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. 2008 Mar 18;152(2):521-5.
doi: 10.1016/j.neuroscience.2008.01.006. Epub 2008 Jan 12.

Role of interleukin-6 in chronic muscle hyperalgesic priming

O A Dina  1 , P G Green, J D Levine
Affiliations

Role of interleukin-6 in chronic muscle hyperalgesic priming

O A Dina et al. Neuroscience. .

Abstract

After recovery from acute muscle pain even minor subsequent muscle use can initiate recurrence of the same mechanical hyperalgesia months or years after the initial injury. We have recently developed a model of this chronic latent hyperalgesia in the rat. In this study, we have examined the possibility that interleukin-6 (IL-6), an inflammatory mediator produced during acute muscle inflammation, can mediate the production of this chronic latent hyperalgesic state in which subsequent exposure to inflammatory mediators produces a markedly prolonged mechanical hyperalgesia. We now report that i.m. injection of IL-6 produced mechanical hyperalgesia, lasting several hours, that was prevented by intrathecal injection of antisense to glycoprotein 130 (gp130), an IL-6 receptor subunit. Furthermore, following complete recovery from i.m. IL-6-induced hyperalgesia, i.m. prostaglandin E(2) produced a mechanical hyperalgesia that was remarkably prolonged compared with naïve controls, indicating the presence of chronic latent hyperalgesia. This ability of IL-6 to produce chronic latent hyperalgesia was prevented by intrathecal administration of antisense for gp130. Furthermore, gp130 antisense also prevented chronic latent hyperalgesia produced by i.m. injection of the inflammogen, carrageenan. These results identify a role for IL-6 in acute inflammatory muscle pain and as a potential target against which therapies might be directed to treat chronic muscle pain.

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Figures

Figure 1
Figure 1. IL-6 induces mechanical hyperalgesia in gastrocnemius muscle
IL-6 (10 ng in 10 μl, filled circles), injected into the belly of the gastrocnemius muscle, decreased nociceptive threshold by ~60% within 30 min, an effect that was maintained at approximately the same level for at least 3 h. Nociceptive thresholds had returned to baseline values by 120 h (5 days). Control animals injected with saline (0.9% NaCl, 10 μl, open circles) exhibited no significant change in threshold.
Figure 2
Figure 2. Admininstration of IL-6 receptor antisense prevents IL-6 hyperalgesia
Intrathecal administration of antisense ODN directed against the IL-6 receptor subunit gp130 daily for 3 days completely prevented hyperalgesia induced by subsequent intramuscular IL-6 (filled circle). Administration of IL-6 in rats receiving mismatch ODN did not affect the magnitude of IL-6-induced muscle hyperalgesia (open squares) compared to IL-6 in naïve rats (cf. Figure 1, filled circles). Administration of IL-6 antisense (closed squares) or mismatch (open squares) did not affect baseline nociceptive thresholds. Of note, some of the error bars are very small and so are hidden within the symbol.
Figure 3
Figure 3. IL-6 induces a chronic latent hyperalgesic priming in muscle
Ten days after IL-6 administration, following complete recovery from the hyperalgesia (leg withdrawal threshold returned to baseline after 5 days), PGE2 (1 μg) was injected into the muscle. In saline pretreated rats (open symbols), PGE2-induced hyperalgesia had completely resolved within 4 h, but in the cytokine-pretreated muscles (filled symbols), hyperalgesia was greatly prolonged, being undiminished 24 h after PGE2 admininstration.
Figure 4
Figure 4. IL-6 receptor antisense inhibits chronic latent hyperalgesia induced by carrageenan
Intrathecal injections of ODN antisense or mismatch for the IL-6 receptor subunit gp130 were given once daily for 3 days prior to carrageenan and daily thereafter for an additional 5 days. Intramuscular PGE2 injected 6 days after the final intrathecal ODN administration, produced hyperalgesia that persisted for more than 14 days in the mismatch ODN treated rats (open symbols) compared to < 4 h in the antisense ODN treated rats (closed symbols).
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