Systemic inflammation decreases pain threshold in humans in vivo

Moniek de Goeij, Lucas T van Eijk, Pascal Vanelderen, Oliver H Wilder-Smith, Kris C Vissers, Johannes G van der Hoeven, Matthijs Kox, Gert Jan Scheffer, Peter Pickkers, Moniek de Goeij, Lucas T van Eijk, Pascal Vanelderen, Oliver H Wilder-Smith, Kris C Vissers, Johannes G van der Hoeven, Matthijs Kox, Gert Jan Scheffer, Peter Pickkers

Abstract

Background: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods.

Methods and results: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20 ± 4 % and 13 ± 3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7 ± 3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques.

Conclusions and significance: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Plasma cytokine levels during human…
Figure 1. Plasma cytokine levels during human endotoxemia.
Data expressed as mean±SEM. At T=0 h endotoxin was administered. A: TNF-α, B: IL-10, C: IL-6, D: IL-1RA. h: hours.
Figure 2. Relative change in pain thresholds…
Figure 2. Relative change in pain thresholds during human endotoxemia.
A: combined pain pressure threshold (PPT) and B: combined electrical pain threshold (EPT) measured 2 hours after endotoxin administration. Values are depicted as percentage change from baseline (-1 h), where baseline was set at 100%. White bars: control subjects, black bars: endotoxin treated subjects. Data expressed as mean±SEM. h: hours.
Figure 3. Change in tolerance to the…
Figure 3. Change in tolerance to the cold pressor test during human endotoxemia.
A and B: Amount of discomfort in response to immersion of one hand in ice water, rated on a 0-10 numeric rating scale (NRS). C and D: Percentage of subjects with hand in ice water. Open circles: . T=-1 hour (before endotoxin treatment), black dots: T=2 hours, (after endotoxin treatment). A and C: results in endotoxin treated group, B and D: results in control group.

