Site-Specific, Dose-Dependent, and Sex-Related Responses to the Experimental Pain Model Induced by Intradermal Injection of Capsaicin to the Foreheads and Forearms of Healthy Humans

Aims: To investigate whether trigeminal manifestations of pain, sensitization, and vasomotor responses following the intradermal injection of capsaicin to the foreheads differ from manifestations following injection of capsaicin in the forearms of healthy humans. Dose dependency and sex-related differences of the evoked responses were also studied. Methods: Twenty-eight healthy volunteers (14 women, 14 men) participated in 2 separate experiments: (1) Features of pain and vasomotor responses following intradermal injection of capsaicin (100 µg/100 µL) to the forehead and forearm were compared. (2) The features after intradermal injection of 2 different doses of capsaicin (50, 100 µg/100 µL) to the forehead were also studied. In both experiments the effect of sex was also investigated. Results: Experiment 1 showed that peak pain intensity (F [1,104] = 24.4, P < .001) and duration (F [1,104] = 13.3, P < .001) were greater in the forehead. However, the areas of visible flare (F [1,104] = 5.7, P < .05) and secondary pinprick hyperalgesia (F [1,104] = 155.1, P < .001) were significantly larger in the forearm. Experiment 2 indicated that peak pain intensity in the forehead was not affected by the capsaicin dose (F [1,52] = 1.6, P = .214), but duration of pain (F [1,52] = 6.0, P < .05) and perceived pain area (F [1,52] = 13.5, P < .001) were greater for the higher dose. The areas of visible flare (F [1,52] = 27.5, P < .001) and secondary pinprick hyperalgesia (F [1,52] = 65.6, P < .001) were also larger for the higher dose. In both experiments, women showed greater manifestations in several responses. Conclusion: Capsaicin-evoked sensory and vasomotor manifestations were different in the forehead and forearm. The differences are most likely due to the differences in innervation density and neurovascular activity. The capsaicin-induced effects were demonstrated to be dose-dependent and sex-related phenomena.

capsaicin; forearm; forehead; sex; trigeminal

1. Hughes A, Macleod A, Growcott J, Thomas I. Assessment of the reproducibility of intradermal administration of capsaicin as a model for inducing human pain. Pain 2002; 99:323–331.

2. Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle, and viscera. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z (eds). Proceedings of the 8th World Congress on Pain. Progress in Pain Research and Management. Seattle: IASP Press, 1997;8: 393–425.

3. Arendt-Nielsen L, Graven-Nielsen T, Drewes A. Referred pain and hyperalgesia related to muscle and visceral pain. Curr Pain Headache Rep 2003;7:426–432.

4. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989;38:99–107.

5. LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: Psychophysical studies of underlying mechanisms. J Neurophysiol 1991;66:190–211.

6. Caterina MJ, Schumacher MA, Tominaga M. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 1997;389:816–824.

7. Ikeda H, Tokita Y, Suda H. Capsaicin-sensitive A delta fibers in cat tooth pulp. J Dent Res 1997;76:1341–1349.

8. Szolcsanyi J. Antidromic vasodilatation and neurogenic inflammation. Agents Actions 1988;23(1–2):4–11.

9. LaMotte RH, Lundberg LE, Torebjork HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol 1992;448:749–764.

10. Matran R, Alving K, Martling CR, Lacroix JS, Lundberg JM. Effects of neuropeptides and capsaicin on tracheobronchial blood flow of the pig. Acta Physiol Scand 1989; 135:335–342.

11. Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn Schmiedebergs Arch Pharmacol 1979;310:175–183.

12. Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11: 153–162.

13. Simone DA, Sorkin LS, Oh U, et al. Neurogenic hyperalgesia: Central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991;66:228–246.

14. Carstens E, Kuenzler N, Handwerker HO. Activation of neurons in rat trigeminal subnucleus caudalis by different irritant chemicals applied to oral or ocular mucosa. J Neurophysiol 1998;80:465–492.

15. Katz DB, Simon SA, Moody A, Nicolelis MA. Simultaneous reorganization in thalamocortical ensembles evolves over several hours after perioral capsaicin injections. J Neurophysiol 1999;82:963–977.

16. de Leeuw R, Albuquerque R, Okeson J, Carlson C. The contribution of neuroimaging techniques to the understanding of supraspinal pain circuits: Implications for orofacial pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:308–314.

17. Pelissier T, Pajot J, Dallel R. The orofacial capsaicin test in rats: Effects of different capsaicin concentrations and morphine. Pain 2002;96(1-2):81–87.

