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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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(a, b) Intraperitoneal (i.p.) administration of SANR (54, 180, and 540 μmol/kg body weight) attenuated mechanical hypersensitivity (a) and thermal hyperalgesia (c) induced by chronic compression of lumbar DRG in a dose-dependent manner (n = 10). Concentration-response curves of SANR at 7 h after drug delivery on mechanical hypersensitivity (b) and thermal hyperalgesia (d) are shown, respectively. (e, f) Motor coordination was not altered by systemic SANR (180 μmol/kg, i.p.). Quantitative analysis showing that i.p. SANR did not affect the latency (e) and speed (f) for rats falling from the accelerating rod, as compared to vehicle group (n = 6 for each group, P > 0.05). All data are expressed as mean ± S.E.M.
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fig4: (a, b) Intraperitoneal (i.p.) administration of SANR (54, 180, and 540 μmol/kg body weight) attenuated mechanical hypersensitivity (a) and thermal hyperalgesia (c) induced by chronic compression of lumbar DRG in a dose-dependent manner (n = 10). Concentration-response curves of SANR at 7 h after drug delivery on mechanical hypersensitivity (b) and thermal hyperalgesia (d) are shown, respectively. (e, f) Motor coordination was not altered by systemic SANR (180 μmol/kg, i.p.). Quantitative analysis showing that i.p. SANR did not affect the latency (e) and speed (f) for rats falling from the accelerating rod, as compared to vehicle group (n = 6 for each group, P > 0.05). All data are expressed as mean ± S.E.M.

Mentions: To investigate the acute effect of SANR on the pain hypersensitivity observed in CCD rats, we administered SANR via intraperitoneal (i.p.) injection once at 3 d after operation when mechanical and thermal hyperalgesia was completely developed. As shown in Figure 4(a), acute administration of SANR (54, 180, 540 μmol/kg body weight) dose-dependently elevated the mechanical threshold to von Frey hairs in ipsilateral paw as compared to predrug level, reflecting as attenuation of mechanical hypersensitivity (Figure 4(a), n = 10). This antinociceptive effect started from 1 h after drug administration, persisting over the test period, namely, 24 h after SANR delivery. Dose-response curve at 7 h after drug was fitted to a Hill equation, which yielded an IC50 of 506.5 ± 14.6 μmol/kg for SANR in attenuation of mechanical hypersensitivity (Figure 4(b)). Similarly, CCD-induced ipsilateral thermal hyperalgesia was dramatically reduced by acute SANR in a dose-dependent manner with a similar time course, as measured by a prolongation of response latency to radiant heat stimuli compared to predrug level (Figure 4(c), n = 10). The dose-response curve revealed an IC50 of 119.9 ± 4.1 μmol/kg for SANR in inhibition of thermal hyperalgesia (Figure 4(d)). In contrast, i.p. vehicle did not alter the magnitude of CCD-induced mechanical hypersensitivity and thermal hyperalgesia (Figures 4(a) and 4(c), n = 10, P > 0.05). In addition, motor coordination was not altered by systemic SANR administration (180 μmol/kg, i.p.), as compared to vehicle group (Figures 4(e) and 4(f), P > 0.05, n = 6).


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)

(a, b) Intraperitoneal (i.p.) administration of SANR (54, 180, and 540 μmol/kg body weight) attenuated mechanical hypersensitivity (a) and thermal hyperalgesia (c) induced by chronic compression of lumbar DRG in a dose-dependent manner (n = 10). Concentration-response curves of SANR at 7 h after drug delivery on mechanical hypersensitivity (b) and thermal hyperalgesia (d) are shown, respectively. (e, f) Motor coordination was not altered by systemic SANR (180 μmol/kg, i.p.). Quantitative analysis showing that i.p. SANR did not affect the latency (e) and speed (f) for rats falling from the accelerating rod, as compared to vehicle group (n = 6 for each group, P > 0.05). All data are expressed as mean ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644553&req=5

fig4: (a, b) Intraperitoneal (i.p.) administration of SANR (54, 180, and 540 μmol/kg body weight) attenuated mechanical hypersensitivity (a) and thermal hyperalgesia (c) induced by chronic compression of lumbar DRG in a dose-dependent manner (n = 10). Concentration-response curves of SANR at 7 h after drug delivery on mechanical hypersensitivity (b) and thermal hyperalgesia (d) are shown, respectively. (e, f) Motor coordination was not altered by systemic SANR (180 μmol/kg, i.p.). Quantitative analysis showing that i.p. SANR did not affect the latency (e) and speed (f) for rats falling from the accelerating rod, as compared to vehicle group (n = 6 for each group, P > 0.05). All data are expressed as mean ± S.E.M.
Mentions: To investigate the acute effect of SANR on the pain hypersensitivity observed in CCD rats, we administered SANR via intraperitoneal (i.p.) injection once at 3 d after operation when mechanical and thermal hyperalgesia was completely developed. As shown in Figure 4(a), acute administration of SANR (54, 180, 540 μmol/kg body weight) dose-dependently elevated the mechanical threshold to von Frey hairs in ipsilateral paw as compared to predrug level, reflecting as attenuation of mechanical hypersensitivity (Figure 4(a), n = 10). This antinociceptive effect started from 1 h after drug administration, persisting over the test period, namely, 24 h after SANR delivery. Dose-response curve at 7 h after drug was fitted to a Hill equation, which yielded an IC50 of 506.5 ± 14.6 μmol/kg for SANR in attenuation of mechanical hypersensitivity (Figure 4(b)). Similarly, CCD-induced ipsilateral thermal hyperalgesia was dramatically reduced by acute SANR in a dose-dependent manner with a similar time course, as measured by a prolongation of response latency to radiant heat stimuli compared to predrug level (Figure 4(c), n = 10). The dose-response curve revealed an IC50 of 119.9 ± 4.1 μmol/kg for SANR in inhibition of thermal hyperalgesia (Figure 4(d)). In contrast, i.p. vehicle did not alter the magnitude of CCD-induced mechanical hypersensitivity and thermal hyperalgesia (Figures 4(a) and 4(c), n = 10, P > 0.05). In addition, motor coordination was not altered by systemic SANR administration (180 μmol/kg, i.p.), as compared to vehicle group (Figures 4(e) and 4(f), P > 0.05, n = 6).

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