title: Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons.
abstract: Long-term potentiation (LTP), a use dependent long-lasting modification of synaptic strength, was first discovered in the hippocampus and later shown to occur in sensory areas of the spinal cord. Here we demonstrate that spinal LTP requires the activation of a subset of superficial spinal dorsal horn neurons expressing the neurokinin-1 receptor (NK1-R) that have previously been shown to mediate certain forms of hyperalgesia. These neurons participate in local spinal sensory processing, but are also the origin of a spino-bulbo-spinal loop driving a 5-hydroxytryptamine 3 receptor (5HT3-R)- mediated descending facilitation of spinal pain processing. Using a saporin-substance P conjugate to produce site-specific neuronal ablation, we demonstrate that NK1-R expressing cells in the superficial dorsal horn are crucial for the generation of LTP-like changes in neuronal excitability in deep dorsal horn neurons and this is modulated by descending 5HT3-R-mediated facilitatory controls. Hippocampal LTP is associated with early expression of the immediate-early gene zif268 and knockout of the gene leads to deficits in long-term LTP and learning and memory. We found that spinal LTP is also correlated with increased neuronal expression of zif268 in the superficial dorsal horn and that zif268 antisense treatment resulted in deficits in the long-term maintenance of inflammatory hyperalgesia. Our results support the suggestion that the generation of LTP in dorsal horn neurons following peripheral injury may be one mechanism whereby acute pain can be transformed into a long-term pain state.
authors.affiliation: Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Lars Jørgen
authors.initials: LJ
authors.lastname: Rygh
authors.forename: Rie
authors.initials: R
authors.lastname: Suzuki
authors.forename: Wahida
authors.initials: W
authors.lastname: Rahman
authors.forename: Yuk
authors.initials: Y
authors.lastname: Wong
authors.forename: Jean Laurent
authors.initials: JL
authors.lastname: Vonsy
authors.forename: Hardip
authors.initials: H
authors.lastname: Sandhu
authors.forename: Mark
authors.initials: M
authors.lastname: Webber
authors.forename: Stephen
authors.initials: S
authors.lastname: Hunt
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000818:Animals; D002908:Chronic Disease; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D016376:Oligonucleotides, Antisense; D018040:Receptors, Neurokinin-1; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D012701:Serotonin; D013373:Substance P