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Gabapentin enhances the morphine anti-nociceptive effect in neuropathic pain via the interleukin-10-heme oxygenase-1 signalling pathway in rats.

Bao YH, Zhou QH, Chen R, Xu H, Zeng LL, Zhang X, Jiang W, Du DP - J. Mol. Neurosci. (2014)

Bottom Line: Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured.Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression.Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.

View Article: PubMed Central - PubMed

Affiliation: Pain Management Center, Shanghai Six People's Hospital, Shanghai Jiaotong University, No. 600 Yishan Road, Shanghai, 200233, People's Republic of China.

ABSTRACT
In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured. Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.

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HO-1 antagonist zinc protoporphyrin reversed the gabapentin-induced upregulation of heme oxygenase-1 (HO-1) expression and potentiated the anti-nociceptive effect of morphine in gabapentin/morphine-co-injected SNL rats. a Western blotting analysis of HO-1 in the rat spinal dorsal horns. β-actin was used as the loading control. The relative band densities for HO-1 after different treatments. Time course of tail–flick test (b) and Von Frey latencies (c) in SNL rats. The maximum anti-nociceptive effect of morphine occurred on days 1–2. From days 4–7, there was no difference between the morphine and saline-treated animals. When gabapentin was co-administered with morphine, it prevented morphine tolerance. In addition, ZnPP partially reversed the potentiating effect of gabapentin on morphine in SNL rats (n = 6, each). *p < 0.05, ***p < 0.001 compared with the saline group; ###p < 0.001 compared with the morphine-injected group; $p < 0.05, $$p < 0.01 $$$p < 0.001 compared with the gabapentin/morphine-injected group
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Fig5: HO-1 antagonist zinc protoporphyrin reversed the gabapentin-induced upregulation of heme oxygenase-1 (HO-1) expression and potentiated the anti-nociceptive effect of morphine in gabapentin/morphine-co-injected SNL rats. a Western blotting analysis of HO-1 in the rat spinal dorsal horns. β-actin was used as the loading control. The relative band densities for HO-1 after different treatments. Time course of tail–flick test (b) and Von Frey latencies (c) in SNL rats. The maximum anti-nociceptive effect of morphine occurred on days 1–2. From days 4–7, there was no difference between the morphine and saline-treated animals. When gabapentin was co-administered with morphine, it prevented morphine tolerance. In addition, ZnPP partially reversed the potentiating effect of gabapentin on morphine in SNL rats (n = 6, each). *p < 0.05, ***p < 0.001 compared with the saline group; ###p < 0.001 compared with the morphine-injected group; $p < 0.05, $$p < 0.01 $$$p < 0.001 compared with the gabapentin/morphine-injected group

Mentions: Daily i.t. injection of the HO-1 antagonist zinc protoporphyrin (ZnPP) with gabapentin/morphine in neuropathic pain rats for 7 days reversed the upregulation of HO-1 expression in gabapentin/morphine injected rats (Fig. 5a). In addition, it blocked the maintenance of morphine’s anti-nociceptive effect by gabapentin in SNL rats. Consistent with these results, the maximal anti-nociceptive effect of morphine was observed on day 1, and the maximal tolerance was observed on day 4 in morphine-injected rats. Co-administration of ZnPP with gabapentin plus morphine blocked the maintenance of morphine’s anti-nociceptive effect by gabapentin and decreased the expression of HO-1 in spinal cords from day 3 to day 7 (Fig. 5b, c).Fig. 5


Gabapentin enhances the morphine anti-nociceptive effect in neuropathic pain via the interleukin-10-heme oxygenase-1 signalling pathway in rats.

Bao YH, Zhou QH, Chen R, Xu H, Zeng LL, Zhang X, Jiang W, Du DP - J. Mol. Neurosci. (2014)

HO-1 antagonist zinc protoporphyrin reversed the gabapentin-induced upregulation of heme oxygenase-1 (HO-1) expression and potentiated the anti-nociceptive effect of morphine in gabapentin/morphine-co-injected SNL rats. a Western blotting analysis of HO-1 in the rat spinal dorsal horns. β-actin was used as the loading control. The relative band densities for HO-1 after different treatments. Time course of tail–flick test (b) and Von Frey latencies (c) in SNL rats. The maximum anti-nociceptive effect of morphine occurred on days 1–2. From days 4–7, there was no difference between the morphine and saline-treated animals. When gabapentin was co-administered with morphine, it prevented morphine tolerance. In addition, ZnPP partially reversed the potentiating effect of gabapentin on morphine in SNL rats (n = 6, each). *p < 0.05, ***p < 0.001 compared with the saline group; ###p < 0.001 compared with the morphine-injected group; $p < 0.05, $$p < 0.01 $$$p < 0.001 compared with the gabapentin/morphine-injected group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig5: HO-1 antagonist zinc protoporphyrin reversed the gabapentin-induced upregulation of heme oxygenase-1 (HO-1) expression and potentiated the anti-nociceptive effect of morphine in gabapentin/morphine-co-injected SNL rats. a Western blotting analysis of HO-1 in the rat spinal dorsal horns. β-actin was used as the loading control. The relative band densities for HO-1 after different treatments. Time course of tail–flick test (b) and Von Frey latencies (c) in SNL rats. The maximum anti-nociceptive effect of morphine occurred on days 1–2. From days 4–7, there was no difference between the morphine and saline-treated animals. When gabapentin was co-administered with morphine, it prevented morphine tolerance. In addition, ZnPP partially reversed the potentiating effect of gabapentin on morphine in SNL rats (n = 6, each). *p < 0.05, ***p < 0.001 compared with the saline group; ###p < 0.001 compared with the morphine-injected group; $p < 0.05, $$p < 0.01 $$$p < 0.001 compared with the gabapentin/morphine-injected group
Mentions: Daily i.t. injection of the HO-1 antagonist zinc protoporphyrin (ZnPP) with gabapentin/morphine in neuropathic pain rats for 7 days reversed the upregulation of HO-1 expression in gabapentin/morphine injected rats (Fig. 5a). In addition, it blocked the maintenance of morphine’s anti-nociceptive effect by gabapentin in SNL rats. Consistent with these results, the maximal anti-nociceptive effect of morphine was observed on day 1, and the maximal tolerance was observed on day 4 in morphine-injected rats. Co-administration of ZnPP with gabapentin plus morphine blocked the maintenance of morphine’s anti-nociceptive effect by gabapentin and decreased the expression of HO-1 in spinal cords from day 3 to day 7 (Fig. 5b, c).Fig. 5

Bottom Line: Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured.Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression.Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.

View Article: PubMed Central - PubMed

Affiliation: Pain Management Center, Shanghai Six People's Hospital, Shanghai Jiaotong University, No. 600 Yishan Road, Shanghai, 200233, People's Republic of China.

ABSTRACT
In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured. Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.

Show MeSH
Related in: MedlinePlus