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. 2008 May;9(5):457-62.
doi: 10.1016/j.jpain.2008.01.328. Epub 2008 Mar 14.

Muscle inflammation induces a protein kinase Cepsilon-dependent chronic-latent muscle pain

Olayinka A Dina  1 , Jon D Levine, Paul G Green
Affiliations

Muscle inflammation induces a protein kinase Cepsilon-dependent chronic-latent muscle pain

Olayinka A Dina et al. J Pain. 2008 May.

Abstract

Skeletal muscle injuries can induce chronic pain, but the underlying mechanism is unknown. One possible cause has been suggested to be an increased sensitivity to inflammatory mediators. We demonstrate that self-limited inflammatory hyperalgesia induced by intramuscular carrageenan (lasting approximately 5 days) results in a state of chronic-latent hyperalgesia, revealed by injection of prostaglandin E(2) (PGE(2)) 10 days after carrageenan at the same site. In carrageenan-pretreated muscle, PGE(2) produced hyperalgesia that was unattenuated even 14 days after injection, markedly longer than the 4-hour hyperalgesia induced by PGE(2) in naive rats. This chronic-latent hyperalgesia was reversed as well as prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cepsilon, a second messenger implicated in long-lasting plasticity in cutaneous nociceptors.

Perspective: We describe a novel experimental model for chronic muscle pain, produced by mild acute muscle inflammation, that has clinical significance since it has the potential to reveal cellular processes by which acute inflammation or muscle trauma underlies chronic muscle pain.

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Figures

Figure 1
Figure 1. Carrageenan muscle hyperalgesia
Carrageenan (1%; 30 μl, filled circles n=3–6), injected into the gastrocnemius muscle of adult male rats decreased nociceptive threshold by ~60% within one day, and nociceptive threshold was lower than saline-injected muscle for 3 days. By day 4, nociceptive threshold was not significantly different from baseline (and saline-treated) values. Control animals injected with saline (0.9% NaCl, 30 μl, open circles n=3–6) exhibited no significant change in threshold.
Figure 2
Figure 2. Chronic-latent muscle hyperalgesia
Ten days after carrageenan (1%; 30μl), PGE2 (100 ng) was injected into the muscle. In saline pretreated rats (open circles, n=3–6), PGE2-induced hyperalgesia had completely resolved within 3 hours, but in the carrageenan-pretreated muscle (filled circles, n=6), the duration of hyperalgesia was greatly enhanced, remaining undiminished 1 week after PGE2 admininstration.
Figure 3
Figure 3. PKCε antisense prevents chronic-latent hyperalgesia
Three days before and 5 days after intramuscular carrageenan (1%; 30 μl in gastrocnemius), PKCε mismatch ODN (open circles, n=6) or antisense (filled circles, n=6), was injected intrathecally once daily. Six days after the final mismatch ODN, PGE2 (100 ng, injected into the gastrocnemius) produced a decrease in nociceptive threshold that lasted at least 14 d. In contrast, PGE2 hyperalgesia in PKCε antisense ODN-treated rats (filled circles, n=6) was significantly shorter, and similar in duration to saline-pretreated rats (cf. open circles Figure 2).
Figure 4
Figure 4. PKCε antisense reverses chronic-latent hyperalgesia
PKCε mismatch ODN (open circles, n=6) or antisense (filled circles, n=6) was injected intrathecally daily for 3 days, 5 days after intramuscular carrageenan (1%; 30μl in gastrocnemius) when nociceptive thresholds had returned to baseline. One day after the final ODN injection, PGE2 (100 ng, injected into the gastrocnemius) was injected into the muscle. In PKCε antisense ODN-injected rats (filled circles, n=6), PGE2 hyperalgesia was present 1 h post-PGE2, but by 4 h nociceptive threshold had returned to baseline, similar to the effect in saline pretreated rats (see open circles Figure 2). In contrast, in PKCε mismatch ODN administered rats, nociceptive threshold was significantly decreased even 24 h post PGE2 administration.
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