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. 2020 Mar-Apr;21(3-4):506-512.
doi: 10.1016/j.jpain.2019.09.004. Epub 2019 Sep 25.

Nociceptor Interleukin 33 Receptor/ST2 Signaling in Vibration-Induced Muscle Pain in the Rat

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

Nociceptor Interleukin 33 Receptor/ST2 Signaling in Vibration-Induced Muscle Pain in the Rat

Pedro Alvarez et al. J Pain. 2020 Mar-Apr.

Abstract

Occupational exposure to mechanical vibration can produce the hand-arm vibration syndrome (HAVS), whose most disabling symptom is persistent muscle pain. Unfortunately, the pathophysiology of HAVS pain is still poorly understood, precluding the development of mechanism-based therapies. Since interleukin 33 (IL-33) is essential for inflammation and recovery that follows skeletal muscle injury, we explored its role in muscle pain in a model of HAVS, in adult male rats. Concomitant to mechanical hyperalgesia, an increase in IL-33 in the ipsilateral gastrocnemius muscle was observed 24 hours after vibration. A similar hyperalgesia was produced by intramuscular injection of recombinant rat IL-33 (rrIL-33, 10-300 ng). Intrathecal administration of an oligodeoxynucleotide antisense to IL-33R/ST2 mRNA decreased the expression of ST2 in DRG and attenuated both rrIL-33 and vibration-induced mechanical hyperalgesia. Together these data support the suggestion that IL-33 plays a central role in vibration-induced muscle pain by action, at least in part, on skeletal muscle nociceptors. PERSPECTIVE: Our findings provide evidence of the contribution of IL-33, acting on its canonical receptor, in nociceptors, to muscle pain induced by ergonomic vibration. This suggests that targeting IL-33/ST2 signaling may be a useful strategy for the treatment of muscle pain in HAVS.

Keywords: Ischemia; muscle pain; muscle strain; nociceptor hyperexcitability; vibration white finger.

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Figures

Figure 1:
Figure 1:. Upregulation of gastrocnemius muscle IL-33 in a model of HAVS, and intramuscular rrIL-3-induced muscle hyperalgesia.
A. Time course of mechanical hyperalgesia induced by exposure to vibration (HAVS model); repeated measures two-way ANOVA showed significant effects for treatment (F1,10 = 1.030, P < 0.0001), time (F6,60 = 270.1; P < 0.0001), and their interaction (F6,60 = 297.7; P < 0.0001). Bonferroni post hoc analysis revealed significant differences between control and HAVS rats between 1 and 14 days after vibration (***P < 0.001). B. Representative Western blots showing IL-33 immunoreactivity in extracts from gastrocnemius muscle of a rat exposed to vibration 24 h prior and a control rat. C. Ratio of reference protein Grk2 to IL-33 showed that IL-33 levels were significantly increased in muscle from HAVS rats (unpaired Student t-test, t = 1.923, df = 10; *P < 0.05).
Figure 2:
Figure 2:. Local IL-33 produces long-lasting muscle mechanical hyperalgesia.
A. Injection of rrIL-33 into the right gastrocnemius muscle produced a dose-dependent decrease in mechanical nociceptive threshold as measured 1 hour after injection; one-way ANOVA showed significant effects for treatment (F4,22 = 106.1, P < 0.001). Dunnett post hoc analysis revealed significant differences between vehicle and rrIL-33 doses (***P < 0.001). B. Time course of hyperalgesia induced by different doses of rrIL-33; repeated measures two-way ANOVA showed significant effects for treatment (F4,22 = 104.8, P < 0.0001), time (F7,154 = 167.9; P < 0.0001), and their interaction (F28,154 = 13.75; P < 0.0001). Bonferroni post hoc analysis revealed significant differences between vehicle and rrIL-33 treated rats over the period 0.5 to 72 h after injection (solid symbols, P < 0.05).
Figure 3:
Figure 3:. Effect of antisense (AS)/mismatch (MM) oligodeoxynucleotides (ODN) treatment directed against IL-33R/ST2 mRNA on protein expression of IL-33R/ST2 in L4-L5 DRG homogenates.
A. Representative Western blots showing expression of IL-33R/ST2 in extracts from L4-L5 DRG from rats treated with AS or MM ODN. B. Quantitative analysis (ratio to β-actin reference protein) showed that, compared to MM, AS treatment significantly attenuated the expression of IL-33R/ST2 (unpaired Student t test, t = 2.296, df = 10, *P < 0.05).
Figure 4:
Figure 4:. Intrathecal ODN antisense to IL-33R/ST2 attenuates both rrIL-33 and HAVS hyperalgesia.
A. One day after the last of 3 daily i.t. injections the ODN treatment did not produce significant differences in nociceptive threshold but significantly attenuated the hyperalgesia induced by i.m. rrIL-33; repeated measures two-way ANOVA showed significant effects for treatment (F1,10 = 164.6; P < 0.0001), time (F2,20 = 693.8; P < 0.0001), and their interaction (F2,20 = 299.7; P < 0.0001). Bonferroni post hoc analysis revealed significant differences between AS and MM treated rats after rrIL-33 injection (***P < 0.001). B. Compared to MM ODN, AS directed against ST2 significantly attenuated vibration-induced mechanical hyperalgesia. Two-way ANOVA showed significant effects for treatment (F1,10 = 62.91; P < 0.0001), time (F5,50 = 411.4; P < 0.0001) and their interaction (F5,50 = 37.04; P < 0.0001). Post hoc analysis revealed significant differences between AS and MM treated rats on days 1 to 3 after exposure to vibration (***P < 0.001).
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