title: Methylprednisolone prevents nerve injury-induced hyperalgesia in neprilysin knockout mice.
abstract: The pathophysiology of the complex regional pain syndrome involves enhanced neurogenic inflammation mediated by neuropeptides. Neutral endopeptidase (neprilysin, NEP) is a key enzyme in neuropeptide catabolism. Our previous work revealed that NEP knock out (ko) mice develop more severe hypersensitivity to thermal and mechanical stimuli after chronic constriction injury (CCI) of the sciatic nerve than wild-type (wt) mice. Because treatment with glucocorticoids is effective in early complex regional pain syndrome, we investigated whether methylprednisolone (MP) reduces pain and sciatic nerve neuropeptide content in NEP ko and wt mice with nerve injury. After CCI, NEP ko mice developed more severe thermal and mechanical hypersensitivity and hind paw edema than wt mice, confirming previous findings. Hypersensitivity was prevented by MP treatment in NEP ko but not in wt mice. MP treatment had no effect on protein levels of calcitonin-gene related peptide, substance P, and bradykinin in sciatic nerves of NEP ko mice. Endothelin-1 (ET-1) levels were higher in naïve and nerve-injured NEP ko than in wt mice, without an effect of MP treatment. Gene expression of the ET-1 receptors ETAR and ETBR was not different between genotypes and was not altered after CCI, but was increased after additional MP treatment. The ETBR agonist IRL-1620 was analgesic in NEP ko mice after CCI, and the ETBR antagonist BQ-788 showed a trend to reduce the analgesic effect of MP. The results provide evidence that MP reduces CCI-induced hyperalgesia in NEP ko mice, and that this may be related to ET-1 via analgesic actions of ETBR.
authors: Department of Neurology, University Hospital of Würzburg, Würzburg, Germany Department of Neurology, Johannes Gutenberg University Mainz, Mainz, Germany Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Lan
authors: L
authors: He
authors: Nurcan
authors: N
authors: Üçeyler
authors: Heidrun H
authors: HH
authors: Krämer
authors: Maria Nandini
authors: MN
authors: Colaço
authors: Bao
authors: B
authors: Lu
authors: Frank
authors: F
authors: Birklein
authors: Claudia
authors: C
authors: Sommer
mesh_terms: D000818:Animals; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008775:Methylprednisolone / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015260:Neprilysin / Q000172:deficiency*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D015260:Neprilysin; D008775:Methylprednisolone
keywords: Complex regional pain syndrome; Endothelin-1; Neprilysin; Nerve injury; Neutral endopeptidase