Neuroscience and Behavioral Physiology

, Volume 48, Issue 2, pp 180–185 | Cite as

Harmful Effects at Early Age Alter Pain Sensitivity in Adult Female Rats and Its Correction with Buspirone


Most studies of the influences of harmful pain and stress during the neonatal period of development on pain sensitivity are performed in males. We report here our studies of inflammatory pain and/or maternal deprivation stress in neonatal female rats on pain sensitivity in adulthood; an attempt was made to correct these changes using the 5-HT1A receptor agonist buspirone. Adult females subjected to early pain showed increased hypoalgesia in the hotplate test, while those subjected to maternal separation stress showed increased hyperalgesia in the formalin test. Pain and subsequent maternal separation had no effect on pain sensitivity in adult females. Chronic administration of buspirone from day 25 to day 39 of life to females subjected to inflammatory pain or maternal separation in the neonatal period normalized pain sensitivity in adults. In female rats, the prepurbertal period was found to be critical for correction of abnormalities in the nociceptive system induced by harmful actions at neonatal age.


neonatal inflammatory pain maternal separation buspirone adult female rats 


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  1. 1.
    I. P. Butkevich, V. A. Mikhailenko, E. A. Vershinina, and N. A. Ulanova, “Differences in adaptive forms of behavior in male and female rats in the adolescent period of development subjected to inflammation or stress in the neonatal state,” Zh. Evolyuts. Biokhim. Fiziol., 51, No. 4, 266–275 (2015).Google Scholar
  2. 2.
    V. A. Mikhailenko, I. P. Butkevich, and M. K. Astapova, “Long-term influences of stressors in the neonatal period of development on the nociceptive system and psychoemotional behavior,” Ros. Fiziol. Zh., 102, No. 5, 540–550 (2016).Google Scholar
  3. 3.
    A. M. Aloisi and G. Sorda, “Relationship of female sex hormones with pain perception: focus on estrogens,” Pain Manag., 1, No. 3, 229–238 (2011).CrossRefPubMedGoogle Scholar
  4. 4.
    K. J. Anand, W. G. Sippell, and A. Aynsley-Green, “Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response,” Lancet, 1, 243–248 (1987).CrossRefPubMedGoogle Scholar
  5. 5.
    M. H. Andrews and S. G. Matthews, “Programming of the hypothalamo-pituitary-adrenal axis: Serotonergic involvement,” Stress, 7, No. 1, 15–278 (2004).CrossRefPubMedGoogle Scholar
  6. 6.
    V. C. Z. Anseloni, F. He, S. I. Novikova, et al., “Alterations in stress-associated behaviors and neurochemical markers in adult rats after neonatal short-lasting local inflammatory insult,” Neuroscience, 131, 635–645 (2005).CrossRefPubMedGoogle Scholar
  7. 7.
    E. C. Azmitia, S. W. Griffi n, D. R. Marshak, et al., “S-100 beta and serotonin: a possible astrocytic-neuronal link to neuropathology of Alzheimer’s disease,” Prog. Brain Res., 94, 459–473 (1992).Google Scholar
  8. 8.
    I. P. Butkevich, V. A. Mikhailenko, E. A. Vershinina, and A. M. Aloisi, “Effects of neonatal pain, stress and their interrelation on pain sensitivity in later life of male rats,” Chinese J. Physiol., 59, No. 4, 253–260 (2016).Google Scholar
  9. 9.
    L. Butkevich, V. Mikhailenko, E. Vershinina, et al., “Maternal buspirone protects against the adverse effects of in utero stress on emotional and pain-related behaviors in offspring,” Physiol. Behav., 102, No. 2, 137–142 (2011).CrossRefPubMedGoogle Scholar
  10. 10.
