Impact of Psychological Stress on Pain Perception in an Animal Model of Endometriosis

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Psychological stress exacerbated endometriosis symptoms and colonic damage in rats, but paradoxically reduced abdominal allodynia, suggesting a stress-induced analgesia effect.

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This study used female rats in which endometriosis was induced by suturing uterine horn tissue near the intestinal mesentery, with sham-sutured controls; rats then underwent 7 days of water avoidance stress or no-stress handling. The authors measured anxiety indices via fecal pellets and serum corticosterone, assessed pain perception with hot plate and Von Frey tests, and examined spinal cord immunohistochemical expression of Substance P, enkephalin, endomorphin-2, and receptors including Mu opioid (MOR) and neurokinin-1. Stress increased corticosterone and fecal pellet measures and was associated with more severe endometriosis-related damage and vesicle mast cell infiltration, while producing significant hyperalgesia but reversing endo-associated abdominal allodynia, alongside reduced MOR expression in endo-no stress animals. The paper’s key caveat is that it uses an animal model and stress protocol where the beneficial allodynia effect is inferred as stress-induced analgesia without direct mechanistic confirmation. This paper is centrally about endometriosis — it tests how psychological stress alters pain thresholds and neuropeptide/opioid receptor-related signaling in an experimentally induced rat endometriosis model.

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Abstract

PurposePain in patients with endometriosis is considered a significant source of stress but does not always correlate with severity of the condition. We have demonstrated that stress can worsen endometriosis in an animal model. Here, we tested the impact of a psychological stress protocol on pain thresholds and pain receptors.MethodsEndometriosis was induced in female rats by suturing uterine horn tissue next to the intestinal mesentery. Sham rats had sutures only. Rats were exposed to water avoidance stress for 7 consecutive days or handled for 5 minutes (no stress). Fecal pellets and serum corticosterone (CORT) levels were measured as an index of anxiety. Pain perception was assessed using hot plate and Von Frey tests. Substance P, enkephalin, endomorphin-2, Mu opioid receptor (MOR), and neurokinin-1 receptor expression in the spinal cord were measured by immunohistochemistry.ResultsFecal pellets and CORT were significantly higher in the endo-stress (ES) group than endo-no stress (ENS; P < .01) and sham-no stress groups (SNS; P < .01). The ES rats had more colonic damage ( P < .001 vs SNS; P < .05 vs ENS), vesicle mast cell infiltration ( P < .01 vs ENS), and more severe vesicles than ENS. The ES developed significant hyperalgesia ( P < .05) but stress reversed the allodynic effect caused by endo ( P < .001). The MOR expression was significantly reduced in ENS versus SNS ( P < .05) and more enkephalin expression was found in endo groups.ConclusionAnimals subjected to stress develop more severe symptoms but interestingly stress seems to have beneficial effects on abdominal allodynia, which could be a consequence of the stress-induced analgesia phenomenon.
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Abstract

Purpose Pain in patients with endometriosis is considered a significant source of stress but does not always correlate with severity of the condition. We have demonstrated that stress can worsen endometriosis in an animal model. Here, we tested the impact of a psychological stress protocol on pain thresholds and pain receptors.

Methods

Endometriosis was induced in female rats by suturing uterine horn tissue next to the intestinal mesentery. Sham rats had sutures only. Rats were exposed to water avoidance stress for 7 consecutive days or handled for 5 minutes (no stress). Fecal pellets and serum corticosterone (CORT) levels were measured as an index of anxiety. Pain perception was assessed using hot plate and Von Frey tests. Substance P, enkephalin, endomorphin-2, Mu opioid receptor (MOR), and neurokinin-1 receptor expression in the spinal cord were measured by immunohistochemistry.

Results

Fecal pellets and CORT were significantly higher in the endo-stress (ES) group than endo-no stress (ENS; P <.01) and sham-no stress groups (SNS; P <.01). The ES rats had more colonic damage (P <.001 vs SNS; P <.05 vs ENS), vesicle mast cell infiltration (P <.01 vs ENS), and more severe vesicles than ENS. The ES developed significant hyperalgesia (P <.05) but stress reversed the allodynic effect caused by endo (P <.001). The MOR expression was significantly reduced in ENS versus SNS (P <.05) and more enkephalin expression was found in endo groups.

