title: Rac1-regulated dendritic spine remodeling contributes to neuropathic pain after peripheral nerve injury.
abstract: Although prior studies have implicated maladaptive remodeling of dendritic spines on wide-dynamic range dorsal horn neurons as a contributor to pain after spinal cord injury, there have been no studies on dendritic spines after peripheral nerve injury. To determine whether dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain after peripheral nerve injury, we analyzed dendritic spine morphology and functional influence in lamina IV-V dorsal horn neurons after sham, chronic constriction injury (CCI) of the sciatic nerve, and CCI treatment with NSC23766, a selective inhibitor of Rac1, which has been implicated in dendritic spine development. 10 days after CCI, spine density increased with mature, mushroom-shaped spines preferentially distributed along dendritic branch regions closer to the cell body. Because spine morphology is strongly correlated with synaptic function and transmission, we recorded the response of single units to innocuous and noxious peripheral stimuli and performed behavioral assays for tactile allodynia and thermal hyperalgesia. Wide dynamic range dorsal horn neurons of CCI animals exhibited hyperexcitable responses to a range of stimuli. They also showed reduced nociceptive thresholds in the ipsilateral hind paw. 3-day treatment with NSC23766 significantly reduced post-CCI spine dimensions and densities, and attenuated injury-induced hyperexcitability. Drug treatment reduced behavioral measures of tactile allodynia, but not for thermal hyperalgesia. Together, our results demonstrate that peripheral nerve injury induces Rac1-regulated remodeling of dendritic spines on dorsal horn neurons, and suggest that this spine remodeling contributes to neuropathic pain.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tan
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Hains
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D049229:Dendritic Spines / Q000473:pathology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D009437:Neuralgia / Q000473:pathology / Q000503:physiopathology*; D009619:Nociceptors / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000473:pathology / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; D004791:Enzyme Inhibitors; C487513:NSC 23766; D011743:Pyrimidines; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein