Humani modeli eksperimentalnog bola
Sažetak
Bol je neprijatno senzorno iskustvo, povezano sa postojećim ili potencijalnim oštećenjem tkiva. Iako je u osnovi bol senzorni stimulus, on je višedimenzionalno senzorno iskustvo zato što ima snažne kognitivne i emocionalne komponente. Stimulus koji uzrokuje bol, prolazi kroz proces nocicepcije koji se sastoji od transdukcije, transmisije, modulacije i percepcije bolnog stimulusa. Zavisno od vrste stimulusa, modeli eksperimentalnog bola se mogu podeliti na mehaničke, električne, termalne i hemijske. Informacije o mehanizmima bola dobijamo iz: 1) in vitro studija, 2) animalnih eksperimenata, 3) humanih eksperimentalnih studija sa bolom i 4) kliničkih studija. Ključnu ulogu u dizajnu studije igra i odabir adekvatne metode za procenu bola, a kombinacijom sa različitim elektrofiziološkim i imaging metodama možemo dobiti veću objektivnost kao i bolju kvantifikaciju i objašnjenje mehanizama bola.
Fokus u eksperimentalnim studijama bola se postepeno prebacuje sa statičkih parametara poput praga bola i maksimalne tolerancije na dinamičke parametre koji mogu pružiti uvid u očuvanost sistema endogene analgezije, što se sprovodi primenom kondicionirane modulacije bola.
Primena eksperimentalnog bola na zdravim ispitanicima je ključni korak u prelasku sa animalnih modela na kliničke studije, pre svega zbog validizacije podataka dobijenih na animalnim modelima, što čini ove eksperimentalne studije bitnim u translacionom istraživanju. Rezultati dobijeni iz eksperimentalnih studija bola nam mogu pomoći u daljem razumevanju nociceptivnih mehanizama akutnog i hroničnog bola i razvoju novih terapijskih modaliteta.
Reference
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10. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001;53:597–652.
11. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010 Oct;23:611–5.
12. Heinricher MM, Morgan MM. Supraspinal Mechanisms of Opioid Analgesia. Opioids Pain Control. 2010;46–69.
13. Moont R, Pud D, Sprecher E, Sharvit G, Yarnitsky D. “Pain inhibits pain” mechanisms: Is pain modulation simply due to distraction? Pain. 2010;150:113–20.
14. Vardeh D, Mannion RJ, Woolf CJ. Toward a Mechanism-Based Approach to Pain Diagnosis. Vol. 17, Journal of Pain. Churchill Livingstone Inc.; 2016. p. T50–69.
15. Reddy KSK, Naidu MUR, Rani PU, Rao TRK. Human experimental pain models: A review of standardized methods in drug development. J Res Med Sci. 2012 Jun;17:587–95.
16. Arendt-Nielsen L, Yücel A. Induction and assessment of experimental pain from human muscle. Agri. 2000;12:9–14.
17. Rocco AG, Raymond SA, Murray E, Dhingra U, Freiberger D. Differential spread of blockade of touch, cold, and pinprick during spinal anesthesia. Anesth Analg. 1985 Sep;64:917–23.
18. Liu SS, Ware PD. Differential sensory block after spinal bupivacaine in volunteers. Anesth Analg. 1997;84:115–9.
19. Burke D, Mackenzie RA, Skuse NF, Lethlean AK. Cutaneous afferent activity in median and radial nerve fascicles: A microelectrode study. J Neurol Neurosurg Psychiatry. 1975;38:855–64.
20. Curatolo M, Petersen-Felix S, Arendt-Nielsen L. Sensory assessment of regional analgesia in humans: a review of methods and applications. Anesthesiology. 2000;93:1517–30.
21. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden AM. Epidural epinephrine and clonidine: Segmental analgesia and effects on different pain modalities. Anesthesiology. 1997;87:785–94.
22. Butterworth J, Ririe DG, Thompson RB, Walker FO, Jackson D, James RL. Differential onset of median nerve block: Randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers. Br J Anaesth. 1998;81:515–21.
23. Staahl C, Drewes AM. Experimental human pain models: A review of standardised methods for preclinical testing of analgesics. Basic Clin Pharmacol Toxicol. 2004 Sep;95:97–111.
24. Fischer AA. Pressure algometry over normal muscles. Standard values, validity and reproducibility of pressure threshold. Pain. 1987;30:115–26.
