BDNF: no gain without pain?

NSC 15446

No. of Pages 17, Model 5G

5 June 2014

Please cite this article in press as: Smith PA. BDNF: No gain without pain? Neuroscience (2014), http://dx.doi.org/10.1016/j.neuroscience.2014.05.044 1

Neuroscience xxx (2014) xxx–xxx

2

REVIEW

3

BDNF: NO GAIN WITHOUT PAIN?

4 5 6 7

8

Q1 P. A. SMITH *

9

Centre for Neuroscience and Department of Pharmacology, 9.75 Medical Sciences Building, University of Alberta, Edmonton, AB T6G 2H7, Canada

Contents Introduction 00 Synthesis and secretion of BDNF 00 Trk B signaling 00 p75NTR 00 Neuropathic pain 00 BDNF and pain 00 Role of BDNF in inflammatory pain 00 Role of BDNF in neuropathic pain 00 BDNF and the ‘‘footprint’’ of neuropathic pain 00 BDNF and decreased inhibition in the spinal dorsal horn 00 Altered chloride gradients in dorsal horn neurons 00 Decreased excitatory drive to inhibitory neurons in Substantia gelatinosa 00 Some unexpected changes in inhibitory synaptic transmission in Substantia gelatinosa 00 BDNF and increased excitation in the spinal dorsal Horn 00 BDNF and increased excitatory drive to excitatory Substantia gelatinosa neurons 00 Other excitatory actions of BDNF in spinal cord 00 Initiation of oscillatory activity by BDNF 00 Actions of BDNF in the periphery 00 BDNF and alterations in descending control mechanisms 00 BDNF and other pain-related phenomena 00 Conclusions 00 Acknowledgements 00 References 00

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’’. This article is part of a Special Issue entitled: [Brain Compensation. For Good?] Ó 2014 Published by Elsevier Ltd. on behalf of IBRO.

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

INTRODUCTION Various forms of stress and/or injury to peripheral nerves, Q4 spinal cord or brain increase the expression of brainderived 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., 1999; Hicks et al., 1997; Lipska Q5 et al., 2001; Wong et al., 1997; Yang et al., 1996; Gao et al., 1997; Dougherty et al., 2000; Frisen et al., 1992; Alboni et al., 2011). 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;

Key words: neuropathic pain, dorsal horn, neurotrophin, electrophysiology, organotypic culture, Central sensitization. Q2 *Tel: + 1-780-492-2643; fax: +1-780-492-4325. E-mail address: [email protected] Q3 Abbreviations: ASIC1a, acid- sensing ion channels; BDNF, brainderived neurotrophic factor; CCI, chronic constriction injury; DRG, dorsal root ganglia; ERK, extracellular signal- related kinase; KCC2, K+-Cl cotransporter; MOR, mu-opioid receptor; p75NTR, p75 neurotrophin receptor; PI3K, phosphatidylinositol 3-kinase; rasMAPK, ras mitogen-activated protein kinase; TrkB, tropomyosinrelated kinase B. http://dx.doi.org/10.1016/j.neuroscience.2014.05.044 0306-4522/Ó 2014 Published by Elsevier Ltd. on behalf of IBRO. 1

39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

NSC 15446


5 June 2014

2 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95

P. A. Smith / Neuroscience xxx (2014) xxx–xxx

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.

96

SYNTHESIS AND SECRETION OF BDNF

97

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 BDNF is also found in several tissues outside the nervous system such as kidney (Huber et al., 1996), prostate gland (Dalal and Djakiew, 1997) blood platelets (Yamamoto and Gurney, 1990) and retina (Herzog et al., 1994). Prepro-BDNF is synthesized in the endoplasmic reticulum. This is cleaved into the smaller 35-kDa precursor, pro-BDNF. There is disagreement as to whether pro-BDNF is secreted intact (Matsumoto et al., 2008; Barker, 2009; Yang et al., 2009; Waterhouse and Xu, 2009; Park and Poo, 2013) or whether it is first

98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116

converted to mature 14-kDa BDNF which is secreted from dense core vesicles in an activity and Ca2+-dependent manner (Lessmann et al., 2003; Trang et al., 2009). Pro-BDNF nevertheless has effects in the nervous system that are independent of mature BDNF and are mediated via the p75 neurotrophin receptor (p75NTR) (Lessmann et al., 2003; Matsumoto et al., 2008; Barker, 2009). In humans, a common single nucleotide polymorphism (SNP) of BDNF has been identified in which valine at position 66 is replaced by methionine (Val66Met BDNF). This polymorphism has been associated with a plethora of effects including molecular, cellular and brain structural modifications that are associated with deficits in social and cognitive functions (Baj et al., 2013). It remains to be determined whether individuals expressing Val66Met BDNF are more or less prone to exhibit maladaptive BDNF responses. This is important in terms of individuals’ responses to nerve injury as the occurrence of neuropathic pain is highly variable and depends on a variety of environmental and genetic factors. Interestingly, it was recently reported that the expression of the Val66Met BDNF genotype impacts spinal plasticity in humans (Lamy and Boakye, 2013). Persons expressing this polymorphism may thus display increased susceptibility to developing chronic pain in response to nerve injury.

