1 Laboratoire d'Anesthésie, UPRES EA 3540, Faculté de Médecine, Université de Paris-Sud, 94276 Le Kremlin Bicêtre Cedex, France. 2 Département d'Anesthésie, Hôpital Ponchaillou, Rennes, France. 3 Département d'Anesthésie, Hôpital Raimond Poincarré, Garches, France
* Corresponding author. E-mail: jean-xavier.mazoit{at}kb.u-psud.fr
Accepted for publication March 3, 2005.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Using a neurolytic nerve block, we assessed the systemic inflammatory response elicited by a local injection of carrageenan in mice. Sixty mice received a unilateral sciatic nerve block with 70% ethanol followed 5 days later by an injection of carrageenan on the ipsilateral or contralateral hind paw. Whole blood was sampled 15 h after carrageenan injection.
Results. Fifty-six animals had a complete nerve block. Tumour necrosis factor-alpha (TNF-), interleukin 1ß (IL-1ß) and interleukin 10 (IL-10) concentrations were measured in the plasma of 20 mice (10 in the ispilateral group and 10 in the contralateral group). In the remaining 36 mice (18 in each group), blood was cultured for 24 h in the presence of lipopolysaccharide or Staphylococcus aureus extract. TNF-
and IL-1ß production in the supernatant were, on average, 30% lower in the ispilateral group than in the contralateral group.
Conclusion. A prolonged nerve block decreases the systemic consequences of the local inflammatory reaction elicited by carrageenan injection.
Keywords: complications, tissue inflammation ; model, mouse ; nerve block ; pharmacology, cytokines
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The aim of the present study was to assess the effect of a neurolytic nerve block on the systemic carrageenan-induced inflammatory response in mice.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the second group, LPS and SAC induced an increase in TNF- and IL-1ß production. In the controls (i.e. without LPS or SAC challenge) cytokine production remained below the limit of detection, indicating the absence of spontaneous activation. TNF-
production in the ipsilateral group decreased by 30% compared with the contralateral group after LPS and SAC challenges (P<0.05), and IL-1ß production decreased by 14% after LPS challenge (NS) and by 36% after SAC challenge (P<0.05) (Table 1 and Fig. 2). IL-10 production was higher after stimulation by SAC than after stimulation by LPS. Indeed, IL-10 concentration remained below the limit of detection in the contralateral group after LPS and increased to just above this limit in the ispilateral group.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The local inflammation produced by carrageenan injection not only induces a local release of pro-inflammatory cytokines, but also sensitizes the circulating leucocytes.4 5 Because this sensitization of leucocytes by carrageenan appears to be delayed, we decided to sample the animals 15 h after carrageenan injection.4 5 Whole-blood cultures were stimulated with LPS and SAC which act on the intracellular inflammatory signalling through Toll-like receptors 4 and 2, respectively.10 11 Two major pro-inflammatory cytokines (TNF- and IL-1ß), which are mainly produced by monocytes, and the anti-inflammatory cytokine IL-10 were measured. The neurolytic nerve block was associated with less leucocyte sensitization after ex vivo LPS and SAC stimulation in the ipsilateral group. This effect was obvious since we observed a decrease of >30% in TNF-
production after LPS or SAC challenge. In a previous study, we showed that bupivacaine injected intramuscularly far from the carrageenan injection was able to decrease the leucocyte sensitization to ex vivo stimulation by LPS or by SAC.5
Increased production of anti-inflammatory cytokines such as IL-10 may counterbalance the production of pro-inflammatory cytokines.12 Just as in our previous experiment showing that bupivacaine was able to limit the sensitization induced by carrageenan, an increased production of IL-10 by the stimulated leucocytes seems to accompany the decreased secretion of TNF- and IL-1ß (Table 1 and Fig. 2). However, this production did not appear to be closely associated with the decreased TNF-
and IL-1ß production. Indeed, IL-10 has been shown to have a limiting effect on the hyperalgesia induced by carrageenan injection in rats,13 but in this experiment the cytokine was injected directly into the hind paw, unlike the conditions of our experiment. Clearly, further experiments are needed to assess the role of IL-10 in the modulation of the systemic inflammatory response after carrageenan injection.
