, Volume 51, Issue 3, pp 223–231 | Cite as

Some Physiological Mechanisms Functioning in Models of Pain-Related Processes

  • O. A. Petrushenko
  • O. O. Luk’yanetzEmail author

Psychophysiological sensing of pain is formed due to the activity of a number of neuronal mechanisms. Among the pain-related processes, nociception per se, peripheral sensitization, synaptic plasticity, central sensitization, forming of abnormal excitability, structural reorganization in the respective neuronal networks, modulation of recurrent suppression, and a few other phenomena/processes can be mentioned. Nociception includes the processes of transduction, transmission, spreading, and perception of the pain signals. Transduction of the pain influences is a process of transformation of excessively strong and/or (sometimes) long-lasting mechanical, thermal, or chemical stimuli in electrical spike activity generated in peripheral processes of primary nociceptive sensory neurons. This process is mediated by specific receptor-channel complexes that are expressed exclusively in the nociceptive units; it also includes synaptic transmission to secondary and higher-order neurons of the nociception system and modulation of this transmission in neuron-to-neuron synapses in the nociception ascending pathways. The abnormal excitability, structural reorganization, and modulation of recurrent suppression are especially typical of neuropathic pain. Central sensitization is a phenomenon typical of inflammation-related pain, neuropathic pain, and “functional” pain. Different mechanisms responsible for the formation of pain can be targets for analgesic agents; naturally, elucidation of the mechanisms of antinociceptive effects is critically important. Some aspects of the nociception and antinociception events can, in many cases, be examined only in model experiments on animals. In this review, we describe the classification of the types of pain, mention some particular experimental models of pain, analyze the respective physiological mechanisms acting in such models, and also discussed some advantages and limitations of different experimental approaches used in these models.


nociceptive pain neuropathic pain chronic pain animal models nociceptors central sensitization peripheral sensitization 