    F. Capone and A. M. Aloisi, “Refinement of pain evaluation techniques. The formalin test,” Ann. Ist. Super. Sanita, 40, 223–229 (2004).PubMedGoogle Scholar
  11. 11.
    K. L. Chang, R. Fillingim, R. W. Hurley, and S. Schmidt, “Chronic pain management: pharmacotherapy for chronic pain,” FP Essent., 432, 27–38 (2015).PubMedGoogle Scholar
  12. 12.
    L. Chen and T. Jackson, “Early maternal separation and responsiveness to thermal nociception in rodent offspring: a meta-analytic review,” Behav. Brain Res., 299, 42–50 (2016).CrossRefPubMedGoogle Scholar
  13. 13.
    F. C. Colpaert, “5-HT(1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief,” Curr. Opin. Investig. Drugs, 7, 40–47 (2006).PubMedGoogle Scholar
  14. 14.
    H. L. Fields and A. I. Basbaum, “Central nervous system mechanisms of pain modulation,” in: Text Book of Pain, P. D. Wall and R. Melzack (eds.), Churchill Livingstone, London (1999), pp. 309–329.Google Scholar
  15. 15.
    R. B. Filligim, C. D. King, M. C. Ribeiro-Dasilva, et al., “Sex, gender, and pain: a review of recent clinical and experimental findings,” J. Pain, 10, No. 5, 447–485 (2009).CrossRefGoogle Scholar
  16. 16.
    M. Fitzgerald, “Developmental biology of inflammatory pain,” Br. J. Anaesth., 75, 177 185 (1995).Google Scholar
  17. 17.
    M. Fitzgerald, “The developmental of nociceptive circuits,” Nat. Rev. Neurosci., 6, 507–520 (2005).CrossRefPubMedGoogle Scholar
  18. 18.
    J. Giordano and L. Rogers, “Putative mechanisms of buspirone-induced antinociception in the rat,” Pain, 50, 365–372 (1992).CrossRefPubMedGoogle Scholar
  19. 19.
    D. P. Holschneider, Y. Guo, E. A. Mayer, and Z. Wang, “Early life stress elicits visceral hyperalgesia and functional reorganization of pain circuits in adult rats,” Neurobiol. Stress, 13, 8–22 (2016).Google Scholar
  20. 20.
    S. P. Hunt, R. Suzuki, W. Rahman, and A. H. Dickenson, “Chronic pain and descending facilitation” in: Proc. XI World Congress on Pain, H. Flor, E. Kalso, and J. O. Dostrovsky (eds.), IASP Press, Seattle (2006), pp. 349–363.Google Scholar
  21. 21.
    J. L. LaPrairie and A. Z. Murphy, “Female rats are more vulnerable to the long-term consequences of neonatal inflammatory injury,” Pain, 132, No. 1, 124–133 (2007).Google Scholar
  22. 22.
    J. L. LaPrairie and A. Z. Murphy, “Neonatal injury alters adult pain sensitivity by increasing opioid tone in the periaqueductal gray,” Front. Behav. Neurosci., 3, 31 (2009), doi: Scholar
  23. 23.
    J. L. LaPrairie and A. Z. Murphy, “Long term impact of neonatal injury in male and female rats: sex differences, mechanisms and clinical implications,” Front. Neuroendocrinol., 31, 193–202 (2010).CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    M. Lima, J. Malheiros, A. Negrigo, et al., “Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats,” Neuropharma cology, 77, 268–276 (2014).CrossRefGoogle Scholar
  25. 25.
    C. Loane and M. Politis, “Buspirone: What is it all about?” Brain Res., 1461, 111–118 (2012).CrossRefPubMedGoogle Scholar
  26. 26.
    D. R. Loyd and A. Z. Murphy, “The neuroanatomy of sexual dimorphism in opioid analgesia,” Exp. Neurol., 259, 57–63 (2014).CrossRefPubMedGoogle Scholar
  27. 27.
    C. M. McCormick and M. R. Green, “From the stressed adolescent to the anxious and depressed adult: investigations in rodent model,” Neuroscience, 249, 242–257 (2013).CrossRefPubMedGoogle Scholar
  28. 28.
    M. Melchior, P. Poisbeau, I. Gaumond, and S. Marchand, “Insights into the mechanisms and the emergence of sex-differences in pain,” Neuroscience, pii: S0306-4522(16)30156-7, doi: (2016).Google Scholar
