title: Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: a pharmacologic and neurophysiological evaluation.
abstract: Dysfunctional γ-aminobutyric acid (GABA)-ergic inhibitory neurotransmission is hypothesized to underlie chronic neuropathic pain. Intraspinal transplantation of GABAergic neural progenitor cells (NPCs) may reduce neuropathic pain by restoring dorsal horn inhibition. Rat NPCs pre-differentiated to a GABAergic phenotype were transplanted into the dorsal horn of rats with unilateral chronic constriction injury (CCI) of the sciatic nerve. GABA signaling in antinociceptive effects of NPC grafts was tested with the GABA(A) receptor antagonist bicuculline (BIC), GABA(B) receptor antagonist CGP35348 (CGP) and GABA reuptake inhibitor SKF 89976A (SKF). NPC-treated animals showed decreased hyperalgesia and allodynia 1-3week post-transplantation; vehicle-injected CCI rats continued displaying pain behaviors. Intrathecal application of BIC or CGP attenuated the antinociceptive effects of the NPC transplants while SKF injection induced analgesia in control rats. Electrophysiological recordings in NPC treated rats showed reduced responses of wide dynamic range (WDR) neurons to peripheral stimulation compared to controls. A spinal application of BIC or CGP increased wind-up response and post-discharges of WDR neurons in NPC treated animals. Results suggest that transplantation of GABAergic NPCs attenuate pain behaviors and reduce exaggerated dorsal horn neuronal firing induced by CCI. The effects of GABA receptor inhibitors suggest participation of continuously released GABA in the grafted animals.
authors.affiliation: University of Miami, Miller School of Medicine, Miami Project to Cure Paralysis, 1095 NW 14 Terrace, Miami, Florida 33136, USA. sjergova@med.miami.edu
authors.forename: Stanislava
authors.initials: S
authors.lastname: Jergova
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hentall
authors.forename: Shyam
authors.initials: S
authors.lastname: Gajavelli
authors.forename: Mathew S
authors.initials: MS
authors.lastname: Varghese
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sagen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005260:Female; D018682:GABA Agents / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007278:Injections, Spinal / Q000379:methods; D007796:Laminectomy / Q000379:methods; D008297:Male; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000637:transplantation; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012585:Sciatica / Q000601:surgery*; D013116:Spinal Cord / Q000601:surgery* / Q000637:transplantation; D013696:Temperature; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018682:GABA Agents; D005680:gamma-Aminobutyric Acid