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A Novel Nitronyl Nitroxide with Salicylic Acid Framework Attenuates Pain Hypersensitivity and Ectopic Neuronal Discharges in Radicular Low Back Pain.

Han WJ, Chen L, Wang HB, Liu XZ, Hu SJ, Sun XL, Luo C - Neural Plast. (2015)

Bottom Line: However, long-term use of these drugs causes unwanted side effects, which limits their implication.The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation.Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, Fourth Military Medical University, Xi'an 710032, China.

ABSTRACT
Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain.

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Related in: MedlinePlus

Repeated treatment of SANR produces antinociceptive effect on CCD-induced mechanical hypersensitivity and thermal hyperalgesia in bilateral hindpaws, which is more potent than parent nitroxide moiety Tempol and parent NSAIDs moiety aspirin. (a, c) Time course of mechanical hypersensitivity (a) and thermal hyperalgesia (c) in ipsilateral hindpaw of CCD rats before and after repeated i.p. SANR (180 μmol/kg) (red) and vehicle treatment (black). Note that ipsilateral mechanical and thermal hyperalgesia was progressively and completely reversed by SANR. (b, d) Comparison of analgesic potency in ipsilateral mechanical (b) and thermal hyperalgesia (d) produced by the same concentration of SANR, Tempol, and aspirin for 18 days. Note that SANR showed significantly stronger effect than Tempol and aspirin. (e, g) Contralateral mechanical hypersensitivity (e) and thermal hyperalgesia (g) were reduced by repeated SANR administration as well. (f, h) Comparison of the efficacy by SANR with Tempol and aspirin in inhibiting mechanical (f) and thermal hyperalgesia (h) at 18 d during continuous drug administration. All data are expressed as mean ± S.E.M. ∗P < 0.05.
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fig6: Repeated treatment of SANR produces antinociceptive effect on CCD-induced mechanical hypersensitivity and thermal hyperalgesia in bilateral hindpaws, which is more potent than parent nitroxide moiety Tempol and parent NSAIDs moiety aspirin. (a, c) Time course of mechanical hypersensitivity (a) and thermal hyperalgesia (c) in ipsilateral hindpaw of CCD rats before and after repeated i.p. SANR (180 μmol/kg) (red) and vehicle treatment (black). Note that ipsilateral mechanical and thermal hyperalgesia was progressively and completely reversed by SANR. (b, d) Comparison of analgesic potency in ipsilateral mechanical (b) and thermal hyperalgesia (d) produced by the same concentration of SANR, Tempol, and aspirin for 18 days. Note that SANR showed significantly stronger effect than Tempol and aspirin. (e, g) Contralateral mechanical hypersensitivity (e) and thermal hyperalgesia (g) were reduced by repeated SANR administration as well. (f, h) Comparison of the efficacy by SANR with Tempol and aspirin in inhibiting mechanical (f) and thermal hyperalgesia (h) at 18 d during continuous drug administration. All data are expressed as mean ± S.E.M. ∗P < 0.05.

Mentions: We further addressed whether repeated treatment of SANR could reverse the development of CCD-induced pain hypersensitivity. To do this, we administered SANR for 21 d once daily beginning at 3 d after DRG compression. As compared to vehicle group, repeated administration of SANR progressively reversed the development of ipsilateral mechanical hypersensitivity in CCD rats (Figure 6(a), n = 10, P < 0.05 at all time points tested). In comparison with Tempol and aspirin, SANR produced more pain relief on mechanical hyperalgesia (Figure 6(b), n = 10 for each drug). Quantitative analysis at 18 d after drug treatment showed that the extent of reversal of mechanical hyperalgesia by SANR was significantly stronger than that of Tempol and aspirin (Figure 6(b), P = 0.043 versus Tempol, P = 0.039 versus aspirin). Similarly, progressive and complete reversal of ipsilateral thermal hyperalgesia was seen after treatment with repeated SANR (Figure 6(c), n = 10). Furthermore, SANR was much more efficacious than Tempol and aspirin alone (Figure 6(d), P = 0.029 versus Tempol, P = 0.018 versus aspirin).


