SEPARABLE YET INTERACTIVE COMPONENTS OF EXPERIMENTAL POST-INCISIONAL MECHANICAL HYPERESTHESIA
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Abstract
Abstract
Acute post-operative pain limits function and slows recovery. To better understand the mechanisms underlying acute pain we have further investigated a post-incisional pain model using tactile hypersensitivity as an index of pain. After 1 cm incision of the medial-dorsal skin of male rats, closed with one silk suture, there is a rapidly developing increase in the responsiveness to punctate stimulation using nylon monofilament von Frey hairs (VFH), appearing as the increased contraction of sub-cutaneous muscles, the graded cutaneous truncii muscle response (CTMR). Such hypersensitivity in rats represents both the perception of pain in response to previously non-painful stimuli (allodynia) and an enlargement of the responses to stimuli that were mildly painful in intact skin (hyperalgesia). We found the probability and vigor of CTMR increases with increasing VFH force, described by a complex Force vs Response (F-R) curve. In intact/pre-incisional skin, such F-R data are well fitted by a single sigmoidal function that has one threshold (liminal force to produce a statistically “just-detectable” response), and one mid-point (force to produce half the maximum response). Four hours after incision, at the peak of post-incisional hypersensitivity, the F-R data are better fit by the sum of two such sigmoidal functions, with post-incisional allodynia accounted for by the emergence of a previously undetected response to VFH forces ten-fold lower than the threshold of intact skin. Interestingly, both the peak amplitude and the duration of these low-threshold, post-incisional allodynic responses are enhanced by “conditioning”, when the skin is also stimulated by strong force VFHs (that test hyperalgesia), a phenomenon that does not occur in intact skin. Actions of sub-incisional bupivacaine suggest that allodynia is initiated by local injury and inflammatory processes, while central sensitization accounts for the enhancement of allodynia by conditioning stimulation.Article Details
How to Cite
MUJENDA, Florence H.; STRICHARTZ, Gary R..
SEPARABLE YET INTERACTIVE COMPONENTS OF EXPERIMENTAL POST-INCISIONAL MECHANICAL HYPERESTHESIA.
Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1518>. Date accessed: 22 dec. 2024.
Keywords
Incision, Allodynia, Hyperalgesia, Nociception, Neuronal plasticity
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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26. Li Y-M, Maggio J, Wingrove D, Too HP, Marnerakis M, E, Strichartz GR. Local anesthetics inhibit substance P binding and evoked increases in intracellular Ca2+. Anesthesiology 1995;82(1):166-73.
27. Makdessi M, Barr TP, Xue W, Strichartz GR. Bupivacaine inhibits Endothelin-1 evoked increases in intracellular calcium in model sensory neurons. Acta Anaesthesiol Scand 2015;59(7):936-45. DOI:10.1111/aas.12481
28. Woolf CJ, Salter MW. Plasticity and pain: role of the dorsal horn, in "Wall and Melzack's Textbook of Pain", 5th Ed. SB McMahon and M Koltzenburg, eds. Elsevier-Churchill Livingstone, London, 2006. pp.91-105.
29. Kawamata M, Watanabe H, Nishikawa K, Takahashi T, Kozuka Y, Kawamata T, Omote K, Namiki A. Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin. Anesthesiology. 2002;97(3):550-9.
30. Pogatzki EM, Vandermeulen EP, Brennan TJ. Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision. Pain 2002;97(1-2):151-61.
31. Lewin GR, McMahon SB. Physiological properties of primary sensory neurons appropriately and inappropriately innervating skin in the adult rat. J Neurophysiol 1991;66(4):1205-17.
32. Davis KD, Meyer RA, Campbell JN. Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J Neurophysiol 1993;69:1071-81.
33. Andrew D and Greenspan JD. Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. J Neurophysiol 1999;82:2649-56.
34. Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992;38:397-421.
35. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765-9
36. Handwerker HO, Kilo S, Reeh PW. Unresponsive afferent nerve fibres in the sural nerve of the rat. J Physiol (Lond) 1991;435:229-42.
37. Ahlgren SC, Wang JF, Levine JD. C-fiber mechanical stimulus-response functions are different in inflammatory versus neuropathic hyperalgesia in the rat. Neuroscience 1997;76(1):285-90.
38. Gokin AP, Philip B, Strichartz, GR. Preferential block of small myelinated sensory and motor fibers by lidocaine: in vivo electrophysiology in the rat sciatic nerve. Anesthesiology 2001;95(6):1441-54.
39. Huang JH, Thalhammer JG, Raymond SA, Strichartz GR. Susceptibility to lidocaine of impulses in different somatosensory afferent fibers of rat sciatic nerve. J Pharmacol Exp Ther 1997;282(2):802-11.
40. Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 2009;462(7273):651-5. DOI: 10.1038/nature08505
41. Zahn PK, Brennan TJ. Incision-induced changes in receptive field properties of rat dorsal horn neurons. Anesthesiology 1999;91(3):772-85.
