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. 2010 Apr;11(4):369-77.
doi: 10.1016/j.jpain.2009.08.007. Epub 2009 Dec 3.

Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat

Affiliations

Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat

Olayinka A Dina et al. J Pain. 2010 Apr.

Abstract

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60-80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for approximately 2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-alpha (TNFalpha) receptor. Finally, in TNFalpha-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged.

Perspective: These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFalpha and the second messenger protein kinase Cepsilon as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome.

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Figures

Figure 1
Figure 1. Vibration induces muscle hyperalgesia
One hind limb was exposed to vibration for either 15 min (filled circles, n=6) or 60 min (filled triangles, n=6), in separate groups of rats and mechanical nociceptive thresholds of the gastrocnemius muscle in that and the contralateral control extremity measured over time. Compared to the control limbs (open symbols, both n=6) there was a significant decrease in nociceptive threshold in the vibrated limbs, which lasted at least 15 days post-vibration.
Figure 2
Figure 2. Vibration induces hyperalgesic priming
A. Priming to subsequent vibration Twenty days after a 15 min exposure to vibration (filled circles, n=8), at which time there was complete recovery to baseline nociceptive threshold, the vibrated hind limb was again exposed to the same vibration protocol. The duration of the decrease in nociceptive threshold in the re-vibrated hind limb was significantly longer than after the initial exposure. In non-vibrated contralateral limbs (open circles, n=8) there was no change in nociceptive threshold. B. Enhancement of PGE2 muscle hyperalgesia by vibration is prevented by PKCε antisense treatment Twenty-one days after a 15 min exposure to vibration, following recovery of nociceptive threshold to baseline, PGE2 (1 μg) was injected into the ipsilateral gastrocnemius muscle. In non-vibrated contralateral limbs (open circles, n=6) PGE2-induced hyperalgesia had completely resolved within 4 h, while in vibrated limbs (filled circles, n=6), hyperalgesia was greatly prolonged, being undiminished 14 d after PGE2 administration. In rats that had received ODN antisense against PKCε, for 3 days before and 3 days after vibration (filled triangles, n=6), PGE2–induced hyperalgesia was no longer enhanced, returning to baseline by 4 h post PGE2. C. PKCε antisense inhibits vibration-induced hyperalgesia Administration of ODN antisense against PKCε (intrathecally) for the 3 days before vibration (filled triangles, n=6) suppressed the acute hyperalgesia measured 2 days post vibration; however by day 7 hyperalgesia developed, and persisted, at the level seen after mismatch ODN treatment (filled squares, n=6). Administration of ODN antisense against PKCε for 3 days before and 3 days after vibration (filled circles, n=6) completely prevented the expression of hyperalgesia. No significant changes in nociceptive threshold in the contralateral non-vibrated hind limb were observed (data not shown).
Figure 3
Figure 3. TNFα receptor antisense prevents TNFα hyperalgesia
A. In rats that received ODN antisense to the TNFα receptor (n=4) for 3 days prior to vibration, hyperalgesia 1 day after vibration (filled squares, n=6) was significantly less than in vibrated limbs of rats receiving mismatch TNFα antisense (open squares, n=4). There was no change in nociceptive threshold in limbs contralateral to the vibrated limbs (circles, both n=6). B. Intrathecal administration of antisense ODN directed against the TNFα receptor (closed circles, n=4) daily for 3 days completely prevented hyperalgesia induced by subsequent intramuscular TNFα. Administration of TNFα in rats that had received mismatch ODN (open squares, n=4) did not affect the magnitude of TNFα-induced muscle hyperalgesia. There was no change in nociceptive threshold after saline in rats pretreated with either TNFα receptor (type I) antisense ODN (filled squares, n=4) or mismatch ODN (open circles, n=4).
Figure 4
Figure 4. TNFα produces priming for subseqent vibration hyperalgesia
Five days after intra-muscular injection of TNFα (filled squares, n=4), following complete recovery from acute hyperalgesia, rats were exposed to a single session of unilateral hind limb vibration (filled circles and filled squares). Mechanical nociceptive thresholds, measured daily for 4 days post-vibration were significantly lower in rats that had previously received TNFα (compared to vehicle treated; filled circles, n=6). There was no change in nociceptive threshold in limbs contralateral to the vibrated limbs (open circles and open squares, both n=4).

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