Models and Mechanisms of Hyperalgesia and Allodynia
Abstract
Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable progress has been made in developing clinically relevant animal models for identifying the most significant underlying mechanisms. This review deals with experimental models that are currently used to measure (sect. II) or to induce (sect. III) hyperalgesia and allodynia in animals. Induction and expression of hyperalgesia and allodynia are context sensitive. This is discussed in section IV. Neuronal and nonneuronal cell populations have been identified that are indispensable for the induction and/or the expression of hyperalgesia and allodynia as summarized in section V. This review focuses on highly topical spinal mechanisms of hyperalgesia and allodynia including intrinsic and synaptic plasticity, the modulation of inhibitory control (sect. VI), and neuroimmune interactions (sect. VII). The scientific use of language improves also in the field of pain research. Refined definitions of some technical terms including the new definitions of hyperalgesia and allodynia by the International Association for the Study of Pain are illustrated and annotated in section I.
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Chronic pain is associated with elevated levels of inflammation and such inflammation drives hyperalgesia.
“chronic pain is also associated with elevated levels of inflammation and that such inflammation drives hyperalgesia, or increased sensitivity to pain”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Sandkühler, 2009
Cites
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
Bennett, G. J., & Xie, Y.-K. (1988) · Pain · doi:10.1016/0304-3959(88)90209-6 · Cited by 5,376 · see citing works
Coderre, T. J., Katz, J., Vaccarino, A. L., & Melzack, R. (1993) · Pain · doi:10.1016/0304-3959(93)90161-h · Cited by 1,966 · cited 1× · see citing works
“Another often used definition implies that “central sensitization” would be an enhanced responsiveness of neurons in the central nervous system leading to hyperalgesia (76).”
BackgroundBDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
Coull, J. A. M., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M. W., & De Koninck, Y. (2005) · Nature · doi:10.1038/nature04223 · Cited by 1,965 · see citing works
Le Bars, D., Gozariu, M., & Cadden, S. W. (2001) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01514-x · Cited by 1,459 · see citing works
Fear and anxiety: divergent effects on human pain thresholds
Rhudy, J. L., & Meagher, M. W. (2000) · Pain · doi:10.1016/s0304-3959(99)00183-9 · Cited by 913 · see citing works
Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network
Ploghaus, A., Narain, C., Beckmann, C. F., Clare, S., Bantick, S., Wise, R., Matthews, P. M., Rawlins, J. N. P., & Tracey, I. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-24-09896.2001 · Cited by 822 · see citing works
Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition
Julien, N., Goffaux, P., Arsenault, P., & Marchand, S. (2005) · Pain · doi:10.1016/j.pain.2004.12.032 · Cited by 634 · see citing works
A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel
Polomano, R. C., Mannes, A. J., Clark, U. S., & Bennett, G. J. (2001) · Pain · doi:10.1016/s0304-3959(01)00363-3 · Cited by 476 · see citing works
Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain
Courteix, C., Eschalier, A., & Lavarenne, J. (1993) · Pain · doi:10.1016/0304-3959(93)90059-x · Cited by 454 · see citing works
Reversal of pathological pain through specific spinal GABAA receptor subtypes
Knabl, J., Witschi, R., Hösl, K., Reinold, H., Zeilhofer, U. B., Ahmadi, S., Brockhaus, J., Sergejeva, M., Hess, A., Brune, K., et al. (2008) · Nature · doi:10.1038/nature06493 · Cited by 438 · see citing works
Vincristine hyperalgesia in the rat: A model of painful vincristine neuropathy in humans
Aley, K. O., Reichling, D. B., & Levine, J. D. (1996) · Neuroscience · doi:10.1016/0306-4522(96)00020-6 · Cited by 185 · see citing works
Description of a short-term Taxol®-induced nociceptive neuropathy in rats
Authier, N., Gillet, J.-P., Fialip, J., Eschalier, A., & Coudore, F. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02910-3 · Cited by 171 · see citing works
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Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206 · see citing works
Neuronal circuitry for pain processing in the dorsal horn
Todd, A. J. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2947 · Cited by 1,475 · see citing works
Identification of Spinal Circuits Transmitting and Gating Mechanical Pain
