A Putative Relay Circuit Providing Low-Threshold Mechanoreceptive Input to Lamina I Projection Neurons via Vertical Cells in Lamina II of the Rat Dorsal Horn

Abstract

BackgroundLamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents.ResultsWe initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin.ConclusionsThese results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia.

Dorsal Horn Circuits for Persistent Mechanical Pain

“…This serial circuit starts with PKCγ neurons, which then activate central cells in lamina II i , vertical cells in lamina II o , and finally the lamina I projection neurons (Lu et al, 2013; Lu and Perl, 2005). More recently, additional circuits have been proposed (Braz et al, 2014; Yasaka et al, 2014) to support the idea that the induction and transmission of mechanical hypersensitivity within the dorsal horn involves integrating information through multiple mechanisms and neuronal networks.…”

The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

“…3A–C) (Brumovsky and Hökfelt, 2007, Neumann et al, 2008, Yasaka et al, 2014). There was an increase in SRSF1 expression in the central sensory terminals 2 days after PSNI, as assessed by immunofluorescence (Fig.…”

Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain

“…Neurons with NK1Rs in lamina I of the dorsal horn are key components of the dorsal horn circuitry that modulates pain in rodents (Gutierrez-Mecinas et al, 2016;Haring et al, 2018;Polgar et al, 2013;Sathyamurthy et al, 2018;Todd, 2017;Yasaka et al, 2014) because many of them send axons to the parabrachial nucleus and the brainstem (Polgár et al, 2010;Ruscheweyh et al, 2004;Todd et al, 2000). These neurons receive direct synapses from peptidergic C/Aδ fibers Torsney and MacDermott, 2006), and these synapses are an important locus of pain regulation .…”

“…These neurons receive direct synapses from peptidergic C/Aδ fibers Torsney and MacDermott, 2006), and these synapses are an important locus of pain regulation . NK1R neurons also receive synapses from vertical cells, which serve as a hub to integrate signals from excitatory and inhibitory interneurons of the dorsal horn (Kato et al, 2009;Peirs and Seal, 2016;Peirs et al, 2015;Yasaka et al, 2010;Yasaka et al, 2014). Activation of NK1Rs in dorsal horn neurons produces slow depolarizations, increases excitability (Murase and Randic, 1984;Murase et al, 1986), increases NMDA receptor currents (Rusin et al, 1993;Rusin et al, 1992), and induces long-term potentiation of their synapses with primary afferents (Ikeda et al, 2003;Liu and Sandkuhler, 1997;Liu and Sandkuhler, 1998).…”