Review
BDNF: a neuromodulator in nociceptive pathways?

https://doi.org/10.1016/S0165-0173(02)00206-0Get rights and content

Abstract

During development, brain-derived neurotrophic factor (BDNF) supports the survival of certain neuronal population in central and peripheral nervous system. In adulthood, BDNF has been suggested to act as an important modulator of synaptic plasticity. This article reviews and discusses its potential role as neuromodulator in the spinal dorsal horn. BDNF is synthesized in the cell body of primary sensory neurons (pre-synaptic neurons) and its expression is regulated in models of inflammatory and neuropathic pain. The high affinity receptor for BDNF, tropomyosine receptor kinase B (TrkB), is expressed by post-synaptic neurons of the dorsal horn. Stimulation of pre-synaptic nociceptive afferent fibres induces BDNF release and consequent activation of TrkB receptors leading to a post-synaptic excitability. Electrophysiological recordings showed that BDNF enhances the ventral root potential induced by C-fibre stimulation in an in vitro preparation. In addition, behavioural data indicate that antagonism of BDNF attenuates the second phase of hyperalgesia induced by formalin (in nerve growth factor-treated animals) and the thermal hyperalgesia induced by carageenan, suggesting that BDNF is involved in some aspects of central sensitisation in conditions of peripheral inflammation. In conclusion, BDNF meets many of the criteria necessary to define it as a neurotransmitter/neuromodulator in small diameter nociceptive neurons.

Introduction

Acetylcholine was the first neurotransmitter to be identified and characterised. Since then, numerous other compounds have been proposed to be neurotransmitters. A series of criteria have been established against which these claims are judged. These can be summarised as follows:

  • (i)

    A putative transmitter should be synthesised and released from neurones.

  • (ii)

    The pre-synaptic neurone should contain both the neurotransmitter and the appropriate enzyme required for its synthesis.

  • (iii)

    The substance should be released from the nerve terminal in a chemically or pharmacologically identifiable form.

  • (iv)

    The putative neurotransmitter should reproduce post-synaptically cell-specific events observed to occur upon stimulation of the pre-synaptic neurone. These effects should be obtained at concentrations that approximate those seen after release of neurotransmitter from nerve stimulation.

  • (v)

    Known competitive antagonists of the transmitter should block the effect of putative neurotransmitter in a dose-dependent manner.

  • (vi)

    There should be appropriate active mechanisms to terminate the action of the putative transmitter.

While numerous exceptions have been reported, these criteria still provide a useful framework to assess putative neurotransmitters.

Nowadays the list of identified neurotransmitters includes l-amino acids, d-amino acids, peptides, gases and lipids. Recently, evidence has accumulated that the neurotrophic factor BDNF (brain derived neurotrophic factor) could be considered a neurotransmitter. In the hippocampus, BDNF has been shown to rapidly depolarise neurones and capable of modulating synaptic strength. It has been suggested that BDNF is a mediator of long-term potentiation (LTP) induction in this system [31]. In the current review we will consider to what extent BDNF meets these criteria in the context of nociceptive transmission in the dorsal horn of the spinal cord.

Section snippets

Expression of BDNF in primary sensory neurones

A neurotransmitter by definition is synthesized by pre-synaptic neurons and accumulated at synaptic sites in those neurons. In the pain-signalling system, the first relay of nociceptive information takes place in the dorsal horn of the spinal cord where primary afferent neurons form the pre-synaptic neurons, and local and projection neurons located in the spinal dorsal horn make up the post-synaptic element. In the following sections we will describe how BDNF is synthesized in a sub-population

Release of BDNF from primary sensory neurones

Many of the sensory neurones that express BDNF also express the neuropeptide substance P (SP). Like SP, BDNF is packaged in large dense core synaptic vesicles in the cell bodies of small diameter-sensory neurone in the dorsal root ganglia and anterogradely transported to axon terminals in the dorsal horn [45], [60]. It is not surprising then, that BDNF is found in laminae I and II of the spinal cord, the known termination site of SP-containing C-fibres [45]. These neurons utilize glutamate

Inactivation of synaptically released BDNF

To satisfy the criteria of a neurotransmitter, BDNF should be degraded by specific enzymes or taken up to terminate its action after release from primary sensory neurone terminals. We do not as yet have any definitive data regarding this point. However, there are several testable possibilities and some circumstantial evidence.

