Elsevier

Neuroscience

Volume 283, 26 December 2014, Pages 107-123
Neuroscience

Review
BDNF: No gain without pain?

https://doi.org/10.1016/j.neuroscience.2014.05.044Get rights and content

Highlights

  • Nervous system injury increases expression and secretion of BDNF.

  • BDNF initiates neuronal repair yet causes pain.

  • BDNF increases excitatory synaptic transmission in the spinal dorsal horn.

  • BDNF reduces inhibitory synaptic transmission in the dorsal horn.

  • Similar pain-producing effects occur throughout the nervous system.

Abstract

Injury to the adult nervous system promotes the expression and secretion of brain-derived neurotrophic factor (BDNF). Because it promotes neuronal growth, survival and neurogenesis, BDNF may initiate compensatory processes that mitigate the deleterious effects of injury, disease or stress. Despite this, BDNF has been implicated in several injury-induced maladaptive processes including pain, spasticity and convulsive activity. This review will concentrate on the predominant role of BDNF in the initiation and maintenance of chronic and/or neuropathic pain at the spinal, peripheral and central levels. Within the spinal dorsal horn, the pattern of BDNF-induced changes in synaptic transmission across five different, identified neuronal phenotypes bears a striking resemblance to that produced by chronic constriction injury (CCI) of peripheral nerves. The appearance of this “pain footprint” thus reflects multiple sensitizing actions of microglial-derived BDNF. These include changes in the chloride equilibrium potential, decreased excitatory synaptic drive to inhibitory neurons, complex changes in inhibitory (GABA/glycinergic) synaptic transmission, increases in excitatory synaptic drive to excitatory neurons and the appearance of oscillatory activity. BDNF effects are confined to changes in synaptic transmission as there is little change in the passive or active properties of neurons in the superficial dorsal horn. Actions of BDNF in the brain stem and periphery also contribute to the onset and persistence of chronic pain. In spite of its role in compensatory processes that facilitate the recovery of the nervous system from injury, the widespread maladaptive actions of BDNF mean that there is literally “no gain without pain”.

Introduction

Various forms of stress and/or injury to peripheral nerves, spinal cord or brain increase the expression of brain-derived neurotrophic factor (BDNF) in the affected regions (Meyer et al., 1992, Cho et al., 1998, Michael et al., 1999, Zochodne and Cheng, 2000, Fukuoka et al., 2001, Hicks et al., 1997, Lipska et al., 2001, Wong et al., 1997, Yang et al., 1996; Dougherty et al., 2000, Frisen et al., 1992). Because it promotes neuronal growth, development, synaptogenesis, differentiation, survival and neurogenesis, this led to the idea that BDNF initiates compensatory mechanisms which seek to counter the deleterious effects of injury or stress (Barde et al., 1982, Leibrock et al., 1989, Pencea et al., 2001, Scharfman et al., 2005, Yoshii and Constantine-Paton, 2010, Park and Poo, 2013, Parkhurst et al., 2013). BDNF thus has the potential to facilitate recovery from traumatic nerve injury (Menei et al., 1998, Gordon et al., 2003, Weishaupt et al., 2012, Huang et al., 2013) and to mitigate neurodegenerative disease (Lynch et al., 2007, Zuccato and Cattaneo, 2009). The obvious implication of these findings is that BDNF itself, or agents that mimic or potentiate its action, would hold considerable therapeutic potential (O’Leary and Hughes, 2003, Binder and Scharfman, 2004, Massa et al., 2010, Nagahara and Tuszynski, 2011, Weishaupt et al., 2012, Longo and Massa, 2013). Such potential may extend to the management of psychiatric disorders as BDNF levels are reduced in both depression and bipolar disorder (Autry and Monteggia, 2012).

Unfortunately, this potential is limited by several undesirable actions of BDNF. For example, it can enhance nociceptive processes and may be a major factor in the development of chronic inflammatory and neuropathic pain (Kerr et al., 1999, Thompson et al., 1999, Garraway et al., 2003, Coull et al., 2005, Pezet and McMahon, 2006, Herradon et al., 2007, Merighi et al., 2008b, Bardoni and Merighi, 2009, Lu et al., 2009a, Biggs et al., 2010, Trang et al., 2011, Beggs and Salter, 2013). BDNF can also promote spasticity (Boulenguez et al., 2010, Fouad et al., 2013) and convulsive activity (Hughes et al., 1999, Gill et al., 2013). It may contribute to opioid dependence (Vargas-Perez et al., 2009) and to “paradoxical” opioid hyperalgesia (Ferrini et al., 2013).