A Novel Nitronyl Nitroxide with Salicylic Acid Framework Attenuates Pain Hypersensitivity and Ectopic Neuronal Discharges in Radicular Low Back Pain.

Han WJ, Chen L, Wang HB, Liu XZ, Hu SJ, Sun XL, Luo C - Neural Plast. (2015)

Repeated treatment of SANR produces antinociceptive effect on CCD-induced mechanical hypersensitivity and thermal hyperalgesia in bilateral hindpaws, which is more potent than parent nitroxide moiety Tempol and parent NSAIDs moiety aspirin. (a, c) Time course of mechanical hypersensitivity (a) and thermal hyperalgesia (c) in ipsilateral hindpaw of CCD rats before and after repeated i.p. SANR (180 μmol/kg) (red) and vehicle treatment (black). Note that ipsilateral mechanical and thermal hyperalgesia was progressively and completely reversed by SANR. (b, d) Comparison of analgesic potency in ipsilateral mechanical (b) and thermal hyperalgesia (d) produced by the same concentration of SANR, Tempol, and aspirin for 18 days. Note that SANR showed significantly stronger effect than Tempol and aspirin. (e, g) Contralateral mechanical hypersensitivity (e) and thermal hyperalgesia (g) were reduced by repeated SANR administration as well. (f, h) Comparison of the efficacy by SANR with Tempol and aspirin in inhibiting mechanical (f) and thermal hyperalgesia (h) at 18 d during continuous drug administration. All data are expressed as mean ± S.E.M. ∗P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644553&req=5

fig6: Repeated treatment of SANR produces antinociceptive effect on CCD-induced mechanical hypersensitivity and thermal hyperalgesia in bilateral hindpaws, which is more potent than parent nitroxide moiety Tempol and parent NSAIDs moiety aspirin. (a, c) Time course of mechanical hypersensitivity (a) and thermal hyperalgesia (c) in ipsilateral hindpaw of CCD rats before and after repeated i.p. SANR (180 μmol/kg) (red) and vehicle treatment (black). Note that ipsilateral mechanical and thermal hyperalgesia was progressively and completely reversed by SANR. (b, d) Comparison of analgesic potency in ipsilateral mechanical (b) and thermal hyperalgesia (d) produced by the same concentration of SANR, Tempol, and aspirin for 18 days. Note that SANR showed significantly stronger effect than Tempol and aspirin. (e, g) Contralateral mechanical hypersensitivity (e) and thermal hyperalgesia (g) were reduced by repeated SANR administration as well. (f, h) Comparison of the efficacy by SANR with Tempol and aspirin in inhibiting mechanical (f) and thermal hyperalgesia (h) at 18 d during continuous drug administration. All data are expressed as mean ± S.E.M. ∗P < 0.05.
Mentions: We further addressed whether repeated treatment of SANR could reverse the development of CCD-induced pain hypersensitivity. To do this, we administered SANR for 21 d once daily beginning at 3 d after DRG compression. As compared to vehicle group, repeated administration of SANR progressively reversed the development of ipsilateral mechanical hypersensitivity in CCD rats (Figure 6(a), n = 10, P < 0.05 at all time points tested). In comparison with Tempol and aspirin, SANR produced more pain relief on mechanical hyperalgesia (Figure 6(b), n = 10 for each drug). Quantitative analysis at 18 d after drug treatment showed that the extent of reversal of mechanical hyperalgesia by SANR was significantly stronger than that of Tempol and aspirin (Figure 6(b), P = 0.043 versus Tempol, P = 0.039 versus aspirin). Similarly, progressive and complete reversal of ipsilateral thermal hyperalgesia was seen after treatment with repeated SANR (Figure 6(c), n = 10). Furthermore, SANR was much more efficacious than Tempol and aspirin alone (Figure 6(d), P = 0.029 versus Tempol, P = 0.018 versus aspirin).

Bottom Line: However, long-term use of these drugs causes unwanted side effects, which limits their implication.The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation.Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, Fourth Military Medical University, Xi'an 710032, China.

ABSTRACT
Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain.

Show MeSH
Related in: MedlinePlus