title: Modulatory and plastic effects of kinins on spinal cord networks.
abstract: CONCLUSIONS
  Inflammatory kinins are released following spinal cord injury or neurotrauma. The effects of these kinins on ongoing locomotor activity of central pattern generator networks are unknown. In the present study, kinins were shown to have short- and long-term effects on motor networks. The short-term effects included direct depolarization of interneurons and motoneurons in the ventral horn accompanied by modulation of transient receptor potential vanilloid 1-sensitive nociceptors in the dorsal horn. Over the long-term, we observed a bradykinin-mediated effect on promoting plasticity in the spinal cord. In a model of spinal cord injury, we observed an increase in microglia numbers in both the dorsal and ventral horn and, in a microglia cell culture model, we observed bradykinin-induced expression of glial-derived neurotrophic factor.
  The expression and function of inflammatory mediators in the developing spinal cord remain poorly characterized. We discovered novel, short and long-term roles for the inflammatory nonapeptide bradykinin (BK) and its receptor bradykinin receptor B2 (B2R) in the neuromodulation of developing sensorimotor networks following a spinal cord injury (SCI), suggesting that BK participates in an excitotoxic cascade. Functional expression of B2R was confirmed by a transient disruptive action of BK on fictive locomotion generated by a combination of NMDA, 5-HT and dopamine. The role of BK in the dorsal horn nociceptive afferents was tested using spinal cord attached to one-hind-limb (HL) preparations. In the HL preparations, BK at a subthreshold concentration induced transient disruption of fictive locomotion only in the presence of: (1) noxious heat applied to the hind paw and (2) the heat sensing ion channel transient receptor potential vanilloid 1 (TRPV1), known to be restricted to nociceptors in the superficial dorsal horn. BK directly depolarized motoneurons and ascending interneurons in the ventrolateral funiculus. We found a key mechanism for BK in promoting long-term plasticity within the spinal cord. Using a model of neonatal SCI and a microglial cell culture model, we examined the role of BK in inducing activation of microglia and expression of glial-derived neurotrophic factor (GDNF). In the neonatal SCI model, we observed an increase in microglia numbers and increased GDNF expression restricted to microglia. In the microglia cell culture model, we observed a BK-induced increased expression of GDNF via B2R, suggesting a novel mechanism for BK spinal-mediated plasticity.
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Mandadi
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.|Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Leduc-Pessah
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Hong
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ejdrygiewicz
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: S A
authors.initials: SA
authors.lastname: Sharples
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.|Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Trang
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.|Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: P J
authors.initials: PJ
authors.lastname: Whelan
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000378:metabolism* / Q000502:physiology; D001920:Bradykinin / Q000378:metabolism*; D002478:Cells, Cultured; D063226:Central Pattern Generators / Q000378:metabolism / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism / Q000502:physiology; D008124:Locomotion; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000502:physiology; D009415:Nerve Net / Q000378:metabolism* / Q000502:physiology; D009473:Neuronal Plasticity; D059225:Nociception; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000502:physiology; D018002:Receptors, Bradykinin / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018002:Receptors, Bradykinin; D050916:TRPV Cation Channels; D001920:Bradykinin