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SCIENCE CHINA Life Sciences, Volume 60, Issue 9: 1013-1018(2017) https://doi.org/10.1007/s11427-017-9061-y

Presynaptic inhibition of nociceptive neurotransmission by somatosensory neuron-secreted suppressors

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  • ReceivedFeb 24, 2017
  • AcceptedMar 15, 2017
  • PublishedJun 15, 2017

Abstract

Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I–II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited. In this review, we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons, the BNP/NPR-A/PKG/BKCa channel pathway, the FSTL1/α1Na+-K+ ATPase pathway and the activin C/ERK pathway. These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain.


Funded by

Chinese Academy of Sciences(XDB02010000)

National Natural Science Foundation of China(31630033)

Shanghai Science and Technology Committee(16JC1420500)


Acknowledgment

This work was supported by National Natural Science Foundation of China (31630033, 31130066, 31671094, 81300961), Chinese Academy of Sciences (XDB02010000, QYZDY-SSW-SMC007), and Shanghai Science and Technology Committee (16JC1420500).


Interest statement

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


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  • Figure 1

    The distribution of key genes encoding the proteins in the BNP/NPR-A/PKG/BKCa channel pathway or the FSTL1/α1Na+-K+ ATPase pathway in different types of DRG neurons. A heatmap shows the expression patterns of selected genes in the types of mouse DRG neurons. Bar indicates the relative expression of individual genes in tested DRG neurons (Figure adapted and modified from Li et al., 2016a).

  • Figure 2

    Proposed model of the endogenous suppressive FSTL1/α1NKA pathway in MHNs for nociceptive transmission. In the physiological conditions, FSTL1 released from the nociceptive afferent terminals activates the presynaptic α1NKA to maintain the normal synaptic transmission and somatic sensation. In the pathological conditions such as peripheral nerve injury, the FSTL1 level in the sensory axon terminals is decreased, resulting in the hyperexcitability of synaptic transmission and pain hypersensitivity. α1, α1 subunit of NKA; VDCC, voltage-dependent Ca2+ channel; +, facilitation; −, suppression.

  • Table 1   Overview of several well established endogenous pain inhibitory systema)

    Suppressor

    Receptor

    Action sites

    Expression in DRG

    Opioid peptides (Endormorphin, β-EP, ENK, DYN, OFQ)

    μ, δ, κ, ORL1

    DH, brainstem, hypothalamus, amygdala

    μ, δ, κ, ORL1

    5-HT

    5-HT1B, 2, 3

    DH, brainstem

    5-HT1B, 1D, 2A, 3, 4

    NE

    α2A, 2B/2C

    DH, brainstem

    α2B/2C

    DA

    D2

    DH, hypothalamus

    D1, 2, 3, 5

    Acetylcholine

    Nicotinic

    DH, brainstem

    Nicotinic

    a)β-EP, β-endormorphin; ENK, enkephalin; DYN, dynorphin; OFQ, orphanin FQ; ORL, opioid receptor like; DH, dorsal horn of spinal cord; 5-HT, serotonin; NE, norepinepherine; DA, dopamine.

  • Table 2   New and traditional classification of mouse DRG neuronsa)

    Cell size

    Traditional classification

    New classification

    Functional phenotype

    Biomarker

    Subtype

    Biomarker

    Small

    IB4 (Pep)

    C1

    Gal

    MN, MT, Heat

    IB4

    C2

    Nppb

    Heat, MN, MT, Itch

    TH

    C3

    Th

    MT, MN

    IB4+ (NP)

    C4

    Mrgpra3

    MN, MT, Heat, Itch

    IB4+ (NP)

    C5

    Mrgprd, Lpar3

    MN, MT, Heat, Itch

    IB4+ (NP)

    C6

    Mrgprd, S100b

    MN, MT, Heat

    Large

    NF200

    C7

    Nxph1

    S100b

    MN, MT, Heat

    NF200

    C8

    Trappc3l, S100b

    MT, Proprioception

    NF200

    C9

    Baiap2l1, S100b

    MN, Heat

    NF200

    C10

    Gal, Rspo1

    MT, Proprioception

    a)MN, mechanical nociception; MT, mechanical touch; Gal, galanin; Nppb, natriuretic peptide B; Th, tyrosine hydroxylase; Mrgpr, Mas-related G-protein coupled receptor; Lpar3, lysophosphatidic acid receptor 3; S100b, S100 calcium-binding protein B; Nxph1, neurexophilin 1; Trappc3l, trafficking protein particle complex 3-like; Baiap2l1, BAI1-associated protein 2-like 1; Rspo1, R-spondin 1; IB4, isolectin B4; Pep, peptidergic; NP, non-peptidergic; NF200, neurofilament 200.

  • Table 3   Functions and pharmacological actions of the three molecular signaling pathwaysa)

    Suppressor

    Action site

    Inflammation pain (CFA)

    Neuropathic pain (SNI)

    BNP

    NPR-A/PKG/BKCa

    Thermal hypergesia

    No effect

    FSTL1

    α1NKA

    No effect

    Mechanical allodynia

    Activin C

    ERK

    Thermal hypergesia

    Mechanical hypergesia

    No effect

    a)BNP, B-type natriuretic peptide; NPR-A, natriuretic peptide receptor-A; PKG, cGMP-dependent protein kinase; BKCa, large-conductance Ca2+-activated K+ channels; α1NKA, α1subunit-containing Na+-K+ ATPase; SNI, spared nerve injury.

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