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Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain.

Orita S, Ishikawa T, Miyagi M, Ochiai N, Inoue G, Eguchi Y, Kamoda H, Arai G, Toyone T, Aoki Y, Kubo T, Takahashi K, Ohtori S - BMC Musculoskelet Disord (2011)

Bottom Line: P < 0.05 was considered significant.CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner.Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. sumihisa@silver.email.ne.jp

ABSTRACT

Background: The exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA.

Methods: Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7, 14, 21, and 28 days post injection. Dorsal root ganglia (DRG) were immunostained for three molecules after 7, 14, 21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant.

Results: Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.

Conclusions: Pain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.

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Related in: MedlinePlus

Modified concentrations of cytokines. (A) TNF-α, (B) IL-6, and (C) NGF. The concentrations of TNF-α and IL-6 were significantly elevated starting on day 1 after the injection and continued to increase with its peak on day 4, and they were gradually decreased as the postinjection period progressed (P < 0.05; Figure 2A, 2B). The concentration of NGF was significantly increased at 7 days after the injection (P < 0.05), and the increasing continued after this point (Figure 2C).
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Figure 2: Modified concentrations of cytokines. (A) TNF-α, (B) IL-6, and (C) NGF. The concentrations of TNF-α and IL-6 were significantly elevated starting on day 1 after the injection and continued to increase with its peak on day 4, and they were gradually decreased as the postinjection period progressed (P < 0.05; Figure 2A, 2B). The concentration of NGF was significantly increased at 7 days after the injection (P < 0.05), and the increasing continued after this point (Figure 2C).

Mentions: Figure 2 shows the modified concentrations of cytokines. The concentrations of TNF-α and IL-6 were significantly elevated starting on day 1 after the injection and continued to increase with its peak on day 4, and they were gradually decreased as the postinjection period progressed (Figure 2A, 2B). The concentration of NGF was significantly increased at 1 week after the injection (P < 0.05), and the increasing continued after this point (Figure 2C).


Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain.

Orita S, Ishikawa T, Miyagi M, Ochiai N, Inoue G, Eguchi Y, Kamoda H, Arai G, Toyone T, Aoki Y, Kubo T, Takahashi K, Ohtori S - BMC Musculoskelet Disord (2011)

Modified concentrations of cytokines. (A) TNF-α, (B) IL-6, and (C) NGF. The concentrations of TNF-α and IL-6 were significantly elevated starting on day 1 after the injection and continued to increase with its peak on day 4, and they were gradually decreased as the postinjection period progressed (P < 0.05; Figure 2A, 2B). The concentration of NGF was significantly increased at 7 days after the injection (P < 0.05), and the increasing continued after this point (Figure 2C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3142251&req=5

Figure 2: Modified concentrations of cytokines. (A) TNF-α, (B) IL-6, and (C) NGF. The concentrations of TNF-α and IL-6 were significantly elevated starting on day 1 after the injection and continued to increase with its peak on day 4, and they were gradually decreased as the postinjection period progressed (P < 0.05; Figure 2A, 2B). The concentration of NGF was significantly increased at 7 days after the injection (P < 0.05), and the increasing continued after this point (Figure 2C).
Mentions: Figure 2 shows the modified concentrations of cytokines. The concentrations of TNF-α and IL-6 were significantly elevated starting on day 1 after the injection and continued to increase with its peak on day 4, and they were gradually decreased as the postinjection period progressed (Figure 2A, 2B). The concentration of NGF was significantly increased at 1 week after the injection (P < 0.05), and the increasing continued after this point (Figure 2C).

Bottom Line: P < 0.05 was considered significant.CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner.Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. sumihisa@silver.email.ne.jp

ABSTRACT

Background: The exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA.

Methods: Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7, 14, 21, and 28 days post injection. Dorsal root ganglia (DRG) were immunostained for three molecules after 7, 14, 21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant.

Results: Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn.

Conclusions: Pain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state.

Show MeSH
Related in: MedlinePlus