One possible mechanism is that BDNF’s actions are terminated because of uptake by TrkB receptors. It is known that BDNF binding to TrkB is followed by internalisation of

Post-synaptic effects of synaptically released BDNF

To satisfy the criteria as a neurotransmitter, receptors for BDNF should be present on post-synaptic neurons and the activation of appropriate synapses should activate this receptor.

Antagonism of BDNF action

A key question for the hypothesis examined in this chapter is whether endogenous BDNF contributes to pain-related responses. This question has not been easy to address because of the lack of relevant tools. There are currently no available specific BDNF receptor antagonists (although some compounds such as K252a are non-specific antagonists). However, BDNF can be sequestered with a synthetic fusion protein consisting of the extracellular domain of and the TrkB receptor fused to a portion of an

Conclusions

As we review here, BDNF meets many of the criteria necessary to establish it as a neurotransmitter/neuromodulator in small diameter nociceptive neurons. It is synthesized by these neurons and packaged in dense core vesicles. The BDNF expressing nociceptive afferents terminate mostly in the superficial dorsal horn, and the post-synaptic cells in this region express full-length TrkB receptors. Spinal neurons are responsive to exogenous BDNF, as evidenced both histochemically (by activation of

Acknowledgements

S.B.M. gratefully acknowledges the Wellcome Trust for support, AMGEN for providing NGF, BDNF and TrkB-IgG. S.P. is supported by the Guy’s and St. Thomas Charitable Foundation. M.M. is a Wellcome Trust CDR Fellow.

References (60)

  • 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)
  • A. Haapasalo et al.

    Truncated trkB.T1 is dominant negative inhibitor of trkB.TK+-mediated cell survival

    Biochem. Biophys. Res. Commun.

    (2001)
  • H. Kang et al.

    Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation

    Neuron

    (1997)
  • V.R. King et al.

    Changes in truncated trkB and p75 receptor expression in the rat spinal cord following spinal cord hemisection and spinal cord hemisection plus neurotrophin treatment

    Exp. Neurol.

    (2000)
  • K. Langley et al.

    Are exocytosis mechanisms neurotransmitter specific?

    Neurochem. Int.

    (1997)
  • D.J. Liebl et al.

    Regulation of Trk receptors following contusion of the rat spinal cord

    Exp. Neurol.

    (2001)
  • S.Y. Lin et al.

    BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities

    Brain Res. Mol. Brain Res.

    (1998)
  • X. Luo et al.

    Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons

    Neurosci. Res.

    (2001)
  • A. Meyer-Franke et al.

    Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons

    Neuron

    (1998)
  • M. Narita et al.

    Up-regulation of the TrkB receptor in mice injured by the partial ligation of the sciatic nerve

    Eur. J. Pharmacol.

    (2000)
  • W. Pan et al.

    Transport of brain-derived neurotrophic factor across the blood–brain barrier

    Neuropharmacology

    (1998)
  • D.L. Small et al.

    Brain derived neurotrophic factor induction of N-methyl-d-aspartate receptor subunit NR2A expression in cultured rat cortical neurons

    Neurosci. Lett.

    (1998)
  • W.D. Snider et al.

    Tackling pain at the source: new ideas about nociceptors

    Neuron

    (1998)
  • L. Urban et al.

    Modulation of spinal excitability: co-operation between neurokinin and excitatory amino acid neurotransmitters

    Trends Neurosci.

    (1994)
  • Q. Yan et al.

    Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system

    Neuroscience

    (1997)
  • X.F. Zhou et al.

    Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat

    Neuroscience

    (1999)
  • X.F. Zhou et al.

    Distribution of trkB tyrosine kinase immunoreactivity in the rat central nervous system

    Brain Res.

    (1993)
  • D.W. Adelson et al.

    H2O2 sensitivity of afferent splanchnic C fiber units in vitro

    J. Neurophysiol.

    (1996)
  • D.W. Adelson et al.

    Warm-sensitive afferent splanchnic C-fiber units in vitro

    J. Neurophysiol.

    (1997)
  • J.K. Angleson et al.

    Regulation of dense core release from neuroendocrine cells revealed by imaging single exocytic events

    Nat. Neurosci.

    (1999)
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