Eccentric exercise induces chronic alterations in musculoskeletal nociception in the rat

Abstract

Eccentric muscle exercise is a common cause of acute and chronic (lasting days to weeks) musculoskeletal pain. To evaluate the mechanisms involved, we have employed a model in the rat, in which eccentric hind limb exercise produces both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to subsequent exposure to an inflammatory mediator. Eccentric exercise of the hind limb produced mechanical hyperalgesia, measured in the gastrocnemius muscle, which returned to baseline at 120 h post-exercise. When nociceptive thresholds had returned to baseline, intramuscular injection of prostaglandin E(2) (PGE(2) ) induced hyperalgesia that was unattenuated 240 h later, much longer than PGE(2) -induced hyperalgesia in unexercised rats (4 h). This marked prolongation of PGE(2) hyperalgesia induced by eccentric exercise was prevented by the spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction of chronic pain. Exercise-induced hyperalgesia and prolongation of PGE(2) hyperalgesia were inhibited by the spinal intrathecal administration of antisense for the interleukin-6 but not the tumor necrosis factor α type 1 receptor. These findings provide further insight into the mechanism underlying exercise-induced chronic muscle pain, and suggest novel approaches for the prevention and treatment of exercise- or work-related chronic musculoskeletal pain syndromes.

Figure 1. Eccentric exercise induces muscle hyperalgesia

The ipsilateral hind limb was exercised eccentrically for 15 min (filled squares) and after exercise mechanical nociceptive threshold of the gastrocnemius muscle in both hind limbs measured over time. Compared to contralateral limbs (filled circle) there was a significant decrease in nociceptive threshold in the vibrated limbs, which lasted at least 120 h post-exercise.

Figure 2. Eccentric exercise induces hyperalgesic priming

Seven days after eccentric exercise, following recovery of nociceptive threshold to pre-exercise baseline, PGE₂ (1 μg) was injected into both the ipsilateral and contralateral gastrocnemius muscle. In non-exercised contralateral limbs (filled circles) PGE₂-induced hyperalgesia had completely resolved within 4 h, while in the exercised limbs (filled squares), hyperalgesia was greatly prolonged, being undiminished 240 h after PGE₂ administration.

Figure 3. PKCε antisense inhibits exercise-induced hyperalgesia

Intrathecal administration of ODN antisense against PKCε for 3 days before and 3 days after eccentric exercise suppressed the acute hyperalgesia in the exercised leg (open squares), while hyperalgesia was still present in exercised leg of mismatch ODN treated rats (filled squares). There was no significant effect of treatment in the contralateral limbs (two-way ANOVA F_1,60 = 3.4; P = 0.095).

Figure 4. PKCε antisense inhibits exercise-induced hyperalgesic priming

In rats that had received ODN antisense against PKCε, for 3 days before and 3 days after vibration (open squares, n=6), PGE₂–induced hyperalgesia returned to baseline by 4 h post PGE₂, while in mismatch-treated rats (filled squares), PGE₂ hyperalgesia remained elevated 240 h after exercise. There was no significant effect of treatment in the contralateral limbs (two-way ANOVA F_1,70 = 0.4; P = 0.53).

Figure 5. IL-6 receptor antisense prevents exercise-induced hyperalgesia

In rats that received antisense ODN to gp130 (open squares) for 3 days prior and 3 days after exercise, hyperalgesia in the exercised leg was significantly less than in exercised leg of rats receiving mismatch ODN to gp130 (filled squares). There was a significant effect of treatment in the contralateral limbs (two-way ANOVA F_1,60 = 6.5; P = 0.021), with a significant difference only at the 24 h time point (Bonferroni post-hoc test, P<0.001).

Figure 6. IL-6 receptor antisense prevents exercise-induced hyperalgesic priming

In rats that received ODN antisense to gp130 (open squares, n=6) for 3 days prior and 3 days after exercise, PGE₂–induced hyperalgesia returned to baseline by 4 h post PGE₂, in contrast to rats treated with mismatch ODN in which PGE₂ produced hyperalgesia that remained enhanced 72 h after exercise. There was a significant effect of antisense treatment in the contralateral limbs (two-way ANOVA, F_1,64 = 9.75; P = 0.007), with a significant difference only at the 4 h time point (Bonferroni post-hoc test, P<0.001).

Figure 7. TNFα type-1 receptor antisense does not prevent exercise-induced hyperalgesia

In rats that received ODN antisense to TNFα receptor type 1 (open squares) for 3 days prior and 3 days after exercise, hyperalgesia in the exercised leg was not significantly different compared to that in exercised leg of rats receiving mismatch ODN (filled squares; two-way ANOVA F_1,90 = 0.4; P = 0.54). There was no significant effect of treatment in the contralateral limbs (two-way ANOVA F_1,90 = 0.29; P = 0.600).

Figure 8. TNFα type-1 receptor antisense does not completely prevent exercise-induced hyperalgesic priming

In rats that received ODN antisense to TNFα receptor type-1 (open squares) for 3 days prior and 3 days after exercise, PGE₂–induced hyperalgesia remained elevated 72 h post PGE₂, similar to rats treated with mismatch ODN. However, hyperalgesia was significantly less at the 4 h time point in antisense- compared to mismatch-treated rats. There was no significant effect of treatment in the contralateral limbs (two-way ANOVA F_1,60 = 0.04; P = 0.84).