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. 2019 Aug;160(8):1876-1882.
doi: 10.1097/j.pain.0000000000001570.

Interleukin 6 decreases nociceptor expression of the potassium channel KV1.4 in a rat model of hand-arm vibration syndrome

Pedro Alvarez  1 , Oliver Bogen  1 , Jon D Levine  1   2
Affiliations

Interleukin 6 decreases nociceptor expression of the potassium channel KV1.4 in a rat model of hand-arm vibration syndrome

Pedro Alvarez et al. Pain. 2019 Aug.

Abstract

Chronic muscle pain is a prominent symptom of the hand-arm vibration syndrome (HAVS), an occupational disease induced by exposure to vibrating power tools, but the underlying mechanism remains unknown. We evaluated the hypothesis that vibration induces an interleukin 6 (IL-6)-mediated downregulation of the potassium voltage-gated channel subfamily A member 4 (KV1.4) in nociceptors leading to muscle pain. Adult male rats were submitted to a protocol of mechanical vibration of the right hind limb. Twenty-four hours after vibration, muscle hyperalgesia was observed, concomitant to increased levels of IL-6 in the gastrocnemius muscle and decreased expression of KV1.4 in the dorsal root ganglia. Local injection of neutralizing antibodies against IL-6 attenuated the muscle hyperalgesia induced by vibration, whereas antisense knockdown of this channel in the dorsal root ganglia mimicked the muscle hyperalgesia observed in the model of HAVS. Finally, knockdown of the IL-6 receptor signaling subunit glycoprotein 130 (gp130) attenuated both vibration-induced muscle hyperalgesia and downregulation of KV1.4. These results support the hypothesis that IL-6 plays a central role in the induction of muscle pain in HAVS. This likely occurs through intracellular signaling downstream to the IL-6 receptor subunit gp130, which decreases the expression of KV1.4 in nociceptors.

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Conflict of interest statement

Conflict of interest statement: The authors report no conflict of interest.

Figures

Figure 1.
Figure 1.. Vibration induces muscle mechanical hyperalgesia and increased levels of IL-6 in the gastrocnemius muscle.
A. Hyperalgesia (i.e., reduction of mechanical nociceptive threshold) was observed in the gastrocnemius muscle in a group of rats submitted to the HAVS model, compared to control (naïve) rats. Two-way ANOVA showed significant effects for treatment (F1,5=383.8, P < 0.001), time (F1,5=222.1, P < 0.001) and treatment by time interaction (F1,5=464.3, P < 0.001). Post hoc analysis revealed significant differences between control and vibration exposed rats one day after vibration exposure; B. Representative Western blots showing IL-6 immunoreactivity in extracts from the ipsilateral gastrocnemius muscle of HAVS rats compared to control rats; C. Quantitative analysis (ratio of IL-6 to housekeeping protein Grk2) showed that, compared to controls, HAVS exhibited significantly increased IL-6 expression in the gastrocnemius muscle; D. Five hours after vibration (Post) nociceptive threshold was significantly reduced compared to baseline (Pre). A neutralizing antibody (anti-rat IL-6 goat IgG), but not vehicle (DPBS), injected into the gastrocnemius muscle 6 h after exposure to vibration significantly reduced the mechanical hyperalgesia. *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 2.
Figure 2.. Vibration down-regulates expression of KV1.4 in DRG innervating the gastrocnemius muscle.
A. Representative Western blots showing KV1.4 immunoreactivity in extracts from the ipsilateral L4-L5 DRGs of HAVS rats compared to control (naïve) rats; B. Quantitative analysis (ratio to reference protein) showed that, compared to controls, HAVS rats exhibited significantly decreased KV1.4 expression in DRG innervating the gastrocnemius muscle (unpaired t test, t = 1.859 df = 10, P = 0.046). β-actin was used as the housekeeping reference protein; C. KV1.4 knockdown in DRG by i.t. AS, but not SE, ODN treatment produced significant mechanical hyperalgesia in the gastrocnemius muscle. Two-way ANOVA showed significant effects for treatment (F1,10=192, P < 0.001), time (F4,40=123.1, P < 0.001) and interaction (F4,40=77.8, P < 0.001). Post hoc analysis of each time point revealed significant differences between AS and SE treated rats from days 1 to 7 after last ODN injection. *P < 0.05; ***P < 0.001.
Figure 3.
Figure 3.. Knockdown of gp130 attenuates vibration-induced muscle hyperalgesia and KV1.4 expression.
A. Compared to baseline mechanical nociceptive threshold (Pre), vibration produced significant muscle mechanical hyperalgesia (Post), which was attenuated by i.t. AS, but not MM, ODN directed against gp130; Two-way ANOVA showed significant effects for treatment (F1,10=6.275, P < 0.031), time (F1,10=253.1, P < 0.001) but not interaction (F1,10=4.869, P = 0.051). Post hoc analysis revealed significant differences between AS and MM treated rats one day after exposure to vibration. B. Representative Western blots showing reduced down-regulation of KV1.4 expression in rats treated with AS ODN against gp130. C. Quantitative analysis (ratio to reference protein) showed that, compared to MM, AS ODN significantly attenuated the down-regulation of KV1.4 and the expression of gp130 in L4-L5 DRG in HAVS model rats; unpaired Student t test (t = 2.187, df = 10) revealed significant differences between AS and MM treated rats in nociceptor expression of gp130 (P = 0.009) and KV1.4 (P = 0.026), one day after exposure to vibration. β-actin was used as housekeeping reference protein. *P < 0.05; **P < 0.01
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