Duan, B., Cheng, L., Bourane, S., Britz, O., Padilla, C., Garcia-Campmany, L., Krashes, M., Knowlton, W., Velasquez, T., Ren, X., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.003 · Cited by 582 · see citing works
Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity
Xanthos, D. N., & Sandkühler, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3617 · Cited by 580 · see citing works
Self-citationDynorphin Acts as a Neuromodulator to Inhibit Itch in the Dorsal Horn of the Spinal Cord
Kardon, A. P., Polgár, E., Hachisuka, J., Snyder, L. M., Cameron, D., Savage, S., Cai, X., Karnup, S., Fan, C. R., Hemenway, G. M., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.046 · Cited by 369 · see citing works
MicroRNAs as modulators and biomarkers of inflammatory and neuropathic pain conditions
Andersen, H. H., Duroux, M., & Gazerani, P. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.003 · Cited by 175 · see citing works
Selective activation of microglia facilitates synaptic strength
Clark, A. K., Gruber-Schoffnegger, D., Drdla-Schutting, R., Gerhold, K. J., Malcangio, M., & Sandkühler, J. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2061-14.2015 · Cited by 171 · see citing works
Self-citationMCNICOL, E. D., SCHUMANN, R., & HAROUTOUNIAN, S. (2014) · Acta Anaesthesiologica Scandinavica · doi:10.1111/aas.12377 · Cited by 167 · see citing works
Musculoskeletal pain and exercise—Challenging existing paradigms and introducing new
Smith, B. E., Hendrick, P., Bateman, M., Holden, S., Littlewood, C., Smith, T. O., & Logan, P. (2019) · British Journal of Sports Medicine · doi:10.1136/bjsports-2017-098983 · Cited by 166 · see citing works
Nocebo and pain: an overview of the psychoneurobiological mechanisms
Blasini, M., Corsi, N., Klinger, R., & Colloca, L. (2017) · PAIN Reports · doi:10.1097/pr9.0000000000000585 · Cited by 139 · see citing works
Central sensitization in humans: assessment and pharmacology
Arendt-Nielsen, L. (2015) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-662-46450-2_5 · Cited by 125 · see citing works
Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain
Cui, L., Miao, X., Liang, L., Abdus-Saboor, I., Olson, W., Fleming, M. S., Ma, M., Tao, Y.-X., & Luo, W. (2016) · Neuron · doi:10.1016/j.neuron.2016.07.038 · Cited by 100 · see citing works
Burston, J. J., Sagar, D. R., Shao, P., Bai, M., King, E., Brailsford, L., Turner, J. M., Hathway, G. J., Bennett, A. J., Walsh, D. A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080440 · Cited by 103 · see citing works
Pain mechanisms in chronic pancreatitis: of a master and his fire.
Demir, I. E., Tieftrunk, E., Maak, M., Friess, H., & Ceyhan, G. O. (2011) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-010-0731-1 · Cited by 101 · see citing works
Boyle, K. A., Gutierrez-Mecinas, M., Polgár, E., Mooney, N., O'Connor, E., Furuta, T., Watanabe, M., & Todd, A. J. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.08.044 · Cited by 92 · see citing works
May, A., Rodriguez‐Raecke, R., Schulte, A., Ihle, K., Breimhorst, M., Birklein, F., & Jürgens, T. P. (2012) · European Journal of Pain · doi:10.1002/j.1532-2149.2011.00023.x · Cited by 51 · see citing works
Genetic Targeting of ERK1 Suggests a Predominant Role for ERK2 in Murine Pain Models
Alter, B. J., Zhao, C., Karim, F., Landreth, G. E., & Gereau, R. W. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.6103-09.2010 · Cited by 47 · see citing works
Understanding and managing pelvic girdle pain from a person-centred biopsychosocial perspective
Beales, D., Slater, H., Palsson, T., & O'Sullivan, P. (2020) · Musculoskeletal Science and Practice · doi:10.1016/j.msksp.2020.102152 · Cited by 36 · see citing works
- Authors
- Sandkühler, J.
- Affiliations
- Medical University of Vienna (AT)
- Corresponding author
- Sandkühler, Jürgen
- ORCID
- Sandkühler, Jürgen
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2009-04
- Volume
- 89
- Issue
- 2
- Pages
- 707-758
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W2128692107
- Cited by
- 1,148
- References
- 12
- Citations by year
- 2026: 35 · 2025: 48 · 2024: 34 · 2023: 59 · 2022: 55 · 2021: 69 · 2020: 56 · 2019: 148 · 2018: 77 · 2017: 80 · 2016: 81 · 2015: 82 · 2014: 75 · 2013: 104 · 2012: 53
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- hyperalgesia, allodynia, animal models of pain, pain mechanisms, spinal cord, synaptic plasticity, inhibitory control, neuroimmune interactions, non-neuronal cells, pain terminology
- MeSH terms
- Animals, Disease Models, Animal, Female, Hyperalgesia, Male, Neuronal Plasticity, Nociceptors, Spinal Nerves, Touch, Rats
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