title: Upregulation of neuregulin-1 reverses signs of neuropathic pain in rats.
abstract: BACKGROUND
  Peripheral nerve injury can result in neuropathic pain, a chronic condition of unclear cause often poorly responsive to current treatments. One possibility is that nerve injury disrupts large A-fiber-mediated inhibition of C-fiber-evoked responses in spinal dorsal horn neurons, leading to central sensitization. A recent study provided a potential molecular mechanism; large dorsal root ganglion (DRG) neurons secrete neuregulin-1 (NRG1), which binds to erbB4 receptors on interneurons and promotes GABA release to inhibit C-fiber-evoked nociceptive transmission. Thus, reduced NRG1 expression following nerve injury could induce chronic pain by disinhibition. We examined if DRG expression of NRG1 is in fact reduced in a rat model of neuropathic pain and if exogenous NRG1 alleviates behavioral signs of this condition.
  
  
  METHODS
  Three neuropathic pain models were established in rats: spared nerve injury of the tibial and common peroneal nerves (SNI model), intraplantar injection of complete Freund's adjuvant (CFA model), and subcutaneous formalin injection. NRG1 expression was assessed by immunofluorescent staining, hyperalgesia by paw withdrawal threshold to von Frey filament stimulation, and pain-like behavior by spontaneous flinching.
  
  
  RESULTS
  NRG1 protein immunoreactivity was reduced in the rat DRG after SNI. Intrathecal administration of neuregulin-1beta 1 (NRG1-1), a 62 amino acid NRG1 mimetic, transiently increased paw withdrawal threshold in SNI model and reduced flinching in the formalin injection model.
  
  
  CONCLUSIONS
  Our results are consistent with a model of neuropathic pain whereby peripheral nerve injury reduces NRG1-mediated inhibition of nociceptive signaling. Modulating NRG1 may have therapeutic potential for treating neuropathic pain.
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China ; Department of Neurosurgery, Central Hospital of Tai'an Tai'an, Shandong Province, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Dai
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital Shanghai, China.
authors.forename: Pengqi
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D005557:Formaldehyde; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000503:physiopathology; D010543:Peroneal Nerve / Q000293:injuries / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D013979:Tibial Nerve / Q000293:injuries / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000700:Analgesics; D020890:Neuregulin-1; C490580:Nrg1 protein, rat; C117467:neuregulin beta; D005557:Formaldehyde; D005620:Freund's Adjuvant
keywords: GABA; Neuregulin-1; dorsal root ganglion; gate control; neuropathic pain; spinal dorsal horn