Conclusion

Animals subjected to stress develop more severe symptoms but interestingly stress seems to have beneficial effects on abdominal allodynia, which could be a consequence of the stress-induced analgesia phenomenon. Similar content being viewed by others

References

Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175-184. McKinnon B, Bersinger N, Wotzkow C, Mueller MD. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertil Steril. 2012;97(2):373–380. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98(3):591–598. Levy BS, Apgar BS, Surrey ES, Wysocki S. Endometriosis and chronic pain: amultispecialty roundtable discussion. J Fam Pract. 2007;56(3 suppl diagnosis):S15–S20. Zhao T, Liu X, Zhen X, Guo SW. Levo-tetrahydropalmatine retards the growth of ectopic endometrial implants and alleviates generalized hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. 2011;18(1):28–45. 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. Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associ-ated with central sensitization: a psychophysical controlled study. J Pain. 2003;4(7):372–380. As-Sanie S, Harris RE, Harte SE, Tu FF, Neshewat G, Clauw DJ. Increased pressure pain sensitivity in women with chronic pelvic pain. Obstet Gynecol. 2013;122(5):1047–1055. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152(3 suppl):S2–S15. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926. Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum. 2007;36(6):339–356. Huntington A, Gilmour JA. A life shaped by pain: women and endometriosis. J Clin Nurs. 2005;14(9):1124–1132. Tariverdian N, Riicke M, Szekeres-Bartho J, et al. Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro. JMol Med (Berl). 2010;88(3):267–278. Toth B. Stress, inflammation and endometriosis: are patients stuck between a rock and a hard place? J Mol Med (Berl). 2010;88(3):223–225. Appleyard CB, Cruz ML, Hernandez S, Thompson KJ, Bayona M, Flores I. Stress management affects outcomes in the pathophysiology of an endometriosis model. Reprod Sci. 2015;22(4):431–441. 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. Nagabukuro H, Berkley KJ. Influence of endometriosis on visceromotor and cardiovascular responses induced by vaginal distention in the rat. Pain. 2008;132(suppl 1):1–13. Myers B, Greenwood-Van Meerveld B. Differential involvement of amygdala corticosteroid receptors in visceral hyperalgesia following acute or repeated stress. Am J Physiol Gastrointest Liver Physiol. 2012;302(2):G260-G266. Moloney RD, O’ Mahony SM, Dinan TG, Cryan JF. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front psychiatry. 2015; 6:15. Parikh D, Hamid A, Friedman TC, et al. Stress-induced analgesia and endogenous opioid peptides: the importance of stress duration. Eur J Pharmacol. 2012;650(2–3):563–567. Rosch PJ. The stress-pain connection: some historical considera-tions and new directions. Compr Ther. 1986;12(7):3–8. Butler RK, Finn DP. Stress-induced analgesia. Prog Neurobiol. 2009;88(3):184–202. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician. 2011;14(3):249–258. Harrison S, Geppetti P. Substance P. Int J Biochem Cell Biol. 2001;33(6):555–576. Ma XP, Tan LY, Yang Y, et al. Effect of electro-acupuncture on substance P, its receptor and corticotropin-releasing hormone in rats with irritable bowel syndrome. World J Gastroenterol. 2009;15(41):5211–5217. Wang GD, Wang XY, Liu S, et al. Innervation of enteric mast cells by primary spinal afferents in guinea pig and human small intestine. Am J Physiol Gastrointest Liver Physiol. 2014;307(7): G719–G731. Shea-Donohue T, Stiltz J, Zhao A, Notari L. Mast cells. Curr Gastroenterol Rep. 2010;12(5):349–357. Torres-Reveron A, Palermo K, Hernandez-Lopez A, et al. Stress and endometriosis affects Mu opioid and NMDA receptors in areas relevant to pain processing. Reprod Sci. 2016;23(9):1158–1167. Hernandez S, Cruz ML, Torres-Reveron A, Appleyard CB. Impact of physical activity on pain perception in an animal model of endometriosis. J Endometriosis Pelvin Pain Disord. 2016;7(3):100–108. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44(5):684–694. Bhatia N, Maiti PP, Choudhary A, et al. Animal models in the study of stress: a review. J Pharm Healthc Manag. 