25. Graven-Nielsen T, Arendt-Nielsen L. Induction and assessment of muscle pain, referred pain, and muscular hyperalgesia. Curr Pain Headache Rep. 2003 Nov;7:443–51.
26. Greenspan JD, Mcgillis SLB. Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain. Somatosens Mot Res. 1991 Jan 10;8:137–47.
27. Mouraux A, Iannetti GD, Plaghki L. Low intensity intra-epidermal electrical stimulation can activate Aδ-nociceptors selectively. Pain. 2010;150:199–207.
28. Koppert W, Dern SK, Sittl R, Albrecht S, Schüttler J, Schmelz M. A new model of electrically evoked pain and hyperalgesia in human skin: The effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology. 2001;95:395–402.
29. Modir JG, Wallace MS. Human experimental pain models 2: the cold pressor model. Methods Mol Biol. 2010;617:165–8.
30. Fowler CJ, Sitzoglou K, Ali Z, Halonen P. The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling. J Neurol Neurosurg Psychiatry. 1988;51:1164–70.
31. Fowler CJ, Sitzoglou K, Ali Z, Halonen P. The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling. J Neurol Neurosurg Psychiatry. 1988;51:1164–70.
32. Arendt-Nielsen L, Chen ACN. Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol Clin. 2003;33:259–68.
33. Hughes AM, Rhodes J, Fisher G, Sellers M, Growcott JW. Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers. Br J Clin Pharmacol. 2002;53:604–12.
34. Handwerker HO, Kobal G. Psychophysiology of experimentally induced pain. Physiol Rev. 1993 Jul 1;73:639–71.
35. Arendt-Nielsen L. First pain event related potentials to argon laser stimuli: Recording and quantification. J Neurol Neurosurg Psychiatry. 1990;53:398–404.
36. Bromm B, Treede RD. Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients. Rev Neurol (Paris). 1991;147:625–43.
37. Tzabazis AZ, Klukinov M, Crottaz-Herbette S, Nemenov MI, Angst MS, Yeomans DC. Selective nociceptor activation in volunteers by infrared diode laser. Mol Pain. 2011 Aug 5;7:1744-8069-7–18.
38. Svensson P, Bjerring P, Arendt‐Nielsen L, Nielsen JC, Kaaber S. Comparison of four laser types for experimental pain stimulation on oral mucosa and hairy skin. Lasers Surg Med. 1991;11:313–24.
39. Culp WJ, Ochoa J, Cline M, Dotson R. Heat and mechanical hyperalgesia induced by capsaicin: Cross modality threshold modulation in human c nociceptors. Brain. 1989;112:1317–31.
40. Wallace MS, Barger D, Schulteis G. The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: A double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95:973–8.
41. Koltzenburg M, Torebjörk HE, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain. 1994;117:579–91.
42. Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-dependent pain, allodynia, and hyperalgesia in humans. J Investig Med. 2006;54:238–44.
43. Petersen KL, Maloney A, Hoke F, Dahl JB, Rowbotham MC. A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization. J Pain. 2003;4:400–6.
44. Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology. 2002;97:102–7.
45. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis. Vol. 13, Journal of Pain. 2012. p. 936–44.
46. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain. 1979;6:283–304.
47. Gozariu M, Bragard D, Willer JC, Le Bars D. Temporal summation of C-fiber afferent inputs: Competition between facilitatory and inhibitory effects on C-fiber reflex in the rat. J Neurophysiol. 1997;78:3165–79.
48. Willer JC, De Broucker T, Le Bars D. Encoding of nociceptive thermal stimuli by diffuse noxious inhibitory controls in humans. J Neurophysiol. 1989;62:1028–38.
49. Goubert D, Danneels L, Cagnie B, Van Oosterwijck J, Kolba K, Noyez H, et al. Effect of Pain Induction or Pain Reduction on Conditioned Pain Modulation in Adults: A Systematic Review. Vol. 15, Pain Practice. Blackwell Publishing Inc.; 2015. p. 765–77.
50. Tousignant-Laflamme Y, Pagé S, Goffaux P, Marchand S. An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res. 2008;1230:73–9.
51. Le Bars D. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res Rev. 2002;40:29–44.
52. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, et al. Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk. Pain. 2008 Aug;138:22–8.
53. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - New perspective of opioid-induced hyperalgesia. Pain. 2008;139:431–8.
54. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse noxious inhibitory controls (DNIC): Association with clinical variables. Pain. 2003;106:427–37.
2. Woolf CJ. What is this thing called pain? Vol. 120, Journal of Clinical Investigation. American Society for Clinical Investigation; 2010. p. 3742–4.
3. Woolf CJ. Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management. Ann Intern Med. 2004;140:441–51.
4. McCleskey EW, Gold MS. Ion Channels of Nociception. Annu Rev Physiol. 1999 Mar 28;61:835–56.
5. D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth. 2008;101:8–16.
6. Steeds CE. The anatomy and physiology of pain. Surg (United Kingdom). 2016;34:55–9.
7. Fields HL BA and HM. Central nervous system mechanisms of pain modulation. In: Textbook of Pain. Elsevier Churchill Livingstone, London.; 2006. p. 125–142.
8. Olesen AE, Andresen T, Staahl C, Drewes AM. Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev. 2012;64:722–79.
9. Maxwell DJ, Belle MD, Cheunsuang O, Stewart A, Morris R. Morphology of inhibitory and excitatory interneurons in superficial laminae of the rat dorsal horn. J Physiol. 2007 Oct 15;584:521–33.
10. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev. 2001;53:597–652.
11. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): Its relevance for acute and chronic pain states. Curr Opin Anaesthesiol. 2010 Oct;23:611–5.
12. Heinricher MM, Morgan MM. Supraspinal Mechanisms of Opioid Analgesia. Opioids Pain Control. 2010;46–69.
13. Moont R, Pud D, Sprecher E, Sharvit G, Yarnitsky D. “Pain inhibits pain” mechanisms: Is pain modulation simply due to distraction? Pain. 2010;150:113–20.
14. Vardeh D, Mannion RJ, Woolf CJ. Toward a Mechanism-Based Approach to Pain Diagnosis. Vol. 17, Journal of Pain. Churchill Livingstone Inc.; 2016. p. T50–69.
15. Reddy KSK, Naidu MUR, Rani PU, Rao TRK. Human experimental pain models: A review of standardized methods in drug development. J Res Med Sci. 2012 Jun;17:587–95.
16. Arendt-Nielsen L, Yücel A. Induction and assessment of experimental pain from human muscle. Agri. 2000;12:9–14.
17. Rocco AG, Raymond SA, Murray E, Dhingra U, Freiberger D. Differential spread of blockade of touch, cold, and pinprick during spinal anesthesia. Anesth Analg. 1985 Sep;64:917–23.
18. Liu SS, Ware PD. Differential sensory block after spinal bupivacaine in volunteers. Anesth Analg. 1997;84:115–9.
19. Burke D, Mackenzie RA, Skuse NF, Lethlean AK. Cutaneous afferent activity in median and radial nerve fascicles: A microelectrode study. J Neurol Neurosurg Psychiatry. 1975;38:855–64.
20. Curatolo M, Petersen-Felix S, Arendt-Nielsen L. Sensory assessment of regional analgesia in humans: a review of methods and applications. Anesthesiology. 2000;93:1517–30.
21. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden AM. Epidural epinephrine and clonidine: Segmental analgesia and effects on different pain modalities. Anesthesiology. 1997;87:785–94.
22. Butterworth J, Ririe DG, Thompson RB, Walker FO, Jackson D, James RL. Differential onset of median nerve block: Randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers. Br J Anaesth. 1998;81:515–21.
23. Staahl C, Drewes AM. Experimental human pain models: A review of standardised methods for preclinical testing of analgesics. Basic Clin Pharmacol Toxicol. 2004 Sep;95:97–111.
24. Fischer AA. Pressure algometry over normal muscles. Standard values, validity and reproducibility of pressure threshold. Pain. 1987;30:115–26.
25. Graven-Nielsen T, Arendt-Nielsen L. Induction and assessment of muscle pain, referred pain, and muscular hyperalgesia. Curr Pain Headache Rep. 2003 Nov;7:443–51.
26. Greenspan JD, Mcgillis SLB. Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain. Somatosens Mot Res. 1991 Jan 10;8:137–47.
27. Mouraux A, Iannetti GD, Plaghki L. Low intensity intra-epidermal electrical stimulation can activate Aδ-nociceptors selectively. Pain. 2010;150:199–207.
