Abstract
BackgroundSpinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI.MethodsSpinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α.ResultsLXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4.ConclusionsCollectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0540-8) contains supplementary material, which is available to authorized users.
Highlights
Spinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation
Lipoxin A4 exerts an antiallodynic effect in mice and rats after SCI To investigate if lipoxin A4 (LXA4) blocks pain associated with SCI, we used the spinal cord thoracic hemisection rodent model of SCI [22]
The 50 % paw withdrawal thresholds was significantly increased by LXA4 treatment at 7 days after SCI in the contralateral paw only and bilaterally at 14 days (ipsilateral paw F(2,8) = 12.41, p = 0.0035; contralateral paw F(2,8) = 13.80, p = 0.0026), as compared with the vehicle-treated mice (Fig. 1b, c), and this attenuation of allodynia by LXA4 was maintained for up to 35 days after SCI (Fig. 1e, f)
Summary
Spinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. We have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI. Spinal cord injury (SCI) is a highly debilitating condition with a worldwide incidence that ranges from 40 to 80 cases per million people per year [1]. It is estimated that 40 to 50 % of patients with SCI develop neuropathic pain within the first year after injury, a chronic pain condition resulting from nerve damage [2, 3]. In recent years, it has become evident that the development of neuropathic pain involves neuronal pathways and components of the immune system and glial cells, such as astrocytes and microglia, that mount a local form of inflammation called neuroinflammation [6, 7]
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