117

TRK B SIGNALING

143

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 Cc1(PLCc1) to Tyr785. This leads to the activation of at least three intracellular signaling cascades:

144

1) the phospholipase Cc1 (PLCc1) pathway, which leads to activation of protein kinase C (PKC) by diacylglycerol and the release of intracellular Ca2+ by inositol trisphosphate (InsP3). 2) the ras mitogen-activated protein kinase (rasMAPK) pathway. MAPK is also known as extracellular signal-related kinase (ERK). Shc interacts with another protein, Grb2 that recruits and activates the guanine exchange factor, SOS. This promotes removal of GDP from the monomeric G-protein, ras. GDP-GTP exchange is facilitated and ras is activated. This triggers the Raf, MEK, ERK phosphorylation cascade (Reichardt, 2006). 3) the Grb2, SOS, ras cascade also leads to activation of phosphatidylinositol 3-kinase (PI3K). This further phosphorylates the membrane phospholipid, phosphatidylinositol biphosphate (PIP2) to the corresponding triphosphate (PIP3), which in turn activates the serine/threonine kinase, Akt.

152

118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142

145 146 147 148 149 150 151

153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171

As well as promoting relatively slow neurotrophic actions which take hours or days to develop, BDNF can promote rapid changes in synaptic transmission and ion channel function (Stoop and Poo, 1996a,b; Lessmann,

Please cite this article in press as: Smith PA. BDNF: No gain without pain? Neuroscience (2014), http://dx.doi.org/10.1016/j.neuroscience.2014.05.044

172 173 174 175

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 176 177 178 179 180 181 182 183 184 185 186

1998; Garraway et al., 2003; Alder et al., 2005; Tyler et al., 2006). It has been suggested that these rapid effects, that take place within seconds or minutes, depend on PLC-c-mediated release of intracellular calcium stores. By contrast, slower developing and longer-lasting effects of BDNF, that involve altered transcription, are thought to be initiated by the PI3K and/or ras-MAPK pathways (Yoshii and Constantine-Paton, 2010). Differential splicing of exons encoding portions of the intracellular domains of TrkB receptors also regulates the signaling initiated by neurotrophin binding (Reichardt, 2006).

187

P75NTR

188

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 controls growth cone motility. Further details of BDNF signaling via p75NTR can be found in the extensive review by Reichardt (2006).

189 190 191 192 193 194 195 196 197 198 199

200

NEUROPATHIC PAIN

201

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 ‘neuropathic’ pain, that results from injury to the somatosensory system, can last for months or years after any injury has healed (Treede et al., 2008; Costigan et al., 2009b). Neuropathic pain is clearly maladaptive and is sometimes referred to as the ‘disease of pain’. It has a 1.5–3% prevalence within the general population and can be associated with diabetic, postherpetic or HIV-related neuropathies, with fibromyalgia and osteoarthritis and with traumatic nerve, spinal cord or brain injury (including stroke). It is characterized by touch-induced pain, (allodynia), an enhanced response to a moderately noxious stimulus (hyperalgesia) and sometimes by ongoing burning pain (causalgia) and spontaneous bouts of shooting pain that are independent of stimulation. Neuropathic pain is characteristically resistant to the action of opioid analgesics and ‘anti-allodynic’ drugs such as canabinoids, amitriptyline, gabapentinoids and other anticonvulsants are only 30% effective in 30% of patients (Gilron et al., 2006; Attal et al., 2006; Moulin et al., 2007; Sandkuhler, 2009). A variety of animal models have been developed to study neuropathic pain, most of which involve chronic injury to peripheral nerves (Kim et al., 1997; Sandkuhler,