References

    1. Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12: 123-137. doi:10.1016/S0149-7634(88)80004-6. PubMed: .
    1. Angst MS, Clark JD (2006) Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104: 570-587. doi:10.1097/00000542-200603000-00025. PubMed: .
    1. Ozaktay AC, Kallakuri S, Takebayashi T, Cavanaugh JM, Asik I et al. (2006) Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptive fields in rats. Eur Spine J 15: 1529-1537. doi:10.1007/s00586-005-0058-8. PubMed: .
    1. Milligan ED, Sloane EM, Langer SJ, Hughes TS, Jekich BM et al. (2006) Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain 126: 294-308. doi:10.1016/j.pain.2006.07.009. PubMed: .
    1. Uçeyler N, Rogausch JP, Toyka KV, Sommer C (2007) Differential expression of cytokines in painful and painless neuropathies. Neurology 69: 42-49. doi:10.1212/01.wnl.0000265062.92340.a5. PubMed: .
    1. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21: 153-160. doi:10.1016/j.bbi.2006.09.006. PubMed: .
    1. Walk D, Sehgal N, Moeller-Bertram T, Edwards RR, Wasan A et al. (2009) Quantitative sensory testing and mapping: a review of nonautomated quantitative methods for examination of the patient with neuropathic pain. Clin J Pain 25: 632-640. doi:10.1097/AJP.0b013e3181a68c64. PubMed: .
    1. Bahador M, Cross AS (2007) From therapy to experimental model: a hundred years of endotoxin administration to human subjects. J Endotoxin Res 13: 251-279. doi:10.1177/0968051907085986. PubMed: .
    1. Dorresteijn MJ, van Eijk LT, Netea MG, Smits P, van der Hoeven JG et al. (2005) Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia. J Endotoxin Res 11: 287-293. doi:10.1179/096805105X58715. PubMed: .
    1. Levine FM, De Simone LL (1991) The effects of experimenter gender on pain report in male and female subjects. Pain 44: 69-72. doi:10.1016/0304-3959(91)90149-R. PubMed: .
    1. Watkins LR, Maier SF, Goehler LE (1995) Cytokine-to-brain communication: a review & analysis of alternative mechanisms. Life Sci 57: 1011-1026. doi:10.1016/0024-3205(95)02047-M. PubMed: .
    1. Maier SF, Watkins LR (1998) Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 105: 83-107. doi:10.1037/0033-295X.105.1.83. PubMed: .
    1. Maier SF, Goehler LE, Fleshner M, Watkins LR (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840: 289-300. doi:10.1111/j.1749-6632.1998.tb09569.x. PubMed: .
    1. Follenfant RL, Nakamura-Craig M, Henderson B, Higgs GA (1989) Inhibition by neuropeptides of interleukin-1 beta-induced, prostaglandin-independent hyperalgesia. Br J Pharmacol 98: 41-43. doi:10.1111/j.1476-5381.1989.tb16860.x. PubMed: .
    1. Poole S, Bristow AF, Lorenzetti BB, Das RE, Smith TW et al. (1992) Peripheral analgesic activities of peptides related to alpha-melanocyte stimulating hormone and interleukin-1 beta 193-195. Br J Pharmacol 106: 489-492. doi:10.1111/j.1476-5381.1992.tb14361.x. PubMed: .
    1. Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ et al. (2007) Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun 21: 686-698. doi:10.1016/j.bbi.2006.10.012. PubMed: .
    1. Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL (2000) Cytokine involvement in dynorphin-induced allodynia. Pain 84: 159-167. doi:10.1016/S0304-3959(99)00195-5. PubMed: .
    1. Chacur M, Milligan ED, Sloan EM, Wieseler-Frank J, Barrientos RM et al. (2004) Snake venom phospholipase A2s (Asp49 and Lys49) induce mechanical allodynia upon peri-sciatic administration: involvement of spinal cord glia, proinflammatory cytokines and nitric oxide. Pain 108: 180-191. doi:10.1016/j.pain.2003.12.023. PubMed: .
    1. Milligan ED, Langer SJ, Sloane EM, He L, Wieseler-Frank J et al. (2005) Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 21: 2136-2148. doi:10.1111/j.1460-9568.2005.04057.x. PubMed: .
    1. Oka T, Oka K, Hosoi M, Hori T (1996) Inhibition of peripheral interleukin-1 beta-induced hyperalgesia by the intracerebroventricular administration of diclofenac and alpha-melanocyte-stimulating hormone. Brain Res 736: 237-242. doi:10.1016/0006-8993(96)00705-6. PubMed: .
    1. Woolf CJ, Allchorne A, Safieh-Garabedian B, Poole S (1997) Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha. Br J Pharmacol 121: 417-424. doi:10.1038/sj.bjp.0701148. PubMed: .
    1. Safieh-Garabedian B, Poole S, Allchorne A, Winter J, Woolf CJ (1995) Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol 115: 1265-1275. doi:10.1111/j.1476-5381.1995.tb15035.x. PubMed: .
    1. van Eijk LT, Pickkers P, Smits P, van den Broek W, Bouw MP et al. (2005) Microvascular permeability during experimental human endotoxemia: an open intervention study. Crit Care 9: R157-R164. doi:10.1186/cc3220. PubMed: .
    1. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F et al. (2013) Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501: 52-57. doi:10.1038/nature12479. PubMed: .
    1. Diogenes A, Ferraz CC, Akopian AN, Henry MA, Hargreaves KM (2011) LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res 90: 759-764. doi:10.1177/0022034511400225. PubMed: .
    1. Benson S, Kattoor J, Wegner A, Hammes F, Reidick D et al. (2012) Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans. Pain 153: 794-799. doi:10.1016/j.pain.2011.12.001. PubMed: .
    1. Wieseler-Frank J, Maier SF, Watkins LR (2005) Immune-to-brain communication dynamically modulates pain: physiological and pathological consequences. Brain Behav Immun 19: 104-111. doi:10.1016/j.bbi.2004.08.004. PubMed: .

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren