title: Neuropathic pain- and glial derived neurotrophic factor-associated regulation of cadherins in spinal circuits of the dorsal horn.
abstract: Neuropathic pain is associated with reorganization of spinal synaptic circuits, implying that adhesion proteins that normally build and modify synapses must be involved. The adhesion proteins E- and N-cadherin delineate different synapses furnished by nociceptive primary afferents, but dynamic aspects of cadherin localization in relationship to onset, maintenance or reversibility of neuropathic pain are uncharacterized. Here, we find very different responses of these cadherins to L5 spinal nerve transection (SNT)-induced mechanical allodynia and to intrathecal glial derived neurotrophic factor (GDNF), which has potent analgesic effects in this pain model. In L5, E-cadherin is rapidly eliminated in patches within lamina IIi contemporaneously with the onset of mechanical allodynia. Intrathecal GDNF in conjunction with, or at 7 days after, L5 SNT prevents or reverses both the loss of E-cadherin and abnormal pain sensation. In contrast, N-cadherin undergoes a delayed and transient increase uniformly across lamina I-II that is insensitive to GDNF. Some N-cadherin-labeled profiles codistribute with GAP-43, suggesting a role in axon sprouting. Patterns of immunolabeling for GDNF receptor components GFRα1, NCAM, and RET after L5 SNT suggest that GFRα1 and NCAM are the principal receptors operative in this model. In addition, GFRα1 codistributes with E-cadherin, but not N-cadherin, profiles. Together, these data indicate strikingly divergent patterns of temporal and molecular regulation of different cadherins at distinct nociceptive circuits in response to spinal nerve injury, suggesting that the two cadherins and the circuits with which they are affiliated participate in different aspects of synaptic and circuit reorganization associated with neuropathic pain.
authors.affiliation: Department of Neuroscience and the Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA Montreal Neurological Institute, Montreal, Quebec, Canada.
authors.forename: Shekhar B
authors.initials: SB
authors.lastname: Patil
authors.forename: John H
authors.initials: JH
authors.lastname: Brock
authors.forename: David R
authors.initials: DR
authors.lastname: Colman
authors.forename: George W
authors.initials: GW
authors.lastname: Huntley
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism* / Q000627:therapeutic use; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000150:complications; D013997:Time Factors
chemical_list: D015820:Cadherins; D019922:GAP-43 Protein; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D019006:Neural Cell Adhesion Molecules; C087857:protein kinase C gamma; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat; D011493:Protein Kinase C