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

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


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)


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.


[1] Ai X., Cappuzzello J., Hall A.K.. Activin and Bone morphogenetic proteins induce calcitonin gene-related peptide in embryonic sensory neurons in vitro. Mol Cell Neurosci, 1999, 14: 506-518 CrossRef PubMed Google Scholar

[2] Bär K.J., Schurigt U., Scholze A., Segond Von Banchet G., Stopfel N., Bräuer R., Halbhuber K.J., Schaible H.G.. The expression and localization of somatostatin receptors in dorsal root ganglion neurons of normal and monoarthritic rats. Neuroscience, 2004, 127: 197-206 CrossRef PubMed Google Scholar

[3] Carlton S.M., Du J., Davidson E., Zhou S., Coggeshall R.E.. Somatostatin receptors on peripheral primary afferent terminals: inhibition of sensitized nociceptors. Pain, 2001, 90: 233-244 CrossRef Google Scholar

[4] Chapman V., Dickenson A.H.. The effects of sandostatin and somatostatin on nociceptive transmission in the dorsal horn of the rat spinal cord. Neuropeptides, 1992, 23: 147-152 CrossRef Google Scholar

[5] Dobretsov M., Hastings S.L., Stimers J.R.. Functional Na+/K+ pump in rat dorsal root ganglia neurons. Neuroscience, 1999a, 93: 723-729 CrossRef Google Scholar

[6] Dobretsov M., Hastings S.L., Stimers J.R.. Non-uniform expression of α subunit isoforms of the Na+/K+ pump in rat dorsal root ganglia neurons. Brain Res, 1999b, 821: 212-217 CrossRef Google Scholar

[7] Fink D.J., Fang D.N., Li T.D., Mata M.. Na,K-ATPase β subunit isoform expression in the peripheral nervous system of the rat. Neurosci Lett, 1995, 183: 206-209 CrossRef Google Scholar

[8] Garty H., Karlish S.J.D.. Role of FXYD proteins in ion transport. Annu Rev Physiol, 2006, 68: 431-459 CrossRef Google Scholar

[9] Hall A.K., Burke R.M., Anand M., Dinsio K.J.. Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides. J Neurobiol, 2002, 52: 52-60 CrossRef PubMed Google Scholar

[10] Hamada K., Matsuura H., Sanada M., Toyoda F., Omatsu-Kanbe M., Kashiwagi A., Yasuda H.. Properties of the Na+/K+ pump current in small neurons from adult rat dorsal root ganglia. British J Pharmacol, 2003, 138: 1517-1527 CrossRef PubMed Google Scholar

[11] Hofmann F., Feil R., Kleppisch T., Schlossmann J.. Function of cGMP-dependent protein kinases as revealed by gene deletion. Physiol Rev, 2006, 86: 1-23 CrossRef PubMed Google Scholar

[12] Hökfelt T., Elde R., Johansson O., Luft R., Nilsson G., Arimura A.. Immunohistochemical evidence for separate populations of somatostatin-containing and substance P-containing primary afferent neurons in the rat. Neuroscience, 1976, 1: 131-IN24 CrossRef Google Scholar

[13] Ji, R.R., Zhang, X., Wiesenfeld-Hallin, Z., and Hökfelt, T. (1994). Expression of neuropeptide Y and neuropeptide Y (Y1) receptor mRNA in rat spinal cord and dorsal root ganglia following peripheral tissue inflammation. J Neurosci 14, 6423–6434. Google Scholar

[14] Ji R.R., Zhang X., Zhang Q., Dagerlind Å., Nilsson S., Wiesenfeld-Hallin Z., Hökfelt T.. Central and peripheral expression of galanin in response to inflammation. Neuroscience, 1995, 68: 563-576 CrossRef Google Scholar

[15] Jiang N., Furue H., Katafuchi T., Yoshimura M.. Somatostatin directly inhibits substantia gelatinosa neurons in adult rat spinal dorsal horn in vitro. Neurosci Res, 2003, 47: 97-107 CrossRef Google Scholar

