl-D-aspartate-induced increase in spinal NR1 subunit phosphorylation and nociceptive behaviors in the rat. Anesthesia and analgesia. 2010;110:622–629.

    CAS  PubMed  Google Scholar 

  34. Arvidsson U, Riedl M, Chakrabarti S, et al.. The kappa-opioid receptor is primarily postsynaptic:combined immunohistochem-ical localization of the receptor and endogenous Opioids. Proc Natl Acad Sci USA. 1995;92:5062–5066.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Abbadie C, Gultekin SH, Pasternak GW. Immunohistochemical localization of the carboxy terminus of the novel mu Opioid receptor splice variant MOR-1C within the human spinal cord. Neu-roreport. 2000;11:1953–1957.

    CAS  Google Scholar 

  36. Drake CT, Milner TA. Mu Opioid receptors are in somatodendritic and axonal compartments of GABAergic neurons in rat hippo-campal formation. Brain Res. 1999;849:203–215.

    CAS  PubMed  Google Scholar 

  37. Kasai S, Yamamoto H, Kamegaya E, et al.. Quantitative detection of micro Opioid receptor:Western blot analyses using micro Opioid receptor knockout mice. Curr Neuropharmacol. 2011; 9(1):219–222.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Garzon J, Juarros JL, Castro MA, Sanchez-Blazquez P. Antibodies to the cloned mu-opioid receptor detect various molecular weight forms in areas of mouse brain. Mol Pharmacol. 1995; 47(4):738–744.

    CAS  PubMed  Google Scholar 

  39. Chen W, McRoberts JA, Marvizon JC. mu-Opioid receptor inhi-bition of substance P release from primary afferents disappears in neuropathic pain but not inflammatory pain. Neuroscience. 2014; 267:67–82.

    CAS  PubMed  Google Scholar 

  40. Siegel SJ, Brose N, Janssen WG, et al.. Regional, cellular, and ultrastructural distribution of N-methyl-D-aspartate receptor subunit 1 in monkey hippocampus. Proc Natl Acad Sci USA. 1994; 91:564–568.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cheng PY, Svingos AL, Wang H, et al.. Ultrastructural immuno-labeling shows prominent presynaptic vesicular localization of delta-opioid receptor within both enkephalin- and nonenkephalin-containing axon terminals in the superficial layers of the rat cervi-cal spinal cord. J Neurosci. 1995;15(9):5976–5988.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Svingos AL, Clarke CL, Pickel VM. Cellular sites for activation of delta-opioid receptors in the rat nucleus accumbens shell:rela-tionship with Met5-enkephalin. J Neurosci. 1998; 18(5):1923–1933.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hsu SM, Raine L, Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying Polypeptide hormones with radioimmunoas-say antibodies. Am J Clin Pathol. 1981;75(5):734–738.

    CAS  PubMed  Google Scholar 

  44. Pierce JP, Kurucz OS, Milner TA. Morphometry of a peptidergic transmitter System:dynorphin B-like immunoreactivity in the rat hippocampal mossy fiber pathway before and after seizures. Hippocampus. 1999;9(3):255–276.

    CAS  PubMed  Google Scholar 

  45. Waters EM, Torres-Reveron A, McEwen BS, Milner TA. Ultrastructural localization of extranuclear progestin receptors in the rat hippocampal formation. J Comp Neurol. 2008; 511(1):34–46.

    PubMed  PubMed Central  Google Scholar 

  46. Paxinos G, Watson C. The Rat Brain Atlas in Stereotaxic Coor-dinates. 2nd ed. Philadelphia, PA:Elsevier, Inc; 1986.

    Google Scholar 

  47. Nakamura NH, McEwen BS. Changes in interneuronal pheno-types regulated by estradiol in the adult rat hippocampus:a potential role for neuropeptide Y. Neuroscience. 2005;136(1):357–369.