  29. 29.
    O. Mohamad, D. Chen, L. Zhang, et al., “Erythropoietin reduces neuronal cell death and hyperalgesia induced by peripheral inflammatory pain in neonatal rats,” Mol. Pain, 7, 51 (2011), doi: Scholar
  30. 30.
    S. A. Mousa, C. P. Bopaiah, J. F. Richter, et al., “Inhibition of inflammatory pain by CRF at peripheral, spinal and supraspinal sites: involvement of areas coexpressing CRF receptors and opioid peptides,” Neuropsychopharmacology, 32, No. 12, 2530–2542 (2007).Google Scholar
  31. 31.
    R. Nadeson and C. S. Goodchild, “Antinociceptive role of 5-HT1A receptors in rat spinal cord,” Br. J. Anaesth., 88, No. 5, 679–684 (2002).CrossRefPubMedGoogle Scholar
  32. 32.
    A. Negrigo, M. Medeiros, R. Guinsburg, and L. Covolan, “Longterm gender behavioral vulnerability after nociceptive neonatal formalin stimulation in rats,” Neurosci. Lett., 190, 196–199 (2012).Google Scholar
  33. 33.
    T. Nishinaka, K. Nakamoto, and S. Tokuyama, “Enhancement of nerve-injury-induced thermal and mechanical hypersensitivity in adult male and female mice following early life stress,” Life Sci., 121, 28–34 (2015).CrossRefPubMedGoogle Scholar
  34. 34.
    G. Pavlakovie, J. Tigges, and T. A. Crozier, “Effect of buspirone on thermal sensory and pain threshold in human volunteers,” BMC Clin. Pharmacol., 29, 9–12 (2009).Google Scholar
  35. 35.
    K. Ren, V. Anseloni, S. P. Zou, et al., “Characterization of basal and re-inflammation-associated long-term alteration in pain responsivity following short-lasting neonatal local inflammatory insult,” Pain, 110, 588–596 (2004).CrossRefPubMedGoogle Scholar
  36. 36.
    B. A. Samuels, I. Mendez-David, C. Faye, et al., “Serotonin 1a and serotonin 4 receptors: essential mediators of the neurogenic and behavioral actions of antidepressants,” Neuroscientist, 22, No. 1, 26–45 (2016).Google Scholar
  37. 37.
    R. M. Sapolsky and M. J. Meaney, “Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period,” Brain Res., 396, 64–76 (1986).CrossRefPubMedGoogle Scholar
  38. 38.
    F. Schwaller and M. Fitzgerald, “The consequences of pain in early life: injury-induced plasticity in developing pain pathways,” Eur. J. Neurosci., 39, 344–355 (2014).CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    R. Screiber and A. Newman-Tancredi, “Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT1A receptor activation,” Neurobiol. Learn. Mem., 110, 72–80 (2014).CrossRefGoogle Scholar
  40. 40.
    N. C. Victoria, M. C. Karom, H. Eichenbaum, and A. Z. Murphy, “Neonatal injury rapidly alters markers of pain and stress in rat pups,” Dev. Neurobiol., 74, No. 1, 42–51 (2014).CrossRefPubMedGoogle Scholar
  41. 41.
    N. C. Victoria and A. Z. Murphy, “The long-term impact of early life pain on adult responses to anxiety and stress: Historical perspectives and empirical evidence,” Exp. Neurol., 275, No. 2, 261–273 (2016).CrossRefPubMedGoogle Scholar
  42. 42.
    S. M. Walker, S. Beggs, and M. L. Baccei, “Persistent changes in peripheral and spinal nociceptive processing after early tissue injury,” Exp. Neurol., 275, 253–260 (2016).CrossRefPubMedGoogle Scholar
  43. 43.
    G. Zheng, S. Hong, J. M. Hayes, and J. W. Wiley, “Chronic stress and peripheral pain: Evidence for distinct, region-specific changes in visceral and somatosensory pain regulatory pathways,” Exp. Neurol., 273, 301–311 (2015).CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pavlov Institute of PhysiologyRussian Academy of SciencesSt. PetersburgRussia

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