Dynamics of Spinal Inotropic Glutamate Receptors During the Development of Prolonged Postoperative Pain in the Rat.

Main Article Content

Gary Strichartz, PhD, MD Yong-Jing Gao


Surgery can cause pain that lasts for weeks to months. Postoperative pain involves an early induction phase (hours to l days), and a longer maintenance phase. Experimental post-operative pain can be lowered by pre-operative spinal glutamate receptor antagonists as well as inhibitors of certain mitogen activated protein kinases (MAPKs). Here a model of postoperative pain in the rat, leading to 4 weeks of secondary mechanical allodynia-hyperalgesia, was used to examine changes in spinal inotropic glutamate receptors and MAPKs. Western blots show that GluR1subunits of AMPA receptors undergo rapid increases in phosphorylation at 4h post-op (2.3x naive), before tactile hyperalgesia is detectable, change to 1.6x naïve at 2d post-op, when hyperalgesia is clearly present, and fall to sub-baseline levels (0.1x naïve) at 14d, when hyperalgesia is maximum. The NR1 subunit of NMDA receptors are 1.7x, 1.8x, and 1.1x the level of naïve at 4h, 2d and 14d, respectively, whilst the phosphorylated form occurs at 1.7x, 0.9x and 0.5x of naïve at these times. NR2B subunit amounts follow a similar trend; 1.6x, 1.7x and 0.8x. Phosphorylation of the MAPK JNK was elevated to 1.45x, 1.35x and fell to 0.8x of naïve at 4h, 2d and 14d postoperative, whilst pERK 1/2 phosphorylation remained unchanged. These results suggest that increases in total NMDA subunits and in phosphorylated NMDA and AMPA receptors, paralleled by elevated P~JNK, contribute to the induction phase of persistent post-operative pain, but are not involved in its maintenance.

Keywords: Postoperative pain, Glutamate receptors, NMDA receptors, AMPA receptors, receptor phosphorylation, spinal MAPKs

Article Details

How to Cite
STRICHARTZ, Gary; GAO, Yong-Jing. Dynamics of Spinal Inotropic Glutamate Receptors During the Development of Prolonged Postoperative Pain in the Rat.. Medical Research Archives, [S.l.], v. 8, n. 2, feb. 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2042>. Date accessed: 03 mar. 2024. doi: https://doi.org/10.18103/mra.v8i2.2042.
Research Articles


1. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367(9522):1618-25. DOI: 10.1016/s0140-6736(06)68700-x
2. Pluijms WA, Steegers MA, Verhagen AF, Scheffer GJ, Wilder-Smith OH. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiol Scand. 2006;50(7):804-8. DOI: 10.1111/j.1399-6576.2006.01065.x
3. Khasabov SG, Malecha P, Noack J, Tabakov J, Jr. GJG, Simone DA. Hyperalgesia and sensitization of dorsal horn neurons following activation of NK-1 receptors in the rostral ventromedial medulla. Journal of Neurophysiology. 2017;118(5):2727-44.
4. Ji R-R, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Research Reviews. 2009;60(1):135-48. DOI: https://doi.org/10.1016/j.brainresrev.2008.12.011
5. Huang L, Gao YJ, Wang J, Strichartz G. Shifts in cell-type expression accompany a diminishing role of spinal p38-mapkinase activation over time during prolonged postoperative pain. Anesthesiology. 2011;115(6):1281-90. DOI:10.1097/ALN.0b013e31823499cc
6. Wang JC, Strichartz GR. Prevention of Chronic Post-Thoracotomy Pain in Rats By Intrathecal Resolvin D1 and D2: Effectiveness of Perioperative and Delayed Drug Delivery. J Pain. 2017;18(5):535-45. DOI: 10.1016/j.jpain.2016.12.012
7. Flatters SJ. Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR). Pain. 2008;135(1-2):119-30.DOI: 10.1016/j.pain.2007.05.013
8. Flatters SJ. Effect of analgesic standards on persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR). Neurosci Lett. 2010;477(1):43-7.DOI: 10.1016/j.neulet.2010.04.033
9. Zhuo M. Ionotropic glutamate receptors contribute to pain transmission and chronic pain. Neuropharmacology. 2017;112(Pt A):228-34. DOI: 10.1016/j.bja.2018.08.025
10. Zahn PK, Sluka KA, Brennan TJ. Excitatory amino acid release in the spinal cord caused by plantar incision in the rat. Pain. 2002;100(1-2):65-76. DOI: 10.1016/s0304-3959(02)00241-5
11. Lee HJ, Pogatzki-Zahn EM, Brennan TJ. The effect of the AMPA/kainate receptor antagonist LY293558 in a rat model of postoperative pain. J Pain. 2006;7(10):768-77. DOI: 10.1016/j.jpain.2006.03.010
12. Pogatzki EM, Niemeier JS, Sorkin LS, Brennan TJ. Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain. 2003;105(1-2):97-107. DOI: 10.1016/s0304-3959(03)00169-6
13. National Research Council Committee for the Update of the Guide for the C, Use of Laboratory A. The National Academies Collection: Reports funded by National Institutes of Health. In: th, editor. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press (US)
National Academy of Sciences.; 2011. DOI: 10.17226/12910
14. Contreras-Hernandez E, Chavez D, Hernandez E, Velazquez E, Reyes P, Bejar J, et al. Supraspinal modulation of neuronal synchronization by nociceptive stimulation induces an enduring reorganization of dorsal horn neuronal connectivity. J Physiol. 2018;596(9):1747-76.
DOI: 10.1113/jp275228
15. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010;62(3):405-96. DOI: 10.1124/pr.109.002451
16. Dolan S, Kelly JG, Monteiro AM, Nolan AM. Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia. Pain. 2003;106(3):501-12. DOI:10.1016/j.pain.2003.09.017
17. Dolan S, Kelly JG, Monteiro AM, Nolan AM. Differential expression of central metabotropic glutamate receptor (mGluR) subtypes in a clinical model of post-surgical pain. Pain. 2004;110(1-2):369-77. DOI: 10.1016/j.pain.2004.04.018
18. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97(4):1108-16.
19. Chen BS, Roche KW. Regulation of NMDA receptors by phosphorylation. Neuropharmacology. 2007;53(3):362-8. DOI: 10.1016/j.neuropharm.2007.05.018
20. Deng M, Chen SR, Pan HL. Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain. Cell Mol Life Sci. 2019;76(10):1889-99. DOI: 10.1007/s00018-019-03047-y
21. Lee CJ, Bardoni R, Tong CK, Engelman HS, Joseph DJ, Magherini PC, et al. Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release. Neuron. 2002;35(1):135-46. DOI: 10.1016/s0896-6273(02)00729-8
22. Tao YX. AMPA receptor trafficking in inflammation-induced dorsal horn central sensitization. Neurosci Bull. 2012;28(2):111-20. DOI: 10.1007/s12264-012-1204-z
23. Chen G, Xie RG, Gao YJ, Xu ZZ, Zhao LX, Bang S, et al. beta-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain. Nat Commun. 2016;7:12531. DOI:10.1038/ncomms12531
24. Li S, Zeng J, Wan X, Yao Y, Wu Y, Zhao N, et al. Enhancement of spinal dorsal horn neuron N-methyl-D-aspartate receptor phosphorylation as the mechanism of remifentanil-induced hyperalgesia: Roles of protein kinase C and calcium/calmodulin-dependent protein kinase II. Molecular Pain. DOI: 10.1177/1744806917723789
25. Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 1999;2(12):1114-9. DOI: 10.1038/16040
26. Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, et al. Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci. 2004;24(45):10211-22. DOI: 10.1523/jneurosci.3388-04.2004
27. Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010;126(1):56-68.DOI: 10.1016/j.pharmthera.2010.01.002
28. Chen H, Jiang YS, Sun Y, Xiong YC. p38 and interleukin-1 beta pathway via toll-like receptor 4 contributed to the skin and muscle incision and retraction-induced allodynia. J Surg Res. 2015;197(2):339-47. DOI: 10.1016/j.jss.2015.04.061
29. Wen YR, Suter MR, Ji RR, Yeh GC, Wu YS, Wang KC, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia. Anesthesiology. 2009;110(1):155-65.
30. Obata H, Eisenach JC, Hussain H, Bynum T, Vincler M. Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat. J Pain. 2006;7(11):816-22.
DOI: 10.1016/j.jpain.2006.04.004
31. Huang L, Wang CF, Serhan CN, Strichartz G. Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1. Pain. 2011;152(3):557-65. DOI: 10.1016/j.pain.2010.11.021
32. Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8(1):1-10.DOI: 10.1006/nbdi.2000.0360
33. Feller L, Khammissa RAG, Bouckaert M, Ballyram R, Jadwat Y, Lemmer J. Pain: Persistent postsurgery and bone cancer-related pain. J Int Med Res. 2019;47(2):528-43.
DOI: 10.1177/0300060518818296