42. Vandermeulen EP and Brennan TJ. Alterations in ascending dorsal horn neurons by a surgical incision in the rat foot. Anesthesiology 2000;93:1294-302.
43. Kawamata M, Koshizaki M, Shimada SG, Narimatsu E, Kozuka Y, Takahashi T, Namiki A, Collins JG. Changes in response properties and receptive fields of spinal dorsal horn neurons in rats after surgical incision in hairy skin. Anesthesiology 2005;102:141-51.
44. Kawamata M, Furue H, Kozuka Y, Narimatsu E, Yoshimura M, Namiki A. Changes in properties of substantia gelatinosa neurons after surgical incision in the rat: in vivo patch-clamp analysis. Anesthesiology 2006;104:432-40.
45. Zahn PK, Pogatzki-Zahn EM, Brennan TJ. Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005;114(3):499-510. DOI:10.1016/j.pain.2005.01.018
46. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A 1999;96:7723-30.
2. Meyer RA, Ringkamp M, Campbell JN, Raja SN. Peripheral mechanisms of cutaneous nociception. in "Wall and Melzack's Textbook of Pain", 5th Ed. SB McMahon and M Koltzenburg, eds. Elsevier-Churchill Livingstone, London, 2006. pp.3-34.
3. Cerevero F, Laird JMA. Mechanisms of touch-evoked pain (allodynia); a new model. Pain 1996;68:13-23. DOI:10.1002/neu.20084
4. Brennan TJ, Vandermeulen EP, Gebhart GF: Characterization of a rat model of incisional pain. Pain 1996; 64:493–501.
5. Banik RK, Subieta AR, Wu C, Brennan TJ. Increased nerve growth factor after rat plantar incision contributes to guarding behavior and heat hyperalgesia. Pain 2005;117(1-2):68-76. DOI:10.1016/j.pain.2005.05.017
6. Zahn PK, Subieta A, Park SS, Brennan TJ. Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision. J Pain 2004;5(3):157-63. DOI: 10.1016/j.jpain.2004.02.538
7. Woo YC, Park SS, Subieta AR, Brennan TJ. Changes in tissue pH and temperature after incision indicate acidosis may contribute to postoperative pain. Anesthesiology. 2004;101(2):468-75.
8. Banik RK, Brennan TJ. Spontaneous discharge and increased heat sensitivity of rat C-fiber nociceptors are present in vitro after plantar incision. Pain. 2004 Nov;112(1-2):204-13.
9. Banik RK, Brennan TJ. Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. Pain. 2009;141(1-2):41-51. DOI: 10.1016/j.pain.2008.10.004
10. Pogatzki-Zahn EM, Shimizu I, Caterina M, Raja SN. Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. Pain. 2005;115(3):296-307.
11. Whiteside GT, Harrison J, Boulet J, Mark L, Pearson M, Gottshall S, Walker K. Pharmacological characterisation of a rat model of incisional pain. Br J Pharmacol. 2004;141(1):85-91.
12. Duarte AM, Pospisilova E, Reilly E, Mujenda F, Hamaya Y, Strichartz GR. Reduction of postincisional allodynia by subcutaneous bupivacaine: findings with a new model in the hairy skin of the rat. Anesthesiology 2005;103:113-25.
13. Guide for the Care and Use of Laboratory Animals. National Research Council of the National Academies, the National Academies Press. 8th Edition, 2011. DOI: 10.17226/5140
14. Theriault E, Diamond J Nociceptive cutaneous stimuli evoke localized contractions in a skeletal muscle. J Neurophysiol 1988;60:446-62.
15. Schmelz M, Schmidt R, Ringkamp M, Handwerker HO, Torebjork HE. Sensitization of insensitive branches of C nociceptors in human skin. J Physiol 1994;480 ( Pt 2):389-94.
16. Cunha FQ, Ferreira SH. Peripheral hyperalgesic cytokines. Advances in Experimental Medicine and Biology 2003;521:22-39.
17. Burnstock G. Purinergic receptors and pain. Curr Pharm Des 2009;15(15):1717-35.
18. Mujenda FH, Duarte AM, Reilly EK, Strichartz GR. Cutaneous endothelin-A receptors elevate post-incisional pain. Pain 2007;133(1-3):161-73. DOI:10.1016/j.pain.2007.03.021.
19. Petho G, Reeh PW. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev 2012;92:1699-775. DOI:10.1152/physrev.00048.2010.
20. Sahbaie P, Shi X, Guo TZ, Qiao Y, Yeomans DC, Kingery WS, Clark JD. Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision. Pain 2009;145(3):341-9. DOI:10.1016/j.pain.2009.06.037.