[16] Kaplan J.H.. Biochemistry of Na,K-ATPase. Annu Rev Biochem, 2002, 71: 511-535 CrossRef Google Scholar

[17] Kim S.J., Chung W.H., Rhim H., Eun S.Y., Jung S.J., Kim J.. Postsynaptic action mechanism of somatostatin on the membrane excitability in spinal substantia gelatinosa neurons of juvenile rats. Neuroscience, 2002, 114: 1139-1148 CrossRef Google Scholar

[18] Kozaki Y., Umetsu R., Mizukami Y., Yamamura A., Kitamori K., Tsuchikura S., Ikeda K., Yamori Y.. Peripheral gene expression profile of mechanical hyperalgesia induced by repeated cold stress in SHRSP5/Dmcr rats. J Physiol Sci, 2015, 65: 417-425 CrossRef PubMed Google Scholar

[19] Krishnan A.V., Kiernan M.C.. Altered nerve excitability properties in established diabetic neuropathy. Brain, 2005, 128: 1178-1187 CrossRef PubMed Google Scholar

[20] Li C.L., Li K.C., Wu D., Chen Y., Luo H., Zhao J.R., Wang S.S., Sun M.M., Lu Y.J., Zhong Y.Q., Hu X.Y., Hou R., Zhou B.B., Bao L., Xiao H.S., Zhang X.. Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity. Cell Res, 2016a, 26: 83-102 CrossRef PubMed Google Scholar

[21] Li, C.L. and Zhang, X. (2016). Somatosensory Gene Expression Database. iBrain (http://www.ibrainproject.org/en/index.php?c=channel&a=type&tid=84). Google Scholar

[22] Li K.C., Wang F., Zhong Y.Q., Lu Y.J., Wang Q., Zhang F.X., Xiao H.S., Bao L., Zhang X.. Reduction of follistatin-like 1 in primary afferent neurons contributes to neuropathic pain hypersensitivity. Cell Res, 2011b, 21: 697-699 CrossRef PubMed Google Scholar

[23] Li K.C., Zhang F.X., Li C.L., Wang F., Yu M.Y., Zhong Y.Q., Zhang K.H., Lu Y.J., Wang Q., Ma X.L., Yao J.R., Wang J.Y., Lin L.B., Han M., Zhang Y.Q., Kuner R., Xiao H.S., Bao L., Gao X., Zhang X.. Follistatin-like 1 suppresses sensory afferent transmission by activating Na+,K+-ATPase. Neuron, 2011a, 69: 974-987 CrossRef PubMed Google Scholar

[24] Li Z.W., Wu B., Ye P., Tan Z.Y., Ji Y.H.. Brain natriuretic peptide suppresses pain induced by BmK I, a sodium channel-specific modulator, in rats. J Headache Pain, 2016b, 17: 90 CrossRef PubMed Google Scholar

[25] Liu X.J., Zhang F.X., Liu H., Li K.C., Lu Y.J., Wu Q.F., Li J.Y., Wang B., Wang Q., Lin L.B., Zhong Y.Q., Xiao H.S., Bao L., Zhang X.. Activin C expressed in nociceptive afferent neurons is required for suppressing inflammatory pain. Brain, 2012, 135: 391-403 CrossRef PubMed Google Scholar

[26] Mata M., Siegel G.J., Hieber V., Beaty M.W., Fink D.J.. Differential distribution of (Na,K)-ATPase α isoform mRNAs in the peripheral nervous system. Brain Res, 1991, 546: 47-54 CrossRef Google Scholar

[27] Millan M.J.. Descending control of pain. Prog Neurobiol, 2002, 66: 355-474 CrossRef Google Scholar

[28] Misono K.S.. Natriuretic peptide receptor: structure and signaling. Mol Cell Biochem, 2002, 230: 49-60 CrossRef Google Scholar