2011;2: 42–50. Maillot C, Million M, Wei JY, Gauthier A, Tache Y. Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology. 2000;119(6):1569–1579. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001;53(4):597–652. Lu Y, Nie J, Liu X, Zheng Y, Guo SW. Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Hum Reprod. 2010;25(4):1014–1025. Long Q, Liu X, Qi Q, Guo SW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor B2. Hum Reprod. 2016;24(31):2506–2519. May V, Vizzard MA. urinary bladder dysfunction and altered somatic sensitivity in pituitary adenylate cyclase activating polypeptide knockout (PACAP-/-) mice. J Urol. 2011;183(2):772–779. Tena B, Escobar B, Arguis MJ, Cantero C, Rios J, Gomar C. Reproducibility of electronic Von Frey and Von Frey monofilaments testing. Clin J Pain. 2012;28(4):318–323 Rudick CN, Schaeffer AJ, Klumpp DJ. Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis. BMC Urol. 2009;9:16. Stagg NJ, Mata HP, Ibrahim MM, et al. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids. Anesthesiology. 2011;114(4):940–948. Ingelmo JM, Quereda F, Acien P. Intraperitoneal and subcutaneous treatment of experimental endometriosis with recombinant human interferon-alpha-2b in a murine model. Fertil Steril. 1999;71(5):907–911. Appleyard CB, Cruz ML, Rivera E, Hernandez GA, Flores I. Experimental endometriosis in the rat is correlated with colonic motor function alterations but not with bacterial load. Reprod Sci. 2007;14(8):815–824. Hernandez GA, Appleyard CB. Bacterial load in animal models of acute and chronic ‘reactivated’ colitis. Digestion. 2003;67(3):161–169. Anderson CR, Keast JR, McLachlan EM. Spinal autonomic preganglionic neurons: the visceral efferent system of the spinal cord. Spinal Cord. 2009;115–129. 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. Luo DS, Huang J, Dong YL, et al. Connections between EM2-and SP-containing terminals and GABAergic neurons in the mouse spinal dorsal horn. Neurol Sci. 2014;35(9):1421–1427. Xu JT, Zhao X, Yaster M, Tao YX. Expression and distribution of mTOR, p70S6K, 4E-BP1, and their phosphorylated counterparts in rat dorsal root ganglion and spinal cord dorsal horn. Brain Res. 2010;1336:46-57. Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011;62(6):591–599. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53(4):865–871. Rivat C, Becker C, Blugeot A, et al. Chronic stress induces tran-sient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain. 2010;150(2):358–368. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327–346. Bradesi S, Schwetz I, Ennes HS, et al. Repeated exposure to water avoidance stress in rats: a new model for sustained visceral hyper-algesia. Am J Physiol Gastrointest Liver Physiol. 2005;289(1): G42-G53. Berkley KJ, Cason A, Jacobs H, Bradshaw H, Wood E. Vaginal hyperalgesia in a rat model of endometriosis. Neurosci Lett. 2001;306(3):185–188. McAllister SL, Dmitrieva N, Berkley KJ. Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis. PLoS One. 2012;7(2): e31758. Lauffenburger DA, Linderman J. Receptors: Models for Binding, Trafficking, and Signaling. 1st ed. New York, NY: Oxford University Press; 1993. Normandin A, Luccarini P, Molat JL, Gendron L, Dallel R. Spinal μ and δ opioids inhibit both thermal and mechanical pain in rats. J N ettrasci. 2013;33(28):11703–11714. Koneru A, Satyanarayana S, Rizman R. Endogenous opioids: their physiological role and receptors. Glob J Pharmacol. 2009;3(3):149–153. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Hernandez, S., Cruz, M.L., Seguinot, I.I. et al. Impact of Psychological Stress on Pain Perception in an Animal Model of Endometriosis. Reprod. Sci. 24, 1371–1381 (2017). https://doi.org/10.1177/1933719116687655 Published: Issue date: DOI: https://doi.org/10.1177/1933719116687655

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Pain Perception Pain Threshold Stress, Psychological Animals Anxiety Anxiety Anxiety Anxiety Corticosterone Corticosterone Disease Models, Animal Endometriosis Endometriosis Endometriosis Enkephalins Enkephalins Female Oligopeptides Oligopeptides

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