21. Carlton SM, Neugebauer V. Peripheral metabotropic glutamate receptors as drug targets for pain relief. Expert Opin Ther Targets 2002;6:349-61. DOI:10.1517/14728222.6.3.349
22. Gokin AP, Fareed MU, Pan H-L, Hans G, Strichartz GR, Davar G. Local injection of endothelin-1 produces pain-like behavior and excitation of nociceptors in rats. J Neurosci 2001;21:5358-66.
23. Hamalainen MM, Gebhart GF, Brennan TJ. Acute effect of an incision on mechanosensitive afferents in the plantar rat hindpaw. J Neurophysiol 2002;87:712-20.
24. Strichartz GR, Khodorova A, Wang J C-F, Chen Y-W, Huang C-C. Contralateral hyperalgesia from injection of endothelin-1 into the ipsilateral paw requires efferent conduction into the contralateral paw. Anesth Analg 2015;121:1065-77. DOI: 10.1213/ANE.0000000000000858
25. Barr T, Hrnjic A, Khodorova A, Sprague J, Strichartz G. Sensitization of Cutaneous Neuronal Purinergic Receptors Contributes to Endothelin-1-Induced Mechanical Hypersensitivity. PAIN 2014;155:1091-101.DOI: 10.1016/j.pain.2014.02.014
26. Li Y-M, Maggio J, Wingrove D, Too HP, Marnerakis M, E, Strichartz GR. Local anesthetics inhibit substance P binding and evoked increases in intracellular Ca2+. Anesthesiology 1995;82(1):166-73.
27. Makdessi M, Barr TP, Xue W, Strichartz GR. Bupivacaine inhibits Endothelin-1 evoked increases in intracellular calcium in model sensory neurons. Acta Anaesthesiol Scand 2015;59(7):936-45. DOI:10.1111/aas.12481
28. Woolf CJ, Salter MW. Plasticity and pain: role of the dorsal horn, in "Wall and Melzack's Textbook of Pain", 5th Ed. SB McMahon and M Koltzenburg, eds. Elsevier-Churchill Livingstone, London, 2006. pp.91-105.
29. Kawamata M, Watanabe H, Nishikawa K, Takahashi T, Kozuka Y, Kawamata T, Omote K, Namiki A. Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin. Anesthesiology. 2002;97(3):550-9.
30. Pogatzki EM, Vandermeulen EP, Brennan TJ. Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision. Pain 2002;97(1-2):151-61.
31. Lewin GR, McMahon SB. Physiological properties of primary sensory neurons appropriately and inappropriately innervating skin in the adult rat. J Neurophysiol 1991;66(4):1205-17.
32. Davis KD, Meyer RA, Campbell JN. Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J Neurophysiol 1993;69:1071-81.
33. Andrew D and Greenspan JD. Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. J Neurophysiol 1999;82:2649-56.
34. Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992;38:397-421.
35. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765-9
36. Handwerker HO, Kilo S, Reeh PW. Unresponsive afferent nerve fibres in the sural nerve of the rat. J Physiol (Lond) 1991;435:229-42.
37. Ahlgren SC, Wang JF, Levine JD. C-fiber mechanical stimulus-response functions are different in inflammatory versus neuropathic hyperalgesia in the rat. Neuroscience 1997;76(1):285-90.
38. Gokin AP, Philip B, Strichartz, GR. Preferential block of small myelinated sensory and motor fibers by lidocaine: in vivo electrophysiology in the rat sciatic nerve. Anesthesiology 2001;95(6):1441-54.
39. Huang JH, Thalhammer JG, Raymond SA, Strichartz GR. Susceptibility to lidocaine of impulses in different somatosensory afferent fibers of rat sciatic nerve. J Pharmacol Exp Ther 1997;282(2):802-11.
40. Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 2009;462(7273):651-5. DOI: 10.1038/nature08505
41. Zahn PK, Brennan TJ. Incision-induced changes in receptive field properties of rat dorsal horn neurons. Anesthesiology 1999;91(3):772-85.
42. Vandermeulen EP and Brennan TJ. Alterations in ascending dorsal horn neurons by a surgical incision in the rat foot. Anesthesiology 2000;93:1294-302.
43. Kawamata M, Koshizaki M, Shimada SG, Narimatsu E, Kozuka Y, Takahashi T, Namiki A, Collins JG. Changes in response properties and receptive fields of spinal dorsal horn neurons in rats after surgical incision in hairy skin. Anesthesiology 2005;102:141-51.
44. Kawamata M, Furue H, Kozuka Y, Narimatsu E, Yoshimura M, Namiki A. Changes in properties of substantia gelatinosa neurons after surgical incision in the rat: in vivo patch-clamp analysis. Anesthesiology 2006;104:432-40.
45. Zahn PK, Pogatzki-Zahn EM, Brennan TJ. Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005;114(3):499-510. DOI:10.1016/j.pain.2005.01.018
46. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A 1999;96:7723-30.