[29] Morth J.P., Pedersen B.P., Toustrup-Jensen M.S., Sørensen T.L.M., Petersen J., Andersen J.P., Vilsen B., Nissen P.. Crystal structure of the sodium-potassium pump. Nature, 2007, 450: 1043-1049 CrossRef PubMed ADS Google Scholar

[30] Ono N., Kroin J.S., Penn R.D., Paice J.A.. Effects of intrathecal nonnarcotic analgesics on chronic tactile allodynia in rats: α2-agonists versus somatostatin analog. Neurol Med Chir (Tokyo), 1997, 37: 6-11 CrossRef Google Scholar

[31] Polgar, E., Shehab, S.A., Watt, C. and Todd, A.J. (1999). GABAergic neurons that contain neuropeptide Y selectively target cells with the neurokinin 1 receptor in laminae III and IV of the rat spinal cord. J Neurosci 19, 2637–2646. Google Scholar

[32] Potter, L.R., Yoder, A.R., Flora, D.R., Antos, L.K. and Dickey, D.M. (2009). Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol, 341–366. Google Scholar

[33] Rodgarkia-Dara C., Vejda S., Erlach N., Losert A., Bursch W., Berger W., Schulte-Hermann R., Grusch M.. The activin axis in liver biology and disease. Mutat Res/Rev Mutat Res, 2006, 613: 123-137 CrossRef PubMed Google Scholar

[34] Schaible, H.G. (1996). On the role of tachykinins and calcitonin gene-related peptide in the spinal mechanisms of nociception and in the induction and maintenance of inflammation-evoked hyperexcitability in spinal cord neurons (with special reference to nociception in joints). Prog Brain Res 113, 423–441. Google Scholar

[35] Simmons D.R., Spike R.C., Todd A.J.. Galanin is contained in GABAergic neurons in the rat spinal dorsal horn. Neurosci Lett, 1995, 187: 119-122 CrossRef Google Scholar

[36] Smith P.A., Moran T.D., Abdulla F., Tumber K.K., Taylor B.K.. Spinal mechanisms of NPY analgesia. Peptides, 2007, 28: 464-474 CrossRef PubMed Google Scholar

[37] Taylor B.K.. Spinal inhibitory neurotransmission in neuropathic pain. Curr Sci Inc, 2009, 13: 208-214 CrossRef Google Scholar

[38] Therien, A.G. and Blostein, R. (2000). Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol 279, C541–C566. Google Scholar

[39] Todd, A.J., Spike, R.C., Price, R.F. and Neilson, M. (1994). Immunocytochemical evidence that neurotensin is present in glutamatergic neurons in the superficial dorsal horn of the rat. J Neurosci 14, 774–784. Google Scholar

[40] Vague P., Coste T.C., Jannot M.F., Raccah D., Tsimaratos M.. C-peptide, Ka+, K+-ATPase, and Diabetes. Exp Diabesity Res, 2004, 5: 37-50 CrossRef PubMed Google Scholar

[41] Ventéo S., Laffray S., Wetzel C., Rivat C., Scamps F., Méchaly I., Bauchet L., Raoul C., Bourinet E., Lewin G.R., Carroll P., Pattyn A.. Fxyd2 regulates Aδ- and C-fiber mechanosensitivity and is required for the maintenance of neuropathic pain. Sci Rep, 2016, 6: 36407 CrossRef PubMed ADS Google Scholar

[42] Wang F., Cai B., Li K.C., Hu X.Y., Lu Y.J., Wang Q., Bao L., Zhang X.. FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation. Cell Res, 2015, 25: 318-334 CrossRef PubMed Google Scholar

[43] Woolf C.J., Ma Q.. Nociceptors—noxious stimulus detectors. Neuron, 2007, 55: 353-364 CrossRef PubMed Google Scholar

[44] Xiao H.S., Huang Q.H., Zhang F.X., Bao L., Lu Y.J., Guo C., Yang L., Huang W.J., Fu G., Xu S.H., Cheng X.P., Yan Q., Zhu Z.D., Zhang X., Chen Z., Han Z.G., Zhang X.. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci USA, 2002, 99: 8360-8365 CrossRef PubMed ADS Google Scholar