On the other hand, attempts to treat chronic and/or neuropathic pain by preventing BDNF action may be precluded by the development of depression (Autry and Monteggia, 2012) and/or disturbance of neuroplastic processes such as long-term potentiation (Montalbano et al., 2013) and memory (Malcangio and Lessmann, 2003).

In view of the theme of this special issue of Neuroscience on “Compensation following injury to the adult brain: always for good?” this review will concentrate on the undesirable actions of BDNF, with particular emphasis on its role in the onset and persistence of neuropathic pain.

Section snippets

Synthesis and secretion of BDNF

The Bdnf gene has unique structural features. The human gene spans >70 kb and is composed of nine exons controlled by nine promoters. The observation that promoter IV is highly responsive to neuronal activity has provided a molecular underpinning to studies of the role of BDNF in the mature nervous system (Park and Poo, 2013). It is made and secreted by neurons, microglia and astrocytes (Lindholm et al., 1992, Rudge et al., 1992, Coull et al., 2005, Lu et al., 2009a, Trang et al., 2011). But

Trk B signaling

Mature BDNF signals both through p75NTR and through the tropomyosin-related kinase B (TrkB) receptor (Reichardt, 2006). Binding of BDNF to TrkB induces receptor dimerization and autophosphorylation. Dimerized receptors recruit the adapter protein Shc to Tyr515 as well as phospholipase Cγ1(PLCγ1) to Tyr785. This leads to the activation of at least three intracellular signaling cascades:

  • 1)

    the phospholipase Cγ1 (PLCγ1) pathway, which leads to activation of protein kinase C (PKC) by diacylglycerol

p75NTR

The discovery of p75NTR (Rodriguez-Tebar et al., 1990) preceded that of TrkB (Klein et al., 1991). It is a member of the tumor necrosis factor (TNF) receptor superfamily and although it does not contain a catalytic motif, p75NTR interacts with several proteins that transmit signals important for regulating neuronal survival and differentiation as well as synaptic plasticity. These include the sphingomyelin pathway (Zhang et al., 2008) and activation of the monomeric G-protein Rho, which

Neuropathic pain

As mentioned above, some of the potential deleterious effects of BDNF relate to its involvement in both inflammatory and neuropathic pain (Pezet et al., 2002b, Malcangio and Lessmann, 2003, Coull et al., 2005, Merighi et al., 2008b, Bardoni and Merighi, 2009, Biggs et al., 2010, Trang et al., 2011). Pain is a vital physiological process that signals actual or potential tissue damage. By so doing, it ensures the survival of the species. By contrast, some forms of chronic pain, including

Role of BDNF in inflammatory pain

Reports of excitatory actions of BDNF in hippocampus and basal forebrain nuclei (Kang and Schuman, 1995, Levine et al., 1995a, Levine et al., 1995b) led to the suggestion that it may be involved in spinal processing of nociceptive information (Kerr et al., 1999, Thompson et al., 1999). Strong support for this notion was provided by the observation that intrathecal injection of BDNF produced hyperalgesia in normal mice while antisense directed against either BDNF or trkB, prevented

BDNF and the “footprint” of neuropathic pain

A series of papers from our laboratory further underlined the importance of BDNF in central sensitization within the Substantia gelatinosa, a major site for termination of nociceptive primary afferents (Lu et al., 2007, Lu et al., 2009a, Biggs et al., 2010). Substantia gelatinosa neurons display a variety of firing patterns in response to depolarizing current commands which we describe as tonic, phasic, delay, irregular and transient (Fig. 2A). In both rats and mice, tonic firing neurons are

BDNF and decreased inhibition in the spinal dorsal horn

The first indication that decreased inhibition in the dorsal horn can contribute to the generation of neuropathic pain came from the demonstration that peripheral nerve injury attenuates GABAergic primary afferent depolarization (Laird and Bennett, 1992) and reduces the amplitude of spontaneous and/or evoked IPSCs (Moore et al., 2002). It was also shown that intrathecal injection of bicuculline and/or strychnine produces allodynia in naive animals (Sherman and Loomis, 1994, Loomis et al., 2001

BDNF and increased excitation in the spinal dorsal Horn

Acute application of BDNF has long been known to facilitate spinal reflexes (Kerr et al., 1999, Thompson et al., 1999) and to increase primary afferent evoked postsynaptic currents (Garraway et al., 2003). It is also known to act acutely on presynaptic TrkB receptors on peptidergic primary afferent terminals to release glutamate, substance P, and CGRP in lamina II. This was reflected in an increase in the frequency of AMPA receptor-mediated mEPSCs and an increase in Ca2+ concentration in