18. Flores CM, Leong AS, Dussor GO, Harding-Rose C, Hargreaves KM, Kilo S. Capsaicin-evoked CGRP release from rat buccal mucosa: Development of a model system for studying trigeminal mechanisms of neurogenic inflammation. Eur J Neurosci 2001;14:1113–1120.

19. Svensson P, Arendt-Nielsen L, Bjerring P, Bak P, Hjorth T, Troest T. Human mastication modulated by experimental trigeminal and extra-trigeminal painful stimuli. J Oral Rehabil 1996;23:838–848.

20. Ngom PI, Dubray C, Woda A, Dallel R. A human oral capsaicin pain model to assess topical anesthetic-analgesic drugs. Neurosci Lett 2001;316:149–152.

21. Baad-Hansen L, Jensen TS, Svensson P. A human model of intraoral pain and heat hyperalgesia. J Orofac Pain 2003;17:333–340.

22. Liu M, Max MB, Robinovitz E, Gracely RH, Bennett GJ. The human capsaicin model of allodynia and hyperalgesia: Sources of variability and methods for reduction. J Pain Symptom Manage 1998;16:10–20.

23. Witting N, Svensson P, Gottrup H, Arendt-Nielsen L, Jensen TS. Intramuscular and intradermal injection of capsaicin: A comparison of local and referred pain. Pain 2000;84:407–412.

24. Romaniello A, Cruccu G, McMillan AS, Arendt-Nielsen L, Svensson P. Effect of experimental pain from trigeminal muscle and skin on motor cortex excitability in humans. Brain Res 2000;882:120–127.

25. Ferrell WR, Wong BB, Lockhart JC, Ramsay JE. Gender differences in regional cutaneous microcirculatory responses to capsaicin. Fundam Clin Pharmacol 2004;18: 195–200.

26. Frot M, Feine JS, Bushnell MC. Sex differences in pain perception and anxiety. A psychophysical study with topical capsaicin. Pain 2004;108:230–236.

27. May A, Kaube H, Buchel C, et al. Experimental cranial pain elicited by capsaicin: A PET study. Pain 1998; 74:61–66.

28. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183–187.

29. Edvinsson L. Experimental headache models in animals and humans. Trends Pharmacol Sci 1995;16:5–9.

30. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47:614–624.

31. Buzzi MG. Trigeminal pain pathway: Peripheral and central activation as experimental models of migraine. Funct Neurol 2001;16(4 suppl):77–81.

32. Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-dependent pain, allodynia, and hyperalgesia in humans. J Investig Med 2006;54:238–244.

33. Fillingim RB, Maixner W. Gender differences in the response to noxious stimuli. Pain Forum 1995;4:209–221.

34. Riley JL III, Robinson ME, Emily W, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: A meta-analysis. Pain 1998;74:181–187.

35. Melzack R. The McGill Pain Questionnaire: Major properties and scoring methods. Pain 1975;1:277–299.

36. Drewes AM, Helweg-Larsen S, Petersen P, et al. McGill Pain Questionnaire translated into Danish: Experimental and clinical findings. Clin J Pain 1993;9:80–87.

37. Lima A, Bakker J. Noninvasive monitoring of peripheral perfusion. Intensive Care Med 2005;31:1316–1326.

38. Essex TJ, Byrne PO. A laser Doppler scanner for imaging blood flow in skin. J Biomed Eng 1991;13:189–194.

39. Quinn AG, McLelland J, Essex T, Farr PM. Measurement of cutaneous inflammatory reactions using a scanning laser-Doppler velocimeter. Br J Dermatol 1991; 125(1):30–37.

40. Francis JE, Rogli R, Love TJ, Robinson CP. Thermography as a means of blood perfusion measurement. J Biomech Eng 1979;101:246–249.

41. Green BG. Measurement of sensory irritation of the skin. Am J Contact Derm 2000;11:170–180.

42. Tominaga M, Julius D. Capsaicin receptor in the pain pathway. Jpn J Pharmacol 2000;83(1):20–24.

43. Silver WL, Clapp TR, Stone LM, Kinnamon SC. TRPV1 Receptors and Nasal Trigeminal Chemesthesis. Chem Senses 2006;31:807–812.

44. Shults RC. Chapter 3: Trigeminal primary afferent receptors. In: Gildenberg PL (ed). Pain and Headache. Vol 12. The Initial Processing of Pain and its Descending Control: Spinal and Trigeminal Systems. Basel, Switzerland: Karger, 1992:50–74.

45. Sessle BJ. Acute and chronic craniofacial pain: Brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 2000;11(1):57–91.

46. Besne I, Descombes C, Breton L. Effect of age and anatomical site on density of sensory innervation in human epidermis. Arch Dermatol 2002;138:1445–1450.

