title: Lentiviral vector-driven inhibition of 5-HT synthesis in B3 bulbo-spinal serotonergic projections - Consequences on nociception, inflammatory and neuropathic pain in rats.
abstract: Although it is well established that bulbo-spinal serotonergic projections contribute to pain control mechanisms, whether they exert anti- or pro-nociceptive modulations is still a matter of debate. In order to reappraise the role of 5-HT in descending controls, we used RNA interference to selectively inhibit 5-HT synthesis in B3 neurons and assess resulting changes in nociception. Rats were injected into the bulbar B3 group with a recombinant lentiviral vector, LV-shTPH2, encoding RNA interfering with tryptophan hydroxylase 2 expression. Together with the long term disappearance of this enzyme in the whole rostro-caudal extent of B3 group, 5-HT was markedly depleted selectively in the dorsal horn at all levels of the spinal cord. In contrast, immunolabeling of the 5-HT transporter was unaffected by LV-shTPH2 injection, indicating the preservation of serotonergic fibers integrity. Whereas mechanical and thermal nociceptive thresholds were unchanged by 5-HT depletion, marked reductions in intraplantar formalin (but not carrageenin)-evoked nocifensive responses, and, in contrast, significant increases in mechanical and thermal hyperalgesia evoked by sciatic nerve ligation were noted in LV-shTPH2-injected rats versus controls. Parallel changes in c-Fos immunolabeling within the dorsal horn confirmed that bulbo-spinal serotonergic projections modulate pain signaling under these various conditions. These results suggest that serotonergic neurons of the B3 group are only moderately concerned, if any, by acute nociception but exert modulatory influences under pain sensitizing conditions. The opposite changes in formalin injected- versus sciatic nerve ligated rats might be related to the implication of different receptors in 5-HT-mediated modulation of inflammatory versus neuropathic pain.
authors.affiliation: INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, 75014 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gautier
authors.affiliation: INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, 75014 Paris, France.
authors.forename: Hanady
authors.initials: H
authors.lastname: El Ouaraki
authors.affiliation: INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, 75014 Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Bazin
authors.affiliation: INSERM UMR 1141 Paris, France; Sorbonne Paris Cité, Université Paris-Diderot, UMRS 1141, Paris, France.
authors.forename: Soha
authors.initials: S
authors.lastname: Salam
authors.affiliation: INSERM UMR 1141 Paris, France; Sorbonne Paris Cité, Université Paris-Diderot, UMRS 1141, Paris, France.
authors.forename: Guilan
authors.initials: G
authors.lastname: Vodjdani
authors.affiliation: INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, 75014 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bourgoin
authors.affiliation: CNRS UMR 8249, Brain Plasticity Unit, ESCPI-ParisTech, 75005 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pezet
authors.affiliation: INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, 75014 Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bernard
authors.affiliation: INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, 75014 Paris, France. Electronic address: michel.hamon@upmc.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000378:metabolism*; D009437:Neuralgia / Q000150:complications / Q000473:pathology*; D059225:Nociception / Q000502:physiology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D014161:Transduction, Genetic; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012701:Serotonin; D002351:Carrageenan; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat
keywords: Chronic constriction injury; Formalin; Noxious stimuli; Recombinant lentiviral vector; Serotonin depletion; Spinal cord