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  1. 1.
    C. S. Sherrington, The Integrative Action of the Nervous System, Charles Scribner and Sons, New York (1906).Google Scholar
  2. 2.
    Yu. I. Gubskii and M. K. Khobzey, Pharmacotherapy in Palliative and Hospice Medicine. Clinical, Pharmaceutical, and Medical/Legal Aspects, Zdorov’ya, Kyiv (2011).Google Scholar
  3. 3.
    A. V. Ataman, Pathological Physiology in Questions and Answers. A Manual, Vyshcha Shkola, Kyiv (2000).Google Scholar
  4. 4.
    H. Merskey and N. Bogduk (Eds.), “Classification of chronic pain: Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by International Association for the Study of Pain,” in: Task Force on Taxonomy, IASP Press, Seattle, USA (1994).Google Scholar
  5. 5.
    C. K. Park, Z.-Z. Xu, T. Berta, et al., “Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1,” Neuron, 82, 47–54 (2014).PubMedPubMedCentralGoogle Scholar
  6. 6.
    R. R. Ji, Z.-Z. Xu, and Y.-J. Gao, “Emerging targets in neuroinflammation-driven chronic pain,” Nat. Rev. Drug. Discov., 13, 533–548 (2014).PubMedPubMedCentralGoogle Scholar
  7. 7.
    A. I. Basbaum, D. M. Bautista, G. Scherrer, and D. Julius, “Cellular and molecular mechanisms of pain,” Cell, 139, 267–284 (2009).PubMedPubMedCentralGoogle Scholar
  8. 8.
    E. A. Petrushenko, “Proton-gated ion currents in neurons of the rat spinal ganglia and the action of ketanov on these currents,” Neurophysiology, 45, 6–12 (2013).Google Scholar
  9. 9.
    M. A. Petrushenko, Ye. A. Petrushenko, and Ye. A. Lukyanetz, “Properties of the vanilloid type-I receptor,” Fiziol. Zh., 64, 98–112 (2018).Google Scholar
  10. 10.
    T. Moriyama, T. Higashi, K. Togashi, et al., “Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins,” Mol. Pain, 1, 10743–10753 (2005).Google Scholar
  11. 11.
    A. V. Dragan, O. A. Petrushenko, O. P. Burlak, and O. O. Lukyanetz, “Effect of activation of TRPA1-reseptors on desensitization of TRPV1 channels in neurons of the rat dorsal ganglia,” Fiziol. Zh., 62, 16–24 (2016).PubMedGoogle Scholar
  12. 12.
    Dysregulatory Pathology (a Manual for Physicians and Biologists), G. N. Kryzhanovskii (ed.), Moscow, Meditsina (2002).Google Scholar
  13. 13.
    P. A. Bland-Ward and P. P. Humphrey, “Acute nociception mediated by hindpaw P2X receptor activation in the rat,” Br. J. Pharmacol.,122, 365–371 (1997).PubMedPubMedCentralGoogle Scholar
  14. 14.
    G.-Y. Xu and L.-Y. M. Huang, “Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons,” J. Neurosci., 22, 93–102 (2002).PubMedPubMedCentralGoogle Scholar
  15. 15.
    P. Li, A. A. Calejesan, and M. Zhuo, “ATP P2x receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats,” J. Neurophysiol.,80, 3356–3360 (1998).PubMedGoogle Scholar
  16. 16.
    P. J. Dyck, І. Zimmerman, and D. A. Gillen, “Cool, warm, and heat-pain detection thresholds: testing methods and inferences about anatomic distribution of receptors,” Neurology, 43, 1500–1508 (1993).PubMedGoogle Scholar
  17. 17.
    P. J. Dyck, I. R. Zimmerman, D. M. Johnson, et al., “A standard test of heat-pain responses using CASE IV,” J. Neurol. Sci., 136, 54–63 (1996).PubMedGoogle Scholar
  18. 18.
    M. S. Angst, M. Tingle, N. G. Phillips, and B. Carvalho, “Determining heat and mechanical pain threshold in inflamed skin of human subjects,” J. Vis. Exp., 23, 1092 (2009)Google Scholar
  19. 19.
    M. M. Backonja, “Defining neuropathic pain,” Anesth. Analg., 97, 785–790 (2003).PubMedGoogle Scholar
  20. 20.
    M. J. Bradman, F. Ferrini, C. Salio, and A. Merighi, “Practical mechanical threshold estimation in rodents using von Frey hairs/Semmes–Weinstein monofilaments: Towards a rational method,” J. Neurosci. Methods, 255, 92–103 (2015).PubMedGoogle Scholar
  21. 21.
    M. L. Kukushkin and N. K. Khitrov, General Pathology of Pain, Moscow, Meditsina (2004).Google Scholar
  22. 22.
    A. V. Osipov and M. L. Kukushkin, “Effect of stress in the development of deafferentation-induced pain syndrome in rats after transection of the sciatic nerve,” Bul. Eksp. Biol.,115, 471–475 (1993).Google Scholar
  23. 23.
    N. A. Krupinina, I. N. Orlova, N. N. Khlebnikov, et al., “Modeling of a dopamine deficiency-dependent depression state against the background of development of the pain syndrome in rats,” Bol’, 13, 11–17(2006).Google Scholar
  24. 24.
    The Paths of Pain (H. Merskey, J. De Loeser, and R. Dubner, Eds), IASP Press, Seattle (1975–2005).Google Scholar
  25. 25.
    J. N. Cambell and R. A. Meyer, “Neuropatic pain: from the nociceptor to the patient,” in: The Paths of Pain, IASP Press, Seattle (2005), рр. 229–242.Google Scholar
  26. 26.
    A. Yu. Bespalov and E. E. Zvartau, Neuropsychopharmacology of Antagonists of NMDA receptors, Nevskii Dialekt, St. Petersburg (2000).Google Scholar
  27. 27.
    C. J. Woolf and S. W. Thompson, “The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states,” Pain, 44, 293–299 (1991).PubMedGoogle Scholar