47. Nolan MF. Two-point discrimination assessment in the upper limb in young adult men and women. Phys Ther 1982;62:965–969.

48. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 1995;15(1 Pt 1):333–341.

49. Schmelz M, Schmid R, Handwerker HO, Torebjork HE. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 2000;123(Pt 3):560–571.

50. Weidner C, Schmidt R, Schmelz M, Hilliges M, Handwerker HO, Torebjork HE. Time course of post-excitatory effects separates afferent human C fibre classes. J Physiol 2000;527(Pt 1):185–191.

51. Schmelz M, Michael K, Weidner C, Schmidt R, Torebjork HE, Handwerker HO. Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport 2000; 11:645–648.

52. Young RF, King RB. Fiber spectrum of the trigeminal sensory root of the baboon determined by electron microscopy. J Neurosurg 1973;38:65–72.

53. Holland GR, Robinson PP. Cell counts in the trigeminal ganglion of the cat after inferior alveolar nerve injuries. J Anat 1990;171:179–186.

54. Ambalavanar R, Morris R. The distribution of binding by isolectin I-B4 from Griffonia simplicifolia in the trigeminal ganglion and brainstem trigeminal nuclei in the rat. Neuroscience 1992;47:421–429.

55. Schmidt R, Schmelz M, Weidner C, Handwerker HO, Torebjork HE. Innervation territories of mechano-insensitive C nociceptors in human skin. J Neurophysiol 2002;88:1859–1866.

56. Smoliar E, Smoliar A, Belkin VS. Innervation of human trigeminal nerve blood vessels. Cells Tissues Organs 1999;165:40–44.

57. Wallengren J. Vasoactive peptides in the skin. J Investig Dermatol Symp Proc 1997;2:49–55.

58. Ziegler EA, Magerl W, Meyer RA, Treede RD. Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 1999;122(Pt 12):2245–2257.

59. Koltzenburg M. Neural mechanisms of cutaneous nociceptive pain. Clin J Pain 2000;16(3 suppl):S131–S138.

60. Klede M, Handwerker HO, Schmelz M. Central origin of secondary mechanical hyperalgesia. J Neurophysiol 2003;90:353–359.

61. Merskey H, Bogduk N. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms.Task Force on Taxonomy, International Association for the Study of Pain, ed 2. Seattle, WA: IASP Press, 1994.

62. Berkley KJ. Sex differences in pain. Behav Brain Sci 1997;20:371–380.

63. Gazerani P, Andersen OK, Arendt-Nielsen L. A human experimental capsaicin model for trigeminal sensitization. Gender-specific differences. Pain 2005;118:155–163.

64. Aloisi AM. Gonadal hormones and sex differences in pain reactivity. Clin J Pain 2003;19:168–174.

65. Bereiter DA, Barker DJ. Hormone-induced enlargement of receptive fields in trigeminal mechanoreceptive neurons. I. Time course, hormone, and sex and modality specificity. Brain Res 1980;184:395–410.

66. Bereiter DA, Barker DJ. Facial receptive fields of trigeminal neurons: Increased size following estrogen treatment in female rats. Neuroendocrinology 1975;18:115–124.

67. Bereiter DA, Stanford LR, Barker DJ. Hormone-induced enlargement of receptive fields in trigeminal mechanoreceptive neurons. II. Possible mechanisms. Brain Res 1980; 184:411–423.

68. Ren K, Weil F, Dubner R, Murphy A, Hoffman GE. Progesterone attenuates persistent inflammatory hyperalgesia in female rats: Involvement of spinal NMDA receptor mechanisms. Brain Res 2000;865:272–277.

69. Zubieta JK, Smith YR, Bueller JA, et al. Mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 2002;22:5100–5107.

70. Lawless HT. Oral chemical irritation: Psychophysical properties. Chem Senses 1984;9:143–155.

71. Rentmeister-Bryant H, Green BG. Perceived irritation during ingestion of capsaicin or piperine: Comparison of trigeminal and non-trigeminal areas. Chem Senses 1997;22:257–266.

72. Green BG, Rentmeister-Bryant H. Temporal characteristics of capsaicin desensitization and stimulus-induced recovery in the oral cavity. Physiol Behav 1998;65: 141–149.

73. Roberts RG, Westerman RA, Widdop RE, Kotzmann RR, Payne R. Effects of capsaicin on cutaneous vasodilator responses inhumans. Agents Actions 1992;37(1–2):53–59.

74. Andrews K, Baranowski A, Kinnman E. Sensory threshold changes without initial pain or alterations in cutaneous blood flow, in the area of secondary hyperalgesia caused by topical application of capsaicin in humans. Neurosci Lett 1999;266:45–48.