title: Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain.
abstract: Recent studies indicate that persistent pain after tissue or nerve injury is accompanied by an enhanced net descending facilitatory drive that contributes to an amplification and spread of pain. Although 5-HT-containing neurons in the rostral ventromedial medulla (RVM) provide the major descending serotonergic projection to the spinal cord, it is not clear whether the neurotransmitter 5-HT itself released from RVM-spinal neurons contributes to descending pain modulation. In the present study, we determined the role of the descending 5-HT in rat nocifensive behaviors after persistent pain by selectively depleting functional phenotypes of 5-HT in RVM neurons with regional shRNA interference (RNAi) of tryptophan hydroxylase-2 (Tph-2), the rate-limiting enzyme in the synthesis of neuronal 5-HT. Compared to negative control shRNA, Tph-2 shRNA induced significantly prolonged downregulation of Tph-2 in the RVM and 5-HT in spinal dorsal horn. The 5-HT-depleted rats showed normal pain sensitivity in responses to acute noxious stimulation. However, the same RNAi treatment attenuated formalin-induced spontaneous nocifensive responses and tissue or nerve injury-induced allodynia and hyperalgesia. Furthermore, in control shRNA-treated animals, intra-RVM microinjection of brain-derived neurotrophic factor produced a reversible hyperalgesia, which was completely prevented by Tph-2 RNAi pretreatment. Descending inhibition induced by intra-RVM electrical stimulation, but not microinjection of the mu- or kappa-opioid receptor agonists in control shRNA-treated animals was eliminated in 5-HT-depleted rats. These results indicate that the descending 5-HT from the RVM is an important contributor to pain facilitation during the development of persistent pain, and may not mediate opioid-induced descending inhibition in acute pain.
authors.affiliation: Department of Neural and Pain Sciences, Dental School, and Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201, USA. fwei@umaryland.edu
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.forename: Guang
authors.initials: G
authors.lastname: Bai
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D004797:Enzyme-Linked Immunosorbent Assay; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism / Q000503:physiopathology; D008845:Microinjections; D009415:Nerve Net / Q000378:metabolism* / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D013997:Time Factors
chemical_list: D012701:Serotonin