title: Neurokinin-1 receptor-expressing neurons that contain serotonin and gamma-aminobutyric acid in the rat rostroventromedial medulla are involved in pain processing.
abstract: The rostroventromedial medulla (RVM) is an important area of the endogenous pain-regulating system, in which 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) are 2 main transmitters involved in pain modulation. However, whether 5-HT and GABA are colocalized is poorly understood. By using glutamate decarboxylase 67-green fluorescence protein (GAD67-GFP) knock-in mouse, we confirmed the colocalization of 5-HT and GABA in the RVM, with a main distribution in the raphe magnus nucleus and paragigantocellular reticular nucleus. Interestingly, more than half (51.6%) of the 5-HT/GABA-immunoreactive (ir) neurons expressed neurokinin-1 receptors (NK-1R) and one-third (30.1%) of the 5-HT/GABA/NK-1R-ir neurons projected to the spinal cord, suggesting that substance P (SP) should regulate the activity of 5-HT/GABA-ir spinal cord-projecting neurons. By combining retrograde and anterograde tracing methods, we observed that the cuneiform nucleus, dorsal raphe nucleus, and lateral periaqueductal gray are the main origin nuclei for the SP-ir fibers and terminals in the RVM. Finally, after formalin injection into the mice hind paw, 29.2% SP-ir RVM-projecting neurons from supra-RVM nuclei and 33.1% NK-1R-ir spinal cord-projecting neurons in the RVM were activated. The present study provides potent morphological evidence that 5-HT and GABA are coexistent in RVM-spinal cord-projecting neurons that are also regulated by SPergic projections.
  
  
  CONCLUSIONS
  The results will greatly enhance our understanding for the modulation of nociceptive information in the descending pain-regulating system.
authors.affiliation: Department of Anatomy & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Qu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Sheng-Xi
authors.initials: SX
authors.lastname: Wu
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D002452:Cell Count; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D008526:Medulla Oblongata / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000473:pathology*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013266:Stilbamidines / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D003911:Dextrans; D018040:Receptors, Neurokinin-1; D013266:Stilbamidines; C076397:biotinylated dextran amine; D049452:Green Fluorescent Proteins; D012701:Serotonin; D013373:Substance P; D005680:gamma-Aminobutyric Acid; D001710:Biotin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: GABA; GAD67-GFP knock-in mouse; Serotonin; neurokinin-1 receptor; rostroventromedial medulla