Antihyperalgesic effects of dexketoprofen and tramadol in a model of postoperative pain in mice - effects on glial cell activation.
OBJECTIVE
To define likely targets (i.e. glia) and protocols (analgesic combinations) to improve postoperative pain outcomes and reduce chronic pain after surgery. Specifically, to assess the antihyperalgesic effects of the dexketoprofen : tramadol (DEX : TRM) combination, exploring the implication of glial activation.


METHODS
In a mouse model of postincisional pain, we evaluated mechanical nociceptive thresholds (Von Frey) for 21 days postoperatively. We assessed DEX and TRM alone and combined (1 : 1 ratio) on postoperative hyperalgesia (POH, day 1) and delayed latent pain sensitisation (substantiated by a naloxone challenge; PS, day 21). The interactions were analysed using isobolograms, and concomitant changes in spinal glial cell activation were measured.


RESULTS
On day 1, DEX completely blocked POH, whereas TRM induced 32% inhibition. TRM, but not DEX, partially (47%) protected against PS, at 21 days. Co-administration of DEX : TRM (1 : 1 ratio) showed additivity for antihyperalgesia. Both drugs and their combination totally inhibited surgery-induced microglia activation on day 1, but had no effect on surgery-induced astrocyte activation (1 day) or re-activation after naloxone (21 days).


CONCLUSIONS
The DEX : TRM combination could have clinical advantages: a complete prevention of POH after surgery, together with a substantial (48%) inhibition of the development of PS by TRM. Microglia, but not astrocyte activation, could play a relevant role in the development of postoperative pain hypersensitivity.
Pain Research Unit, Department of Anesthesiology, IMIM-Institut Hospital del Mar d'Investigacions Biomèdiques, Universitat Autònoma de Barcelona School of Medicine, Barcelona, Spain.
Elizabeth
E
Romero-Alejo
Pain Research Unit, Department of Anesthesiology, IMIM-Institut Hospital del Mar d'Investigacions Biomèdiques, Universitat Autònoma de Barcelona School of Medicine, Barcelona, Spain.
Margarita M
MM
Puig
Pain Research Unit, Department of Anesthesiology, IMIM-Institut Hospital del Mar d'Investigacions Biomèdiques, Universitat Autònoma de Barcelona School of Medicine, Barcelona, Spain.
Asunción
A
Romero
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004338:Drug Combinations; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007660:Ketoprofen / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy*; D014147:Tramadol / Q000494:pharmacology / Q000627:therapeutic use*
D000700:Analgesics; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D009270:Naloxone; D014147:Tramadol; D007660:Ketoprofen
dexketoprofen; glial cells; latent pain sensitisation; postoperative hyperalgesia; tramadol