ReviewBDNF: a neuromodulator in nociceptive pathways?
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.
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)
- et al.
c-fos expression in rat lumbar spinal cord during the development of adjuvant-induced arthritis
Neuroscience
(1992) - et al.
c-fos expression in rat lumbar spinal cord following peripheral stimulation in adjuvant-induced arthritic and normal rats
Brain Res.
(1993) - et al.
Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system
Mol. Cell. Neurosci.
(1996) Brain-derived neurotrophic factor-like immunoreactivity is localized mainly in small sensory neurons of rat dorsal root ganglia
J. Neurosci. Methods
(1996)- et al.
Functional consequences of coexistence of classical and peptide neurotransmitters
Prog. Brain Res.
(1986) - et al.
Changes in brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia, spinal cord, and gracile nuclei following cut or crush injuries
Exp. Neurol.
(1998) - et al.
Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation
Brain Res.
(1997) - et al.
Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation
Brain Res.
(1997) Spinal cord pharmacology of pain
Br. J. Anaesth.
(1995)- et al.
Afferent volley patterns and the spinal release of immunoreactive substance P in the dorsal horn of the anaesthetized spinal cat
Neuroscience
(1995)
Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain
Neuroscience
Truncated trkB.T1 is dominant negative inhibitor of trkB.TK+-mediated cell survival
Biochem. Biophys. Res. Commun.
Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation
Neuron
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.
Are exocytosis mechanisms neurotransmitter specific?
Neurochem. Int.
Regulation of Trk receptors following contusion of the rat spinal cord
Exp. Neurol.
BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities
Brain Res. Mol. Brain Res.
Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons
Neurosci. Res.
Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons
Neuron
Up-regulation of the TrkB receptor in mice injured by the partial ligation of the sciatic nerve
Eur. J. Pharmacol.
Transport of brain-derived neurotrophic factor across the blood–brain barrier
Neuropharmacology
Brain derived neurotrophic factor induction of N-methyl-d-aspartate receptor subunit NR2A expression in cultured rat cortical neurons
Neurosci. Lett.
Tackling pain at the source: new ideas about nociceptors
Neuron
Modulation of spinal excitability: co-operation between neurokinin and excitatory amino acid neurotransmitters
Trends Neurosci.
Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system
Neuroscience
Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat
Neuroscience
Distribution of trkB tyrosine kinase immunoreactivity in the rat central nervous system
Brain Res.
H2O2 sensitivity of afferent splanchnic C fiber units in vitro
J. Neurophysiol.
Warm-sensitive afferent splanchnic C-fiber units in vitro
J. Neurophysiol.
Regulation of dense core release from neuroendocrine cells revealed by imaging single exocytic events
Nat. Neurosci.
Cited by (190)
Advance in Functional Restoration of Injured Nerve with Low Level Laser and its Utilization in the Dental and Maxillofacial Region
2020, Chinese Medical Sciences Journal5.10 - Neurotrophins and Pain
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second EditionUpdating perspectives on spinal cord function: motor coordination, timing, relational processing, and memory below the brain
2024, Frontiers in Systems Neuroscience