A review of dorsal root ganglia and primary sensory neuron plasticity mediating inflammatory and chronic neuropathic pain

Abstract

Pain is a sensory state resulting from complex integration of peripheral nociceptive inputs and central processing. Pain consists of adaptive pain that is acute and beneficial for healing and maladaptive pain that is often persistent and pathological. Pain is indeed heterogeneous, and can be expressed as nociceptive, inflammatory, or neuropathic in nature. Neuropathic pain is an example of maladaptive pain that occurs after spinal cord injury (SCI), which triggers a wide range of neural plasticity. The nociceptive processing that underlies pain hypersensitivity is well-studied in the spinal cord. However, recent investigations show maladaptive plasticity that leads to pain, including neuropathic pain after SCI, also exists at peripheral sites, such as the dorsal root ganglia (DRG), which contains the cell bodies of sensory neurons. This review discusses the important role DRGs play in nociceptive processing that underlies inflammatory and neuropathic pain. Specifically, it highlights nociceptor hyperexcitability as critical to increased pain states. Furthermore, it reviews prior literature on glutamate and glutamate receptors, voltage-gated sodium channels (VGSC), and brain-derived neurotrophic factor (BDNF) signaling in the DRG as important contributors to inflammatory and neuropathic pain. We previously reviewed BDNF's role as a bidirectional neuromodulator of spinal plasticity. Here, we shift focus to the periphery and discuss BDNF-TrkB expression on nociceptors, non-nociceptor sensory neurons, and non-neuronal cells in the periphery as a potential contributor to induction and persistence of pain after SCI. Overall, this review presents a comprehensive evaluation of large bodies of work that individually focus on pain, DRG, BDNF, and SCI, to understand their interaction in nociceptive processing.

Keywords: BDNF; Dorsal root ganglia; Nociceptors; Pain; Spinal cord injury; TrkB.

Graphical abstract

Fig. 1

Examples of some review literature on pain, SCI, neurotrophins, and nociceptors through the past 30 years. This figure shows 12 recent review articles related to the field. Each number in the diagram can be linked to an article listed in Table 1. Although not demonstrative of the full scope of each topic, these reviews i) show most recent developments in the field or ii) are highly cited in other work, which implies their impact on driving the direction of other research. It should be noted that while several articles focus on 2 (article #2, 3, 5 and 7) or 3 (article # 8, 9, 11 and 12) topics, none of the articles examines all 4 topics (center space designated by ‘?’). This demonstrates a lack of reviews that discuss all the topics together to shed light on central as well as peripheral mechanisms including DRG and nociceptor plasticity in pain hypersensitivity, including neuropathic pain after SCI. The gap in perspective shows potential future research opportunities and development of new research questions for the field.

Fig. 2

Comparison of nociceptive and neuropathic pain. Diagram illustrates an overview of critical mechanisms that lead to development of nociceptive and neuropathic pain after peripheral or central (e.g., SCI) injuries. Some mechanisms overlap, but distinct pathways and modulators involved are noted. Highlighted text indicates negative (red) or positive (green) outcomes of neural plasticity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Summary of various components in the periphery implicated for dysregulation of nociceptive circuit after SCI with BDNF-TrkB system as an example. A) Keratinocytes release growth factors (including BDNF) and cytokines to recruit macrophages and neutrophils, which further amplify inflammatory response by secreting more pro-inflammatory cytokines and chemokines (e.g., IL-1β, TNF-α). TrkB receptors are expressed on non-nociceptor sensory neurons (e.g., Aδ-LTMRs). During pathological conditions, BDNF derived from immune, epithelial, and Schwann cell can presumably interact with peripherally situated TrkB receptors to functionally alter the nociceptive circuit. B) BDNF acting through TrkB may participate in nociceptor hyperactivity by subsequent activation of downstream signaling cascades, such as PI3K and MAPK (p38). Studies implicate p38-dependent PKA signaling that stimulates T-type calcium Cav3.2 to regulate T-currents that may contribute to nociceptor hyperfunction. Certain subtype of VGSCs (TTX-R Nav 1.9) have been observed to underlie BDNF-TrkB-evoked excitation. Interaction between TrkB and VGSCs has not been clarified, but it may alter influx of sodium to change nociceptor excitability. DRGs also express TRPV1, which is sensitized by cytokines such as TNF-α. Proliferating SGCs surrounding DRGs release cytokines to further activate immune cells and trigger release of microglial BDNF. Sympathetic neurons sprout into the DRGs to form Dogiel’s arborization, which have been observed in spontaneously firing DRG neurons. Complex interactions between these components lead to changes in nociceptor threshold and behavior, leading to hyperexcitability. C) Synaptic interactions between primary afferent terminals and dorsal horn neurons lead to central sensitization. Primary afferent terminals release neurotransmitters and modulators (e.g., glutamate and BDNF) that activate respective receptors on SCDH neurons. Sensitized C-fibers release glutamate and BDNF. BDNF binds to TrkB receptors, which engage downstream intracellular signaling cascades including PLC, PKC, and Fyn to increase intracellular Ca²⁺. Consequently, increased Ca²⁺ increases phosphorylation of GluN2B subunit of NMDAR to facilitate glutamatergic currents. Released glutamate activates NMDA/AMPA receptors to activate post-synaptic interneurons.