Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Nov;152(11):2549-2556.
doi: 10.1016/j.pain.2011.07.021. Epub 2011 Aug 23.

Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

Paul G Green  1 , Xiaojie Chen, Pedro Alvarez, Luiz F Ferrari, Jon D Levine
Affiliations

Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

Paul G Green et al. Pain. 2011 Nov.

Abstract

Chronic pain in adults has been associated with early-life stress. To examine the pronociceptive effect of early-life stress, we evaluated cutaneous and muscle nociception and activity in muscle nociceptors in an animal model of neonatal stress, limited bedding, in the rat. In this neonatal limited bedding (NLB) model, litters are exposed to limited bedding between postnatal days 2 and 9, and controls to standard bedding. In adult NLB-treated rats, mechanical nociceptive threshold in skeletal muscle was significantly lower (~22%) than in controls. Furthermore, administration of prostaglandin E(2) in skin as well as muscle produced markedly prolonged hyperalgesia, an effect prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cε (PKCε), a second messenger in nociceptors that has been implicated in the induction and maintenance of chronic pain. In electrophysiological studies, mechanical threshold of muscle nociceptors was reduced by ~31% and conduction velocity significantly increased (~28%). These findings indicate that neonatal stress induces a persistent hyperalgesia and nociceptor sensitization manifest in the adult and that the second messenger PKCε may be a target against which therapies might be directed to treat a chronic pain syndrome that is associated with early-life traumatic stress.

PubMed Disclaimer

Conflict of interest statement

The authors do not have a conflict of interest.

Figures

Figure 1
Figure 1. NLB stress produces a decrease mechanical nociceptive threshold and prolongation of PGE2 hyperalgesia in skeletal muscle
PGE2 (1 μg in 20 μl intramuscular) produced a marked decrease in mechanical nociceptive threshold in the gastrocnemius muscle 1 h post-injection that returns to near baseline in control (non-stressed) rats (open circles, n=9), when tested 4 h post-injection. In adult rats that were exposed to limited bedding on postnatal days 2 – 9 (NLB rats, see Methods, filled circles, n=12), PGE2 hyperalgesia was present 1 h post-injection, near maximal 4 h post-injection and still present 24 h post-injection. In adult NLB rats, mechanical nociceptive threshold of the gastrocnemius muscle was significantly lower (2.07±0.04 N) than the threshold in control rats (2.66±0.01 N).
Figure 2
Figure 2. NLB stress produces a prolongation in PGE2 hyperalgesia in skin
PGE2 (1 μg in 2.5 μl, intradermally) produced a marked decrease in mechanical nociceptive threshold in the hind paw measured 1 h post-injection that returns to near baseline in control (non-stressed) rats (open circles, n=6), when tested 4 h post-injection. In adult NLB rats (filled circles, n=10), PGE2 hyperalgesia was present 1 h post-injection and was still near maximal 4 h post-injection, and still present 24 h post injection. In adult NLB rats, mechanical nociceptive threshold of the skin on the dorsum of the hind paw was not significantly different from the threshold in control rats.
Figure 3
Figure 3. PKCε antisense inhibits NLB-induced hyperalgesic priming in muscle
In adult NLB rats that had received ODN antisense against PKCε for 3 days (filled circles, n=10), PGE2–induced hyperalgesia in the gastrocnemius muscle returned to baseline by 4 h post PGE2, while in mismatch-treated rats (open circles, n=10), PGE2 hyperalgesia remained elevated 24 h after PGE2.
Figure 4
Figure 4. PKCε antisense inhibits NLB-induced hyperalgesic priming in skin
In adult NLB rats that had received ODN antisense against PKCε for 3 days (filled circles, n=10), PGE2–induced hyperalgesia in the skin on the dorsum of the hind paw returned to baseline by 4 h post PGE2, while in mismatch-treated rats (open circles, n=10), PGE2 hyperalgesia remained elevated 4 h after PGE2.
Figure 5
Figure 5. Afferent fiber response to mechanical stimulation
Single-unit recording of muscle afferent fiber action potentials evoked by a sustained (60 s) suprathreshold (10 g) von Frey hair mechanical stimulation.
Figure 6
Figure 6. NLB stress decreases muscle nociceptor threshold
Mechanical threshold in nociceptors innervating the gastrocnemius muscle of NLB-treated rats was significantly lower (0.71 ± 0.07 mN, n=38) than the threshold of nociceptors from naive control rats (1.0 ± 0.11 mN, n= 26, P=0.0176, one-tailed Student’s t-test with Welch’s correction; top panel). Scattergram of mechanical thresholds of individual muscle nociceptors from naive control and NLB-treated rats (bottom panel).
Figure 7
Figure 7. NLB stress increases muscle nociceptor conduction velocity
Mean conduction velocity of muscle nociceptors in NLB-treated rats (2.44 ± 0.15 m/s, n=38) were significantly greater than from naive rats (1.91 ± 0.2 m/s, n=26, Student’s t-test with Welch’s correction, P=0.036). Scattergram of conduction velocities of muscle nociceptors in naive control and paclitaxel-treated rats (bottom panel).
Figure 8
Figure 8. NLB stress shifts muscle nociceptor conduction velocity frequency distribution
A plot of frequency distribution of conduction velocity indicates that there is a shift to faster conducting fibers in NLB-treated rats. Graph overlay shows smoothing curve of data (6th order polynomial, 4 neighbor averaging) to illustrate shift in conduction velocity distribution.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fibromyalgia problem case. Monotherapy is mostly insufficient. MMW Fortschr Med. 2002;144:52. - PubMed
    1. Ablin J, Neumann L, Buskila D. Pathogenesis of fibromyalgia - a review. Joint Bone Spine. 2008;75:273–279. - PubMed
    1. Ablin JN, Cohen H, Clauw DJ, Shalev R, Ablin E, Neumann L, Sarzi-Puttini P, Buskila D. A tale of two cities - the effect of low intensity conflict on prevalence and characteristics of musculoskeletal pain and somatic symptoms associated with chronic stress. Clin Exp Rheumatol. 2010 - PubMed
    1. Alvarez P, Levine JD, Green PG. Eccentric exercise induces chronic alterations in musculoskeletal nociception in the rat. Eur J Neurosci. 2010;32:819–825. - PMC - PubMed
    1. Amano T, Yamakuni T, Okabe N, Sakimura K, Takahashi Y. Production of nerve growth factor in rat skeletal muscle. Neurosci Lett. 1991;132:5–7. - PubMed

Publication types