28. Koppert W, Dern SK, Sittl R, Albrecht S, Schüttler J, Schmelz M. A new model of electrically evoked pain and hyperalgesia in human skin: The effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology. 2001;95:395–402.
29. Modir JG, Wallace MS. Human experimental pain models 2: the cold pressor model. Methods Mol Biol. 2010;617:165–8.
30. Fowler CJ, Sitzoglou K, Ali Z, Halonen P. The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling. J Neurol Neurosurg Psychiatry. 1988;51:1164–70.
31. Fowler CJ, Sitzoglou K, Ali Z, Halonen P. The conduction velocities of peripheral nerve fibres conveying sensations of warming and cooling. J Neurol Neurosurg Psychiatry. 1988;51:1164–70.
32. Arendt-Nielsen L, Chen ACN. Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol Clin. 2003;33:259–68.
33. Hughes AM, Rhodes J, Fisher G, Sellers M, Growcott JW. Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers. Br J Clin Pharmacol. 2002;53:604–12.
34. Handwerker HO, Kobal G. Psychophysiology of experimentally induced pain. Physiol Rev. 1993 Jul 1;73:639–71.
35. Arendt-Nielsen L. First pain event related potentials to argon laser stimuli: Recording and quantification. J Neurol Neurosurg Psychiatry. 1990;53:398–404.
36. Bromm B, Treede RD. Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients. Rev Neurol (Paris). 1991;147:625–43.
37. Tzabazis AZ, Klukinov M, Crottaz-Herbette S, Nemenov MI, Angst MS, Yeomans DC. Selective nociceptor activation in volunteers by infrared diode laser. Mol Pain. 2011 Aug 5;7:1744-8069-7–18.
38. Svensson P, Bjerring P, Arendt‐Nielsen L, Nielsen JC, Kaaber S. Comparison of four laser types for experimental pain stimulation on oral mucosa and hairy skin. Lasers Surg Med. 1991;11:313–24.
39. Culp WJ, Ochoa J, Cline M, Dotson R. Heat and mechanical hyperalgesia induced by capsaicin: Cross modality threshold modulation in human c nociceptors. Brain. 1989;112:1317–31.
40. Wallace MS, Barger D, Schulteis G. The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: A double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95:973–8.
41. Koltzenburg M, Torebjörk HE, Wahren LK. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain. 1994;117:579–91.
42. Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-dependent pain, allodynia, and hyperalgesia in humans. J Investig Med. 2006;54:238–44.
43. Petersen KL, Maloney A, Hoke F, Dahl JB, Rowbotham MC. A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization. J Pain. 2003;4:400–6.
44. Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology. 2002;97:102–7.
45. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis. Vol. 13, Journal of Pain. 2012. p. 936–44.
46. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain. 1979;6:283–304.
47. Gozariu M, Bragard D, Willer JC, Le Bars D. Temporal summation of C-fiber afferent inputs: Competition between facilitatory and inhibitory effects on C-fiber reflex in the rat. J Neurophysiol. 1997;78:3165–79.
48. Willer JC, De Broucker T, Le Bars D. Encoding of nociceptive thermal stimuli by diffuse noxious inhibitory controls in humans. J Neurophysiol. 1989;62:1028–38.
49. Goubert D, Danneels L, Cagnie B, Van Oosterwijck J, Kolba K, Noyez H, et al. Effect of Pain Induction or Pain Reduction on Conditioned Pain Modulation in Adults: A Systematic Review. Vol. 15, Pain Practice. Blackwell Publishing Inc.; 2015. p. 765–77.
50. Tousignant-Laflamme Y, Pagé S, Goffaux P, Marchand S. An experimental model to measure excitatory and inhibitory pain mechanisms in humans. Brain Res. 2008;1230:73–9.
51. Le Bars D. The whole body receptive field of dorsal horn multireceptive neurones. Brain Res Rev. 2002;40:29–44.
52. Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, et al. Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk. Pain. 2008 Aug;138:22–8.
53. Ram KC, Eisenberg E, Haddad M, Pud D. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - New perspective of opioid-induced hyperalgesia. Pain. 2008;139:431–8.
54. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse noxious inhibitory controls (DNIC): Association with clinical variables. Pain. 2003;106:427–37.
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