Actions of BDNF in the periphery

The observation by Pitcher and Henry (2008) that application of lidocaine to injured peripheral nerves in vivo reduced the elevated discharge rate of single, second-order wide dynamic range neurons in the spinal cord underlined a role for peripheral sensitization in the etiology of neuropathic pain. The above sections (‘BDNF and decreased inhibition in the spinal dorsal horn’ and ‘BDNF and increased excitation in the spinal dorsal horn’) underline changes in synaptic transmission in the dorsal

BDNF and alterations in descending control mechanisms

As well as actions in the periphery and spinal cord, there is evidence that BDNF augments nociceptive transmission at the level of descending control mechanisms by a TrkB-dependent mechanism (Guo et al., 2006). Thus BDNF-containing neurons in the midbrain periaqueductal gray project to and release BDNF in the rostral ventromedial medulla. Neurons from here project to pain-processing circuits in the spinal dorsal horn. Experimentally-induced inflammation of the hind paw upregulates BDNF in the

BDNF and other pain-related phenomena

Under certain circumstances, which can be reproduced in animal models, morphine can produce a paradoxical hyperalgesia (Bannister and Dickenson, 2010). Like neuropathic pain, opioid hyperalgesia may involve activation of P2X4 receptors, microglial-derived BDNF and disturbance of KCC2 function (Ferrini et al., 2013). Blocking BDNF–TrkB signaling preserved Cl− homeostasis and reversed hyperalgesia and selective deletion of Bdnf from microglia prevented its development. However, neither morphine

Conclusions

BDNF was first identified on the basis of its ability to promote neuronal growth, differentiation, survival and maintenance of adult phenotype (Barde et al., 1982, Thoenen, 1995, Lewin, 1996). The generation and release of BDNF after nerve injury are not altogether unexpected and it may be argued that it converts the neuron from a transmitting to a growth mode in order to restore function after injury. Despite this, there can be little doubt that BDNF plays a major role in activation of

Acknowledgements

Supported by Canadian Institutes of Health Research (CIHR) MOP 81089. We thank Dr. Nataliya Bukhanova for the artwork in Fig. 1.

References (225)

  • B. Everill et al.

    Sodium currents of large (Abeta-type) adult cutaneous afferent dorsal root ganglion neurons display rapid recovery from inactivation before and after axotomy

    Neuroscience

    (2001)
  • A. Fabbro et al.

    Activity-independent intracellular Ca2+ oscillations are spontaneously generated by ventral spinal neurons during development in vitro

    Cell Calcium

    (2007)
  • R. Govrin-Lippmann et al.

    Ongoing activity in severed nerves: source and variation with time

    Brain Res

    (1978)
  • R. Groth et al.

    Spinal brain-derived neurotrophic factor (BDNF) produces hyperalgesia in normal mice while antisense directed against either BDNF or trkB, prevent inflammation-induced hyperalgesia

    Pain

    (2002)
  • S.O. Ha et al.

    Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain

    Neuroscience

    (2001)
  • G. Herradon et al.

    Changes in BDNF gene expression correlate with rat strain differences in neuropathic pain

    Neurosci Lett

    (2007)
  • R.R. Hicks et al.

    Alterations in BDNF and NT-3 mRNAs in rat hippocampus after experimental brain trauma

    Brain Res Mol Brain Res

    (1997)
  • L.J. Huber et al.

    Neurotrophin and neurotrophin receptors in human fetal kidney

    Dev Biol

    (1996)
  • D.I. Hughes et al.

    HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus

    Neuroscience

    (2013)
  • P.E. Hughes et al.

    Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system

    Prog Neurobiol

    (1999)
  • K. Inoue

    The function of microglia through purinergic receptors: neuropathic pain and cytokine release

    Pharmacol Ther

    (2006)
  • D.S. Kim et al.

    Downregulation of voltage-gated potassium channel alpha gene expression in dorsal root ganglia following chronic constriction injury of the rat sciatic nerve

    Brain Res Mol Brain Res

    (2002)
  • R. Klein et al.

    The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3

    Cell

    (1991)
  • J.M.A. Laird et al.

    Dorsal root potentials and afferent input to the spinal cord in rats with an experimental peripheral neuropathy

    Brain Res

    (1992)
  • F.A. Abdulla et al.

