Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. © 2013 Wiley Periodicals, Inc.

Key pointsr Inflammatory kinins are released following spinal cord injury or neurotrauma. r The effects of these kinins on ongoing locomotor activity of central pattern generator networks are unknown.r In the present study, kinins were shown to have short-and long-term effects on motor networks. r 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.r Over the long-term, we observed a bradykinin-mediated effect on promoting plasticity in the spinal cord. r 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.Abstract 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.

Pediatric spinal cord injury (SCI) often leads to increased nociceptive input resulting in aberrant motor output like tremor and spasticity. Acute plasticity within spinal pain and motor networks following pediatric SCI may result in long-term sensorimotor disabilities. Despite this, pediatric SCI remains poorly understood. Part of the problem lies in the paucity of detailed studies aimed at defining sensorimotor control by nociceptors during development. This review provides an overview of work that highlights afferent control of sensorimotor networks by defined nociceptors in the developing spinal cord. Here, we focus on the well established and widely used neonatal sensorimotor model called sacrocaudal afferent (SCA) pathway. Until recently, the identity of specific subclasses of nociceptive afferents in the SCA pathway controlling developing sensorimotor networks was unknown. We highlight here the use of members of the Transient Receptor Potential (TRP) ion channels and mouse genetics to identify specific subsets of nociceptive afferents in the SCA pathway. In addition, we highlight the use of mouse genetics to map sensorimotor networks during development and potential future applications. A neonatal spinal cord model of central neuropathic pain via a defined set of nociceptors is presented as a probe into potential therapeutic avenues in neonatal SCI. Finally, knowledge translation from neonatal basic research to the pediatric population in the clinic is described. In conclusion, studies in neonatal models may lead to therapeutic strategies and pharmaceuticals for chronic pain and motor dysfunction after SCI during development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.