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Review
. 2020 Apr;127(4):505-525.
doi: 10.1007/s00702-020-02159-1. Epub 2020 Apr 2.

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

Cedric Peirs  1   2 , Radhouane Dallel  3   4 , Andrew J Todd  4
Affiliations
Review

Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia

Cedric Peirs et al. J Neural Transm (Vienna). 2020 Apr.

Erratum in

Abstract

The dorsal horns of the spinal cord and the trigeminal nuclei in the brainstem contain neuron populations that are critical to process sensory information. Neurons in these areas are highly heterogeneous in their morphology, molecular phenotype and intrinsic properties, making it difficult to identify functionally distinct cell populations, and to determine how these are engaged in pathophysiological conditions. There is a growing consensus concerning the classification of neuron populations, based on transcriptomic and transductomic analyses of the dorsal horn. These approaches have led to the discovery of several molecularly defined cell types that have been implicated in cutaneous mechanical allodynia, a highly prevalent and difficult-to-treat symptom of chronic pain, in which touch becomes painful. The main objective of this review is to provide a contemporary view of dorsal horn neuronal populations, and describe recent advances in our understanding of on how they participate in cutaneous mechanical allodynia.

Keywords: Chronic pain; Cutaneous mechanical allodynia; Dorsal horn; Neurons.

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Conflict of interest statement

The author(s) declares that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Spinal cord dorsal horn lamination. a Confocal image of a transverse section of mouse lumbar spinal cord immunostained with antibodies directed against NEUN to mark all neurons (blue), and against PAX2 to reveal only inhibitory neurons (white). Dotted lines represent boundaries of the six dorsal horn laminae. LSN, lateral spinal nucleus. Scale = 100 µm. b Schematic of the location and trajectories of projection neurons within the dorsal horn. ALT antero-lateral tracts, PSDC post-synaptic dorsal columns.
Fig. 2
Fig. 2
Morphological, electrophysiological and neurochemical features of interneurons in laminae I–II of the mouse dorsal horn. Top panel Morphological features of lamina II dorsal horn neurons observed in sagittal slices. Confocal images of neurons filled with neurobiotin showing vertical (green), radial (gray), central (blue) or islet (red) morphologies. Scale = 100 µm. Lower left panel Electrophysiological whole-cell patch-clamp recording of dorsal horn neurons. Firing pattern of dorsal horn neurons can be tonic, phasic, with a gap between spikes, or with one or no action potential upon depolarizing current injection. Traces in black display membrane potential at -20pA or at rehobase respectively. Superimposed blue traces are representative firing patterns observed at suprathreshold current injection. Value for hyperpolarizing and depolarizing currents are indicated. Lower right panel The proportions of excitatory and inhibitory interneurons in this region that belong to different neurochemical populations. The relationship to the different transcriptomic populations identified by Haring et al. (2018) is also shown. Note that the NKB neurokinin B, NTS neurotensin, CCK cholecystokinin, SP substance P, NPFF neuropeptide FF and GRP–GFP cells form largely non-overlapping populations of excitatory interneurons, although there is some overlap between NKB/NTS and CCK/SP populations [reproduced from Gutierrez-Mecinas et al. (2019a)]. The GRP–GFP cells are defined as those that express GFP in the BAC transgenic GRP::eGFP line. For inhibitory interneurons, there is overlap between the galanin/dynorphin (GAL/DYN) population and the neuronal nitric oxide synthase (NNOS) population, and this is shown in purple. Similarly, the GAL/DYN population overlaps with the NPY population, and this is shown in brown. There is limited overlap between NPY cells and both NNOS and parvalbumin (PV) cells, although this is not shown on the pie chart. Reproduced from Boyle et al. (2017)
Fig. 3
Fig. 3
Populations of dorsal horn neurons involved in cutaneous mechanical allodynia. Schematic representation on the right illustrates the segregation of touch and pain in the spinal cord dorsal horn. In physiological conditions, non-nociceptive sensory neurons (LTMRs) innervate the deep DH (green), whereas nociceptive fibers terminate in the superficial laminae (red). During cutaneous mechanical allodynia (CMA), touch induces pain through activation of a polysynaptic circuit (blue) that connects the non-nociceptive deep DH to the pain‐related superficial layers. Populations of neurons that have been implicated in CMA are indicated on the left part of the figure, with distinctions between static/dynamic and neuropathic/inflammatory CMA. Populations of neurons that are mostly excitatory are displayed in light blue ellipses and those that are mostly inhibitory neurons are displayed in light pink ellipses. Lamina I neurons expressing dynorphin (DYN) include both inhibitory and excitatory cells and are displayed as gray ellipses. Populations of neurons that have not been tested for the respective conditions are transparent. Outlines in red indicate that the population has been implicated in the expression of CMA, in green indicates that the population is engaged but not required for CMA and in black indicates that the population is dispensable for CMA. Dotted outlines indicate that the requirement of the population for CMA is unclear. DH dorsal horn, DRG dorsal root ganglion, LTMR low‐threshold mechanoreceptor, NK1R neurokinin 1 receptor, CR calretinin, PKCγ gamma isoform of protein kinase C, VGLUT3 vesicular glutamate transporter 3, DYN dynorphin, NKB neurokinin B, NPYY1R neuropeptide Y Y1 receptor, CCK cholecystokinin, SOM somatostatin, PAX2 paired box gene 2, NPY neuropeptide Y, GLYT2 glycine transporter 2, PV parvalbumin, RET receptor tyrosine kinase
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