ReviewBDNF: No gain without pain?
Graphical abstract
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:
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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.
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