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. 2017 Aug;158(8):1481-1488.
doi: 10.1097/j.pain.0000000000000936.

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Pedro Alvarez  1   2 , Oliver Bogen  1   2 , Paul G Green  1   2 , Jon D Levine  1   2   3
Affiliations

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Pedro Alvarez et al. Pain. 2017 Aug.

Abstract

Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL-10, acting on its canonical receptor in muscle nociceptors.

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Figures

Figure 1
Figure 1. Effect of single and repeated exposure to eccentric exercise
The RBE was studied by evaluating the effect of repeated exposure to bouts of eccentric exercise and 2 different length intervals between these bouts (5 or 12 days) on muscle mechanical nociceptive threshold. A. After assessment of baseline nociceptive threshold (0), rats were submitted to eccentric exercise (double EE, open symbols, n=6) or sham procedure (single EE, solid symbols, n=6). Five days later, both groups were exposed to a bout of eccentric exercise (EE). B. A similar approach was used to study RBE after an interval of 12 days between bouts of eccentric exercise. *P < 0.05; ***P < 0.001.
Figure 2
Figure 2. Effect of AS/MM ODN treatment directed against IL-10R1 mRNA on protein expression of IL-10R1 in L4 and L5 DRG neurons
A. Western blot analysis of DRG extracts from rats injected i.t. daily with 40 μg of AS or MM ODNs for 5 consecutive days revealed significant down-regulation of IL-10R1 (see results section for details). The calculated molecular weight of IL-10R1 is 63 kDA (according to UniProtKB database entry G3V830). β-actin was used as a housekeeping gene product in this analysis, which has a calculated molecular weight of ~42 kDa (according to UniProtKB database entry P60771). B. Comparison of the protein expression by Western blotting demonstrated a significant decrease in IL-10R1 immunoreactivity (arbitrary units, a.u.) of DRG extracts from rats treated with AS ODN compared to MM ODN treated group. *P < 0.05
Figure 3
Figure 3. Effect of intrathecal treatment with AS/MM ODN directed against IL-10R1 mRNA on muscle nociceptive threshold
(A) Effect of AS/MM ODN (40 μg/20 μl, i.t.) injections for 5 days on muscle mechanical nociceptive threshold in naïve rats. Bars were plotted from readings taken before (Pre) and after (Post) ODN treatment. B. Effect of a first bout of eccentric exercise (EE) on muscle mechanical nociceptive threshold in rats to be submitted to AS or MM ODN treatment. C. Effect of daily AS/MM ODN (40 μg/20 μl) i.t. injections (starting on day 8 after first bout of EE) on muscle mechanical nociceptive threshold in rats submitted to a first bout of EE 12 days prior. The effect of this treatment on RBE12 was also evaluated on days 1 to 8 after second bout of EE. ***P < 0.001.
Figure 4
Figure 4. Effect of repeated exposure to eccentric exercise on IL-10 levels in the gastrocnemius muscle
The right gastrocnemius muscle was sampled in control rats (n=6, Naïve) and rats submitted to double bout of eccentric exercise (n=6, RBE). The IL-10 levels were assessed by ELISA from muscle samples (in duplicate) obtained 24 h after last exposure to EE. *P < 0.05
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