  28. 28.
    F. Svendsen, A. Tjolsen, and K. Hole, “AMPA and NMDA receptor-dependent spinal LTP after nociceptive tetanic stimulation,” NeuroReport,9, 1185–1190 (1998).PubMedGoogle Scholar
  29. 29.
    D. J. Mayer, J. Mao, J. Holt, and D. D. Price, “Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions,” Proc. Natl. Acad. Sci. USA, 96, 7731–7736 (1999).PubMedGoogle Scholar
  30. 30.
    K. Lutfy, S. X. Cai, R. M. Woodward, and E. Weber, “Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice,” Pain, 70, 31–40 (1997).PubMedGoogle Scholar
  31. 31.
    T. Olivar and J. M. Laird, “Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes,” Pain, 79, 67–73 (1999).PubMedPubMedCentralGoogle Scholar
  32. 32.
    S. Felsby, J. Nielsen, L. Arendt-Nielsen, and T. S. Jensen, “NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride,” Pain, 64, 283–291 (1996).PubMedGoogle Scholar
  33. 33.
    A. Dickenson and A. Sullivan, “Differential effects of excitatory amino acid antagonists on dorsal horn nociceptive neurones m the rat,” Brain Res., 506, 31–39 (1990).PubMedGoogle Scholar
  34. 34.
    A. L. Vaccarino, P. Marek, B. Kest, et al., “NMDA receptor antagonists, MK-801 and ACEA-1011, prevent the development of tonic pain following subcutaneous formalin,” Brain Res., 615, 331–334 (1993).PubMedGoogle Scholar
  35. 35.
    J. D. Kristensen, R. Karlsten, T. Gordh, and O. G. Berge, “The NMDA antagonist 3-(2-carboxypiperazin-4-yl) propyl-l-phosphonic acid (CPP) has antinociceptive effect after intrathecal injection in the rat,” Pain, 56, 59–67 (1994).PubMedGoogle Scholar
  36. 36.
    K. Lutfy and E. Weber, “Attenuation of nociceptive responses by ACEA-1021, a competitive NMDA receptor/glycine site antagonist, in the mice,” Brain Res., 743, 17–23 (1996).PubMedGoogle Scholar
  37. 37.
    M. J. Millan and L. Seguin, “Chemically-diverse ligands at the glycine В site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice,” Neurosci. Lett., 178, 139–143 (1994).PubMedGoogle Scholar
  38. 38.
    C. Y. Chiang, S. J. Park, C. L. Kwan, et al., “NMDA receptor mechanisms contribute to neuroplasticity induced in caudalis nociceptive neurons by tooth pulp stimulation,” J. Neurophysiol., 80, 2621–2631 (1998).PubMedGoogle Scholar
  39. 39.
    B. D. Grubb, R. C. Riley, P. J. Hope, et al., “The burstlike firing of spinal neurons in rats with peripheral inflammation is reduced by an antagonist of N-methyl-D-aspartate,” Neuroscience, 74, 1077–1086 (1996).PubMedGoogle Scholar
  40. 40.
    S. M. Carlton, and R. E. Coggeshall, “Inflammationinduced changes in peripheral glutamate receptor populations,” Brain Res., 820, 63–70 (1999).PubMedGoogle Scholar
  41. 41.
    S. R. Chaplan, A. B. Malmberg, and T. L. Yaksh, “Efficacy of spinal NMDA receptor antagonism informalin hyperalgesia and nerve injury evoked allodynia in the rat,” J. Pharmacol. Exp. Ther., 280, 829–838 (1997).PubMedGoogle Scholar
  42. 42.
    D. A. Bereiter, D. F. Bereiter, and C. B. Hathaway, “The NMDA receptor antagonist MK-801 reduces Foslike immunoreactivity in central trigeminal neurons and blocks select endocrine and autonomic responses to corneal stimulation in the rat,” Pain, 64, 179–189 (1996).PubMedGoogle Scholar
  43. 43.
    C. Advokat and D. Rutherford, “Selective antinociceptive effect of excitatory amino acid antagonists in intact and acute spinal rats,” Pharmacol. Biochem. Behav., 51, 855–860 (1995).PubMedGoogle Scholar
  44. 44.
    N. R. Krenz and L. C. Weaver, “Effect of spinal cord transection on N-methyl-D-aspartate receptors in the cord,” J. Neurotrauma, 15, 1027–1036 (1998).PubMedGoogle Scholar
  45. 45.
    S. H. Tseng, “Suppression of autotomy by N-methyl-D-aspartate receptor antagonist (MK-801) in the rat,” Neurosci. Lett., 240, 17–20 (1998).PubMedGoogle Scholar
  46. 46.
    C. S. Wong, C. H. Cherng, and C. S. Tung, “Intrathecal administration of excitatory amino acid receptor antagonists or nitric oxide synthase inhibitor reduced autotomy behavior in rats,” Anesth. Analg., 87, 605–608 (1998).PubMedGoogle Scholar
  47. 47.
    N. A. Calcutt and S. R. Chaplan, “Spinal pharmacology of tactile allodynia in diabetic rats,” Br. J. Pharmacol., 122, 1478–1482 (1997).PubMedPubMedCentralGoogle Scholar
  48. 48.
    M. Malcangio and D. R. Tomhnson, “A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats,” Pain, 76, 151–157 (1998).PubMedGoogle Scholar
  49. 49.
    G. D. Sher, S. M. Cartmell, L. Gelgor, and D. Mitchell, “Role of N-methyl-D-aspartate and opiate receptors in nociception during and after ischemia in rats,” Pain, 49, 241–248 (1992).PubMedGoogle Scholar
  50. 50.
    M. L. Kukushkin, V. S. Smirnova, A. A. Tikhonovskii, and A. V. Kiselyev, “Gabapentin prevents the development of tolerance to morphine,” Bol,13, No. 4, 30–34 (2006).Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Bogomolets Institute of the NAS of UkraineKyivUkraine

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