BackgroundChronic　post-surgical　pain　(CPSP)　remains　a　major　clinical　problem　and　is　often　refractory　to　current　treatments.　New　analgesic　medications　and　strategies　for　pain　relief　are　needed.　Hepatocyte　growth　factor　(HGF)　is　known　to　be　a　multi-functional　growth　factor　and　regulates　various　biological　activities.　MethodsWe　investigated　the　analgesic　effect　and　underlying　mechanism　of　plasmid　pUDK-HGF　encoding　human　HGF　gene　on　CPSP　induced　by　skin/muscle　incision　and　retraction　(SMIR)　in　rats.　The　possible　changes　of　inflammatory　factors,　glial　cell　activation　and　pain　sensitivity　after　pUDK-HGF　administration　were　investigated　by　ELISA,　western　blot　and　Von　Frey　tests,　respectively.　ResultsIn　behavioural　assays,　we　found　that　a　single　intramuscular　or　intrathecal　injection　of　pUDK-HGF　significantly　attenuated　mechanical　hypersensitivity　to　von　Frey　stimulation　of　plantar　ipsilateral　hind　paw　after　SMIR.　Intramuscular　injection　of　pUDK-HGF　promoted　blood　flow　and　proliferation　of　satellite　cells　and　inhibited　inflammatory　cells　recruitment,　collagen　accumulation　and　expression　of　pronociceptive　factors.　Intrathecal　injection　of　pUDK-HGF　inhibited　activation　of　spinal　glial　cells　and　production　of　inflammatory　mediators　induced　by　SMIR.　ConclusionspUDK-HGF　has　a　strong　analgesic　potency　and　efficacy　in　CPSP　induced　by　SMIR　in　rats.　This　study　highlights　a　new　strategy　for　the　treatment　of　CPSP.　SignificanceThe　CPSP　occurs　following　various　surgical　procedures　and　remains　a　major　clinical　problem　due　to　the　lack　of　study　on　the　mechanisms　of　CPSP.　Our　findings　provide　the　first　evidence　that　pUDK-HGF　attenuates　SMIR-induced　pain　behaviuors　through　peripheral　or　central　mechanisms.　The　peripheral　analgesic　effect　of　pUDK-HGF　is　associated　with　promoting　tissue　repair　and　inhibiting　inflammatory　response;　furthermore,　pUDK-HGF　inhibits　activation　of　spinal　glial　cells　and　overexpression　of　inflammatory　mediators　in　spinal　cord.　Therefore,　naked　pUDK-HGF　may　be　a　potential　therapeutic　strategy　for　treatment　of　CPSP　in　clinic.