202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232

3

2009; Stemkowski and Smith, 2013). These manipulations promote an enduring increase in dorsal horn excitability known as ‘‘central sensitization’’ (Woolf, 1983; Latremoliere and Woolf, 2009). The processes by which chronic injury of a peripheral nerve leads to ‘‘central sensitization’’ are incompletely understood but some of the major hypotheses are outlined in Fig. 1. Pro-inflammatory cytokines, growth factors and other mediators are released from damaged and inflamed tissue at the site of the injury (Ma et al., 2003; Binshtok et al., 2008; Sandkuhler, 2009; Costigan et al., 2009b). These mediators act directly on the surviving axons of primary afferent neurons to produce an enduring increase in their excitability (Binshtok et al., 2008; Stemkowski and Smith, 2012a). The resultant aberrant activity of injured primary afferents contributes to the release of a second set of mediators from the terminals of these neurons in the spinal dorsal horn (Abbadie et al., 2009) These mediators include the chem okines, CCL-21 and CCL-2 (also known as monocyte chemo-attractant protein 1, MCP-1) as well as the cytokine, CX3CL-1 (also known as fractalkine or neurotactin) (Milligan et al., 2005; de Jong et al., 2005; Zhang and de Koninck, 2006; Zhang et al., 2007; de Jong et al., 2008a,b; Beggs et al., 2012b; Beggs and Salter, 2013). Their interaction with their cognate receptors on quiescent microglia promotes the appearance of a phenotype expressing the ionotropic purinergic receptor P2X4R (Tsuda et al., 2003; Ulmann et al., 2008; Trang et al., 2009). Interestingly ‘‘resting’’ microglia express only very low levels of P2X4 receptors. But these may be upregulated and/or trafficked to the plasma membrane following nerve injury and the release and action of cytokines (Biber et al., 2011; Toyomitsu et al., 2012; Ferrini and De Koninck, 2013). Induction of the P2X4+ phenotype may also involve arrival of interferon c from the blood following alterations in the permeability of the blood–brain barrier (Tsuda et al., 2009a; Costigan et al., 2009a; Beggs et al., 2010, 2012b) as well as changes in fibronectin signaling (Tsuda et al., 2009b) and release of tryptase from mast cells (Yuan et al., 2010). ATP-gated Ca2+ influx through P2X4R stimulates the phosphorylation and activation p38-MAPK which in turn promotes synthesis of BDNF and its release from microglia (Beggs and Salter, 2013). This promotes a slowly developing alteration in the activity of second-order neurons in lamina I and II of the spinal dorsal horn (Coull et al., 2005; Zhang and de Koninck, 2006; Scholz and Woolf, 2007; Lu et al., 2007, 2009a; Keller et al., 2007; Latremoliere and Woolf, 2009; Sandkuhler, 2009; Costigan et al., 2009b; Biggs et al., 2010). These changes lead to an overall increase in network excitability that is responsible for the onset of central sensitization (Woolf, 1983; Woolf and Mannion, 1999; Dalal et al., 1999; Moore et al., 2002; Keller et al., 2007; Sandkuhler, 2009). The idea that changes in microglial phenotype and the Q6 release of BDNF triggers central sensitization is well accepted (Beggs et al., 2012b; Beggs and Salter, 2013). Although the persistence of neuropathic pain depends on enduring activation of astrocytes (Zhang and de Koninck, 2006; Milligan and Watkins, 2009), continued activation of the P2X4+-microglia-BDNF pathway may also be involved. For example, spinal microglial activation


233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293

NSC 15446


5 June 2014

4


Fig. 1. Scheme to show interactions between primary afferents, dorsal horn neurons microglia and astroctyes in the context of chronic pain. Literature citations supporting the illustrated interactions include; IL-1b, MCP-1/CCL-2 and TNF-a in acute and chronic excitation of primary afferents (Binshtok et al., 2008; Stemkowski and Smith, 2012a,b); MCP-1/CCL-2, CCL-21 and fractalkine in alteration of microglial phenotype (Tsuda et al., 2003, 2005; Verge et al., 2004; Milligan et al., 2005; Zhang and de Koninck, 2006); regulation of microglial phenotype by fibronectin (Tsuda et al., 2009b); interferon gamma and tryptase (Tsuda et al., 2009a; Yuan et al., 2010); appearance of P2X4 receptors on microglia (Inoue, 2006; Beggs et al., 2012b; Beggs and Salter, 2013; Tsuda et al., 2013b); IL-1b release from microglia (Milligan et al., 2003; Clark et al., 2006, 2010) and its actions on neurons (Kawasaki et al., 2008; Gustafson-Vickers et al., 2008); BDNF release from microglia and its actions on neurons (Coull et al., 2005; Bardoni et al., 2007; Lu et al., 2007; Lu et al., 2009a,b; Merighi et al., 2008a; Merighi et al., 2008b; Bardoni and Merighi, 2009; Beggs and Salter, 2010; Biggs et al., 2010; Beggs et al., 2012a); role of MCP-1/CCL-2 and neurotransmitters in astrocyte–neuron interactions (Gao et al., 2009; Milligan and Watkins, 2009); actions of TNF-a on astrocytes and neurons (Kawasaki et al., 2008); actions of IL-1b on astrocytes (Gruber-Schoffnegger et al., 2013).

