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. 2011 Sep;15(8):796-800.
doi: 10.1016/j.ejpain.2011.02.005. Epub 2011 Mar 17.

Enhanced cytokine-induced mechanical hyperalgesia in skeletal muscle produced by a novel mechanism in rats exposed to unpredictable sound stress

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

Enhanced cytokine-induced mechanical hyperalgesia in skeletal muscle produced by a novel mechanism in rats exposed to unpredictable sound stress

Olayinka A Dina et al. Eur J Pain. 2011 Sep.

Abstract

Stress exacerbates both experimental and clinical pain, most well-characterized in irritable bowel and fibromyalgia syndromes. Since it has been hypothesized that cytokines play an etiopathogenic role in fibromyalgia and other chronic widespread pain conditions, we investigated the relationship between stress and cytokines in a model of stress-induced chronic somatic pain. A series of experiments were performed to evaluate the impact of stress on the hyperalgesia-induced by endotoxin (lipopolysaccharide, LPS) and the role of two pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis α (TNFα). Fourteen days after exposure to a 4-day protocol of unpredictable sound stress, the ability of systemic LPS (100 μg/kg, i.p) to elicit cytokine-mediated mechanical hyperalgesia was measured in gastrocnemius muscle. LPS-induced hyperalgesia was significantly greater in stressed rats, but when rats were treated intrathecally with antisense oligodeoxynucleotide (ODN), to decrease either the gp130 subunit of the IL-6 receptor or the TNFα receptor, in nociceptors, skeletal muscle hyperalgesia in sound stressed, but not control, rats was prevented. These data suggest that chronic stress alters signaling in the primary afferent nociceptor for the hyperalgesia induced by endogenously produced pro-inflammatory cytokines.

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Figures

Figure 1
Figure 1
Time line for stress exposure, administration of antisense and LPS and nociceptive testing
Figure 2
Figure 2. LPS-induced muscle hyperalgesia: role of IL-6
A. Administration of LPS (100 μg/kg i.p.), in control (mismatch ODN, filled circles n=12, baseline nociceptive threshold: 3.12±0.04 N, data point not shown) decreased nociceptive threshold ~20% beginning one day after administration. This hyperalgesia remained, undiminished, for the 7-day post-administration testing period. In rats treated with antisense ODN to gp130 (open circles, n=12, baseline nociceptive threshold: 3.13±0.03 N), to decrease expression of the gp130 subunit of the IL-6 receptor in primary afferent neurons, the magnitude and duration of LPS-induced hyperalgesia was not different from mismatch control rats. B. Fifteen days after the last exposure to sound stress, administration of LPS in rats treated with mismatch ODN (filled triangles n=12; baseline nociceptive threshold: 3.17±0.05 N, data point not shown) decreased nociceptive threshold ~30%, beginning one day after administration; this decrease in nociceptive threshold was significantly greater than in non-stressed rats receiving mismatched ODN (P<0.05). In stressed rats treated with antisense ODN to gp130 (open triangles, n=12; baseline nociceptive threshold: 3.14±0.03 N), LPS-induced hyperalgesia was prevented during ODN administration and 1 day post administration. 4 d post ODN administration, at a time when antisense effects would have reversed, the magnitude of LPS-induced hyperalgesia was not different from stressed rats receiving mismatch ODN.
Figure 3
Figure 3. LPS-induced muscle hyperalgesia: role of TNFα
A. Administration of LPS (100 μg/kg i.p.), in control (mismatch ODN, filled circles n=12; baseline nociceptive threshold: 3.09±0.04 N, data point not shown) decreased nociceptive threshold ~20% beginning one day after administration. This hyperalgesia remained undiminished for the 7-day post-administration testing period. In rats treated with ODN antisense to the TNFα receptor (open circles, n=12; baseline nociceptive threshold: 3.12±0.03 N), to decrease expression of this receptor in primary afferent neurons, the magnitude and duration of LPS-induced hyperalgesia was not different from control rats. Fifteen days after sound stress, administration of LPS in rats treated with mismatch ODN (filled triangles n=12; baseline nociceptive threshold: 3.12±0.04 N, data point not shown) decreased nociceptive threshold ~30% beginning one day after administration; this decrease in nociceptive threshold was significantly greater than in non-stressed rats receiving mismatched ODN (P
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