[45] Xie, W.J., Sun, T., Yang, X.R. and Ma, M. (2012). Expressions of BNP and NPR-A in rat models of chronic nonbacterial prostatitis and their significance (in Chinese). Nat J Androl 18, 204–207. Google Scholar

[46] Xu P., Hall A.K.. Activin acts with nerve growth factor to regulate calcitonin gene-related peptide mRNA in sensory neurons. Neuroscience, 2007, 150: 665-674 CrossRef PubMed Google Scholar

[47] Xu P., Van S.C., Berti-Mattera L., Hall A.K.. Activin induces tactile allodynia and increases calcitonin gene-related peptide after peripheral inflammation. J Neurosci, 2005, 25: 9227-9235 CrossRef Google Scholar

[48] Xu Z.Q.D., Zhang X., Grillner S., Hökfelt T.. Electrophysiological studies on rat dorsal root ganglion neurons after peripheral axotomy: changes in responses to neuropeptides. Proc Natl Acad Sci USA, 1997, 94: 13262-13266 CrossRef Google Scholar

[49] Zhang F.X., Liu X.J., Gong L.Q., Yao J.R., Li K.C., Li Z.Y., Lin L.B., Lu Y.J., Xiao H.S., Bao L., Zhang X.H., Zhang X.. Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons. J Neurosci, 2010, 30: 10927-10938 CrossRef Google Scholar

[50] Zhang X., Shi T., Holmberg K., Landry M., Huang W., Xiao H., Ju G., Hökfelt T.. Expression and regulation of the neuropeptide Y Y2 receptor in sensory and autonomic ganglia. Proc Natl Acad Sci USA, 1997, 94: 729-734 CrossRef ADS Google Scholar

[51] Zhang X., Xu Z.Q., Shi T.J., Landry M., Holmberg K., Ju G., Tong Y.G., Bao L., Cheng X.P., Wiesenfeld-Hallin Z., Lozano A., Dostrovsky J., Hökfelt T.. Regulation of expression of galanin and galanin receptors in dorsal root ganglia and spinal cord after axotomy and inflammation. Ann NY Acad Sci, 1998, 863: 402-413 CrossRef ADS Google Scholar

[52] Zhang, X., Xu, Z.Q., Bao, L., Dagerlind, A. and Hökfelt, T. (1995). Complementary distribution of receptors for neurotensin and NPY in small neurons in rat lumbar DRGs and regulation of the receptors and peptides after peripheral axotomy. J Neurosci 15, 2733–2747. Google Scholar

[53] Zhu W., Xu P., Cuascut F.X., Hall A.K., Oxford G.S.. Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I. J Neurosci, 2007, 27: 13770-13780 CrossRef Google Scholar

  • 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)



    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-HT1B, 2, 3

    DH, brainstem

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


    α2A, 2B/2C

    DH, brainstem




    DH, hypothalamus

    D1, 2, 3, 5



    DH, brainstem


    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





    IB4 (Pep)



    MN, MT, Heat




    Heat, MN, MT, Itch




    MT, MN

    IB4+ (NP)



    MN, MT, Heat, Itch

    IB4+ (NP)


    Mrgprd, Lpar3

    MN, MT, Heat, Itch

    IB4+ (NP)


    Mrgprd, S100b

    MN, MT, Heat






    MN, MT, Heat



    Trappc3l, S100b

    MT, Proprioception



    Baiap2l1, S100b

    MN, Heat



    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)


    Action site

    Inflammation pain (CFA)

    Neuropathic pain (SNI)



    Thermal hypergesia

    No effect



    No effect

    Mechanical allodynia

    Activin C


    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.

Copyright 2020 Science China Press Co., Ltd. 《中国科学》杂志社有限责任公司 版权所有

京ICP备17057255号       京公网安备11010102003388号