It is well known that leucocytes act at the site of inflammation to modulate nociception by releasing endogenous opioids,14 15 cytokines and other pro- or anti-inflammatory mediators.16 However, the inverse relationship, i.e. the effect of local inflammation on the general inflammatory status, has not been extensively studied in the context of nociception. In this setting, we speculate that a modulation of a local inflammatory reaction induces a critical effect on the systemic inflammatory response.
In conclusion, we have shown that a neurolytic nerve block can limit the systemic inflammatory response observed in mice after intraplantar injection of carrageenan. This study emphasized the evidence for neurogenic inflammation and its relationship with the general inflammatory response. A prolonged nerve block decreases not only the local inflammatory reaction observed after carrageenan injection,3 but also its systemic consequences.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Kissin I, Lee SS, Bradley EL Jr. Effect of prolonged nerve block on inflammatory hyperalgesia in rats: prevention of late hyperalgesia. Anesthesiology 1998; 88: 22432[CrossRef][ISI][Medline]
3 Gentili ME, Mazoit JX, Samii K, Fletcher D. The effect of a sciatic nerve block on the development of inflammation in carrageenan injected rats. Anesth Analg 1999; 89: 97984
4 Ogata M, Matsui T, Kita T, Shigematsu A. Carrageenan primes leukocytes to enhance lipopolysaccharide-induced tumor necrosis factor alpha production. Infect Immun 1999; 67: 32849
5 Beloeil H, Asehnoune K, Moine P, Benhamou D, Mazoit JX. Bupivacaine action on the carrageenan-induced inflammatory response in mice: cytokine production by leukocytes after ex-vivo stimulation. Anesth Analg 2005; 100: 10816
6 Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983; 16: 10910[CrossRef][ISI][Medline]
7 Thalhammer JG, Vladimirova M, Bershadsky B, Strichartz GR. Neurologic evaluation of the rat during sciatic nerve block with lidocaine. Anesthesiology 1995; 82: 101325[CrossRef][ISI][Medline]
8 Hu D, Hu R, Berde CB. Neurologic evaluation of infant and adult rats before and after sciatic nerve blockade. Anesthesiology 1997; 86: 95765[CrossRef][ISI][Medline]
9 Saadé NE, Massaad CA, Ochoa-Chaar CI, Jabbur SJ, Safieh-Garabedian B, Atweh SF. Upregulation of proinflammatory cytokines and nerve growth factor by intraplantar injection of capsaicin in rats. J Physiol 2002; 545: 24153
10 Rabehi L, Irinopoulou T, Cholley B, Haeffner-Cavaillon N, Carreno MP. Gram-positive and gram-negative bacteria do not trigger monocytic cytokine production through similar intracellular pathways. Infect Immun 2001; 69: 45909
11 Lehner MD, Morath S, Michelsen KS, Schumann RR, Hartung T. Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different Toll-like receptors independent of paracrine mediators. J Immunol 2001; 166: 51617
12 Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Ann Rev Immunol 2001; 19: 683765[CrossRef][ISI][Medline]
13 Poole S, Cunha FQ, Selkirk S, Lorenzetti BB, Ferreira SHl. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-10. Br J Pharmacol 1995; 115: 6848[ISI][Medline]
14 Stein C, Hassan AH, Przewlocki R, Gramsch C, Peter K, Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA 1990; 87: 59359
15 Brack A, Labuz D, Schiltz A, et al. Tissue monocytes/macrophages in inflammation: hyperalgesia versus opioid-mediated peripheral antinociception. Anesthesiology 2004; 101: 20411[ISI][Medline]
16 Watkins LR, Maier SF. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 2002; 82: 9811011