| BackgroundLumbar disc herniation is the most common cause of radicular pain, and low back pain and radicular pain induced by herniated disc are the major pain of patients. This disease greatly affects the quality of patients’life. Physicians have paid more and more attention to the multiple causes of radicular pain. It has been proven that, in addition to the mechanical compression, inflammatory response induced by chemical substances and mediators, immune response and sensitization of pain receptors might play crucial roles in the process of radicular pain. It has been proven that, the neuroinflammation and immune response induced by the herniated nucleus pulposus (NP) might play an important role in the generation of radicular pain. The NP tissue exists in the body as a normal disk, once herniated and exposed to the systemic circulation, could induced serious autoimmune responses and inflammations in the nervous system. What’ more, it would also induce the activation and penetration of leukocyte, release of inflammatory cytokine and degeneration of nerve cells, resulting in the generation of neuropathic pain.Resolvins, derived from ω-3 polyunsaturated fatty acid, are important endogenous mediators that have potent anti-inflammation and pro-resolution effects. Resolvins can mediate a number of processes, including inhibition of the infiltration of leukocytes, regression of inflammatory mediators and promotion of phagocytosis of apoptotic neutrophil and cell debris. Rather than blocking inflammation at early stage, Resolvins promote the resolution of inflammation timely. Resolvins has been proven to have anti-inflammation and pro-resolution effects against various inflammatory diseases such as asthma, sepsis, retinopathy and periodontal diseases. Furthermore, it has been shown that Resolvins can serve as a potent analgesic in several inflammatory and neuropathic pain models of rats. However, few studies have reported the effect of Resolvins on radicular pain caused by intervertebral disc herniation. The present study was aimed to explore the analgesic effect of RvD1 in the rat model of non-compressive lumbar disc herniation and discover the underlying mechanisms.ObjectiveTo establish the rat model of non-compressive lumbar disc herniation and investigate the analgesic effect and underlying mechanisms of Resolvin D1 on radicular pain.Methods1. Rats were divided into four groups (n=38/group):sham group (sham operation+10μl PBS), vehicle group (model+10ul PBS), RvD1 10ng group (model+10ng RvD1), RvD1 100ng (model+100ng RvD1). Models of non-compressive lumbar disc herniation were established and intrathecal catheter for drug administration was performed in all rats. PBS (10μl) or RvD1 (10μl) were administered to rats by using a 10μl microinjection syringe on each of three successive days post-operation.2. The 50% paw withdrawal threshold (50% PWT) of all rats was evaluated at 1 day before and also on 1,2,3,4,7,10,21 days after surgery. After the behavioral tests on postoperative day 7, rats in four groups were killed and the ipsilateral lumbar segments (L4-6) of spinal dorsal horns were quickly removed for the determination of expressions of TNF-a (tumor necrosis factor-a), IL-1β (interleukin-1β), IL-10 (interleukin-10) and TGF-β1 (transforming growth factor-(31) by RT-PCR (real-time polymerase chain reaction) and ELISA (enzyme-linked immune sorbent assay), and L5 DRGs were collected for the examination of protein expressions of TNF-α, IL-1β, IL-10 and TGF-(31 by ELISA. The protein expressions of NF-κB/p65 (nuclear factor-KB/p65) and ERK (extracellular signal-regulated kinase) signaling in the spinal dorsal horns were determinated by Western blot; and the positive cells expressing NF-KB/p65 and p-ERK were determinate by immunohistochemistry.ResultsDuring the observation period, compared with the sham group, the 50%PWT of vehicle group was significantly decreased since day 1 to day 21. The 50%PWT was significantly increased after the administration of RvD1 (lOng or 100ng). Compared with the sham group, the expressions of TNF-a and IL-1β were significant increased and the expressions of IL-10 and TGF-β1 were significantly decreased in both the spinal dorsal horns and DRGs; After the administration of RvD1 (10ng or 100ng), the expressions of TNF-α and IL-1β were significant decreased and the levels of IL-10 and TGF-β1 were significantly raised in the spinal dorsal horns and DRGs. Compared with sham group, the expressions of NF-KB/p65 and p-ERK in the spinal dorsal horns of the vehicle group rats were significantly up-regulated; the positive expressions of NF-KB/p65 and p-ERK were significantly increased in the vehicle group compared with the sham group, both in the spinal dorsal horns and DRGs; Intrathecal injection of RvDl (10ng or 100ng) dose-dependently attenuated the expressions of NF-κB/p65 and p-ERK in the spinal dorsal horns and the active expressions of NF-κB/p65 and p-ERK in the spinal dorsal horns and DRGs.ConclusionThe present study showed that intrathecal RvD1 might alleviate the radicular pain and inflammation induced by the herniated disc significantly via down-regulating the expression of pro-inflammatory cytokines (TNF-a and IL-1β), up-regulating the expression of anti-inflammatory mediators (TGF-β and IL-10) and inhibiting the activation of NF-κB/p65 and p-ERK pathways. Its anti-inflammatory and pro-resolution properties may offer novel therapeutic approaches for the management of neuropathic pain. Thus, RvDl may offer novel approaches and basis for the management of radicular inflammation and sciatica. |
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