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Objective：The current study intended to examine the antinociceptive effect of growth differentiation factor 15（GDF⁃15） and to elucidate its possible mechanism of action. Methods：Mice formalin⁃induced pain model with intrathecal administration of GDF ⁃ 15（50 ng）and intraperitoneal administration of GDF ⁃ 15（10，30，100 μg/kg）was used in this study to examine the antinociceptive effect of GDF⁃15. The expression of glial cell⁃line derived neurotrophic factor receptor alpha⁃like（GFRAL）which is considered to be the specific receptor of GDF ⁃15 was assessed using Western blot and immunofluorescence techniques. The expression of interleukin （IL）⁃6，IL⁃1β，tumor necrosis factor（TNF）⁃α，prodynorphin（PDYN）and proenkephalin（PENK）in the formalin micespinal cords was also evaluated. Results：Intrathecal administration of GDF ⁃15（50 ng）showed a significant antinociceptive effect informalin⁃induced tonic pain（P＜0.05）but not in formalin⁃induced acute pain. Intraperitoneal administration of GDF⁃15（10，30，100 μg/kg）produced a dose ⁃ dependent antinociceptive effect in mice formalin ⁃induced tonic pain. GFRAL was expressed in brain，cerebellum and spinal cord，and only in neurons of the spinal cord dorsal horn. Moreover，intrathecal injection of GDF ⁃15 inhibited the expression of pro ⁃ inflammatory mediators IL ⁃6（P＜0.05）and TNF ⁃α（P＜0.05）in the spinal cord of formalin mice. Conclusion：GDF ⁃15 exhibits a significant antinociceptive effect in formalin ⁃induced inflammatory hyperalgesia and its possible mechanism may be by reducing the expression of pro⁃inflammatory factors IL⁃6 and TNF⁃α. [ABSTRACT FROM AUTHOR]