Effect And Mechanism Of Lipoxin A₄ On Radicular Pain Caused By Intervertebral Disc Herniation

BackgroundRadicular pain, most commonly caused by a herniated intervertebral disc, is hardly to be cured. The disease greatly affects patients’quality of life. Studies have proven that, in addition to mechanical compression, inflammatory response induced by protrused nucleus pulposus (NP) might play a crucial role in the process of radicular pain. It has been proven that the herniated NP tissue, once exposed to the systemic circulation, could be recognized as a foreign antigen and induce autoimmune responses and strong inflammations in the nerve root,DRG and central nervous system. A variety of inflammatory and immune cells were recruited to the peripheral and central nervous system and potentially release cytokines, such as TNF-a, IL-6, IL-1β and prostaglandin.Lipoxins (LXs) are important lipid mediators of endogenous anti-inflammation and resolution, generated from arachidonic acid via sequential actions of lipoxygenases and subsequent reactions to give specific trihydroxytetraene-containing eicosanoids. LXs can function as "braking signals" in inflammation to mediate a number of processes, including inhibition of the recruitment of neutrophils, promotion of nonphlogistic phagocytosis of apoptotic leukocytes, and regression of cytokines or chemokines. LXs has been shown to protect against various inflammatory disorders such as acute lung injury, asthma, renal fibrosis and other diseases. However, few studies have shown the effect of LXs on radicular pain caused by intervertebral disc herniation. The present study was aimed to explore the analgesic effect of LXA4 on rat models of non-compressive lumbar herniated intervertebral disc and discover its underlying mechanisms.ObjectiveTo establish rat models of non-compressive lumbar herniated intervertebral disc and investigate the effect and mechanism of lipoxin A4 on radicular pain.Methods1.Rat models of non-compressive lumbar herniated intervertebral disc were established and intrathecal catheterization for drug administration was performed in rats. Normal saline(10 μl) or LXA4 (10 μl) were administered to rats on each of three successive days post-operation. Thus, seventy-two adult male Sprague-Dawley rats were divided into 4 groups according to the random number table (n=18 each):sham group (sham operation with 10 μl normal saline), model group (model with 10 μl normal saline), LXA4 lOng group (model with 10 ng LXA4) and LXA4 100ng group (model with 100 ng LXA4).2.General behaviors were observed and 50% paw withdrawal threshold (50% PWT) was measured at 1 day before and on each of 7 successive days after surgery in each group. After behavioral tests on the postoperative day 7, all rats were killed and the ipsilateral lumbar (L4-6) segment of spinal dorsal horns were removed for the determination of NF-κB/p65 and MAPK (ERK, JNK and P38)expression by Western blot technique and TNF-α, IL-1β, TGF-β1 and IL-10expression by ELISA and PCR.ResultsCompared with sham group, the 50% PWT of model group was significant decreased (p< 0.05); Compared with model group, the 50% PWT of LXA410ng group and LXA4 100ng group was significant elevated (p< 0.05). Compared with sham group, the protein and mRNA expression of TNF-α and IL-1β were significant rised(p< 0.05),the protein and mRNA expression of TGF-β1 and the protein expression of IL-10 were significant decreased in model group (p< 0.05); Compared with model group, the protein and mRNA expression of TNF-α and IL-1β were significant decreased (p< 0.05),the protein and mRNA expression of TGF-β1 and the protein expression of IL-10 were significant rised in a dose dependent manner in LXA4 lOng group and LXA4 100ng group (p< 0.05). Compared with sham group,NF-κB/p65, p-ERK, p-JNK and p-p38 expression were significant rised in model group (p< 0.05); Compared with model group, NF-κB/p65, p-ERK and p-JNK expression were significant decreased in a dose dependent manner in LXA4 lOng group and LXA4 100ng group (p< 0.05), No changes of p38 expression were observed after LXA4 application (p> 0.05).ConclusionLXA4 can alleviate radicular pain in rats with non-compressive lumbar herniated intervertebral disc. The underlying mechanism involved inhibiting the activation of NF-κB/p65, ERK and JNK pathways and reducing the expression of pro-inflammatory cytokines (TNF-α and IL-1β) and increasing the expression of anti-inflammatory cytokines (TGF-β1 and IL-10).