    CAS  PubMed  Google Scholar 

  48. Torres-Reveron A, Williams TJ, Chapleau JD, et al.. Ovarian Steroids alter mu Opioid receptor trafficking in hippocampal parval-bumin GABAergic interneurons. Exp Neurol. 2009;219(1):319–327.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ:Laurence Earlbaum Associates; 1988.

    Google Scholar 

  50. Murakami S, Okamura H, Yanaihara C, Yanaihara N, Ibata Y. Immunocytochemical distribution of met-enkephalin-Arg6-Gly7-Leu8 in the rat lower brainstem. J Comp Neurol. 1987;261(2):193–208.

    CAS  PubMed  Google Scholar 

  51. Kow LM, Commons KG, Ogawa S, Pfaff DW. Potentiation of the excitatory action of NMDA in ventrolateral periaqueductal gray by the mu-opioid receptor agonist, DAMGO. Brain Res. 2002; 935(1-2):87–102.

    CAS  PubMed  Google Scholar 

  52. Simsek Y, Gul M, Yilmaz E, Ozerol IH, Ozerol E, Parlakpinar H. Atorvastatin exerts anti-nociceptive activity and decreases serum levels of high-sensitivity C-reactive protein and rumor necrosis factora in a rat endometriosis model. Arch Gynecol Obstet. 2014 Nov;290(5):999–1006.

    CAS  PubMed  Google Scholar 

  53. Nagabukuro H, Berkley KJ. Influence of endometriosis on viscer-omotor and cardiovascular responses induced by vaginal disten-tion in the rat. Pain. 2007;132(suppl I):s96-sl03.

    Google Scholar 

  54. McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat:role of the ectopic growths and their innervation. Pain. 2009;147(1-3):255–264.

    PubMed  PubMed Central  Google Scholar 

  55. Fyfe LW, Cleary DR, Macey TA, Morgan MM, Ingram SL. Tol-erance to the antinocieeptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons. J Pharmacol Exp Ther. 2010;335(3):674–680.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bagley EE, Chieng BC, Christie MJ, Connor M. Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine. Br J Pharmacol. 2005;146(1):68–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Loyd DR, Murphy AZ. The role of the periaqueductal gray in the modulation of pain in males and females:are the anatomy and physiology really that different? Neural Plast. 2009;2009:462879.

    PubMed  PubMed Central  Google Scholar 

  58. Babst R, Bongiorno L, Marini M, et al.. Age-induced increase of leucine enkephalin enzyme degradation in human plasma. Peptides. 1998;19(7):1155–1163.

    CAS  PubMed  Google Scholar 

  59. Staud R. Abnormal endogenous pain modulation is a shared char-acteristic of many chronic pain conditions. Expert Rev Neurother. 2012;12(5):577–585.

    PubMed  PubMed Central  Google Scholar 

  60. Wouters MM, Boeckxstaens GE. Neuroimmune mechanisms in functional bowel disorders. Neth J Med. 2011;69(2):55–61.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Basic Sciences: Physiology and Pharmacology, Ponce Health Sciences University, Ponce Research Institute, 395 Zona Ind Reparada 2, Ponce, PR, 00716-2347, USA

    Annelyn Torres-Reverón PhD, Karylane Palermo BS, Anixa Hernández-López BS, Siomara Hernández PhD, Myrella L. Cruz MA, Kenira J. Thompson PhD & Caroline B. Appleyard PhD

  2. Department of Clinical Psychology, Ponce Health Sciences University/Ponce Research Institute, Ponce, PR, USA

    Annelyn Torres-Reverón PhD

  3. Department of Microbiology, Ponce Health Sciences University, Ponce, PR, USA

    Idhaliz Flores PhD

Authors
  1. Annelyn Torres-Reverón PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karylane Palermo BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anixa Hernández-López BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siomara Hernández PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Myrella L. Cruz MA
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenira J. Thompson PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Idhaliz Flores PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Caroline B. Appleyard PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annelyn Torres-Reverón PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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. 23, 1158–1167 (2016). https://doi.org/10.1177/1933719116630410

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719116630410

Keywords

Search

Navigation