    Axotomy and autotomy-induced changes in the excitability of rat dorsal root ganglion neurons

    J Neurophysiol

    (2001)
  • F.A. Abdulla et al.

    Axotomy- and autotomy-induced changes in Ca2+and K+ channel currents of rat dorsal root ganglion neurons

    J Neurophysiol

    (2001)
  • F.A. Abdulla et al.

    Changes in Na+ channel currents of rat dorsal root ganglion neurons following axotomy and axotomy-induced autotomy

    J Neurophysiol

    (2002)
  • M. Ahn et al.

    Regulation of NaV1.2 channels by brain-derived neurotrophic factor, TrkB, and associated Fyn kinase

    J Neurosci

    (2007)
  • J. Alder et al.

    Early presynaptic and late postsynaptic components contribute independently to brain-derived neurotrophic factor-induced synaptic plasticity

    J Neurosci

    (2005)
  • N. Attal et al.

    EFNS guidelines on pharmacological treatment of neuropathic pain

    Eur J Neurol

    (2006)
  • A.E. Autry et al.

    Brain-derived neurotrophic factor and neuropsychiatric disorders

    Pharmacol Rev

    (2012)
  • G. Baj et al.

    Towards a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking

    Front Neurosci

    (2013)
  • S. Balasubramanyan et al.

    Sciatic chronic constriction injury produces cell-type specific changes in the electrophysiological properties of rat substantia gelatinosa neurons

    J Neurophysiol

    (2006)
  • A. Balkowiec et al.

    Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ

    J Neurosci

    (2000)
  • K. Bannister et al.

    Opioid hyperalgesia

    Curr Opin Support Palliat Care

    (2010)
  • Y.A. Barde et al.

    Purification of a new neurotrophic factor from mammalian brain

    EMBO J

    (1982)
  • R. Bardoni et al.

    BDNF-mediated modulation of GABA and glycine release in dorsal horn lamina II from postnatal rats

    Dev Neurobiol

    (2007)
  • R. Bardoni et al.

    Glutamate-mediated astrocyte-to-neuron signalling in the rat dorsal horn

    J Physiol (Lond)

    (2010)
  • R. Bardoni et al.

    BDNF and TrkB mediated mechanisms in the spinal cord

  • P.A. Barker

    Whither proBDNF?

    Nat Neurosci

    (2009)
  • P.E. Batchelor et al.

    Inhibition of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression reduces dopaminergic sprouting in the injured striatum

    Eur J Neurosci

    (2000)
  • S. Beggs et al.

    Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity

    Brain

    (2012)
  • S. Beggs et al.

    Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood–brain barrier

    Mol Pain

    (2010)
  • S. Beggs et al.

    P2X4R+ microglia drive neuropathic pain

    Nat Neurosci

    (2012)
  • M. Besson et al.

    Antihyperalgesic effect of the GABA(A) ligand clobazam in a neuropathic pain model in mice: a pharmacokinetic–pharmacodynamic study

    Basic Clin Pharmacol Toxicol

    (2013)
  • K. Biber et al.

    Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development

    EMBO J

    (2011)
  • J.E. Biggs et al.

    Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization?

    Mol Pain

    (2010)
  • D.K. Binder et al.

    Brain-derived neurotrophic factor

    Growth Factors

    (2004)
  • A.M. Binshtok et al.

    Nociceptors are interleukin-1{beta} sensors

    J Neurosci

    (2008)
  • J.A. Black et al.

    Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn

    Mol Pain

    (2012)
  • Cited by (91)

    • Characterization of an immune-evading doxycycline-inducible lentiviral vector for gene therapy in the spinal cord

      2022, Experimental Neurology
      Citation Excerpt :

      However, prolonged expression resulted in local trapping of the regenerating axons (Blits et al., 2004; Eggers et al., 2008; Tannemaat et al., 2008; Santosa et al., 2013) and impeded functional recovery (Blits et al., 2003; Hoyng et al., 2014b). Overexpression of brain-derived neurotrophic factor (BDNF) in the injured spinal cord promoted sprouting and reorganization of locomotor circuits (Blits et al., 2003) but continued expression induced spasticity in spinal cord injured rats [(Boyce et al., 2012, Fouad et al., 2015), reviewed in (Smith, 2014)]. Uncontrolled overexpression of NGF following a spinal cord lesion resulted in extensive sprouting of sensory afferents but also induced hyperalgesia and autonomic dysreflexia [(Romero et al., 2000, Cameron et al., 2006), reviewed in (Brown and Weaver, 2012)].

    View all citing articles on Scopus
    View full text