294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315

may persist for 4 months or more in female mice subject to nerve injury (Vacca et al., 2014). The possibility that persistant TrkB signaling is involved in the maintenance of neuropathic pain was also suggested from experiments with transgenic mice that expressed mutant, but fully functional TrkB receptors, which could be selectively disabled following treatment with a novel kinase inhibitor, 1NM-PP1. Oral administration of 1NM-PPI prevented the development of tissue- or nerve injury-induced heat and mechanical hypersensitivity but, more importantly, established hypersensitivity was transiently reversed by intraperitoneal injection of the inhibitor (Wang et al., 2009). The is also evidence for enduring ‘‘activation’’ of microglia in association with chronic pain following spinal cord injury (Hains and Waxman, 2006). This too may involve long-term signaling via BDNF (Dougherty et al., 2000; Wu et al., 2013). Following the onset and persistence of central sensitization at the spinal level, nerve injury promotes enduring changes in thalamic and cortical physiology (Craig and Dostrovsky, 1999; Xu et al., 2008; Li et al.,

2010), changes in descending inhibition from the rostral ventromedial medulla (Guo et al., 2006; Sandkuhler, 2009). There is also long-term sensitization of peripheral nociceptors (Gold and Gebhart, 2010) and, the persistence of aberrant activity in primary afferent fibers (Pitcher and Henry, 2008). As described below (in sec- Q7 tion ‘BDNF and increased excitation in the spinal dorsal horn’), this latter effect likely plays a role in maintaining ‘‘central sensitization’’ at the spinal level.

BDNF AND PAIN

316 317 318 319 320 321 322 323 324

325

Role of BDNF in inflammatory pain

326

Reports of excitatory actions of BDNF in hippocampus and basal forebrain nuclei (Kang and Schuman, 1995; Levine et al., 1995a,b) 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,

327


328 329 330 331 332 333 334

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351

352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374

375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392

prevented inflammation-induced hyperalgesia (Groth and Aanonsen, 2002). Excitatory actions of acutely applied BDNF on lamina II neurons were also described (Garraway et al., 2003; Matayoshi et al., 2005) and in a more thorough study BDNF was shown to attenuate stimulation-evoked inhibitory synaptic transmission (Bardoni et al., 2007). Because intrathecally administered drugs may have access to midbrain structures such as the periaqueductal gray (Siuciak et al., 1995), acute actions of BDNF in the brainstem (Guo et al., 2006) may contribute to pro-nociceptive effects generated at the spinal level. BDNF can nevertheless be released by stimulation of primary afferent fibers (Balkowiec and Katz, 2000; Lever et al., 2001). These and other data have led to the suggestion that while primary afferent-derived BDNF may contribute to inflammatory pain, microglial-derived BDNF contributes to neuropathic pain. Role of BDNF in neuropathic pain. Reports of increased levels of BDNF in dorsal root ganglia (DRG) and in the spinal cord following injury first started to appear in the late 1990s (Cho et al., 1997, 1998; Li et al., 1999; Dougherty et al., 2000; Ha et al., 2001). It was subsequently shown that sustained and prolonged exposure to BDNF in vivo, as achieved by intrathecal administration of a BDNF-transducing recombinant adenovirus, caused a progressive decrease in paw withdrawal threshold over a 4-d testing period (Coull et al., 2005). Additional correlative evidence to support a role for BDNF in central sensitization was provided by the observation that nerve injury-induced thermal hyperalgesia correlated temporarily with changes in spinal levels of BDNF (Miletic and Miletic, 2002). More importantly, this type of thermal hyperalgesia was attenuated by intrathecal injection of BDNF antibodies (Yajima et al., 2002) and was absent in heterozygous BDNF knockout mice (Yajima et al., 2005). The latter paper also demonstrated loss of mechanical hyperalgesia in the knockout mice following nerve injury. Moreover, both thermal and mechanical hyperalgesia were attenuated when BDNF was sequestered by intrathecal application of the BDNF binding protein TrkB/fc.

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, 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 often GABA/glycinergic whereas delay firing neurons are usually excitatory (Heinke et al., 2004; Yasaka et al., 2010; Hughes et al., 2013; Punnakkal et al., 2014). The neurotransmitter phenotype of irregular, phasic and transient (single-spike) neurons is less well-established. Recent data from mice does however associate single-spike (transient) neurons with a glutamatergic phenotype (Punnakkal et al., 2014). We

5

examined the effects of sciatic nerve CCI on spontaneous excitatory synaptic activity in tonic, phasic, delay, irregular and transient firing neurons (Balasubramanyan et al., 2006; Chen et al., 2009). Examination of the frequency and amplitude of both spontaneous, action potentialdependent EPSCs (sEPSCs) and miniature EPSCs (mEPSCs recorded in TTX) yielded a clear pattern of changes (Fig. 2B) which we refer to as a ‘‘pain footprint’’. We reasoned that any manipulation that could replicate this ‘‘footprint’’ would provide useful information about the etiology of neuropathic pain. We then studied spinal cord slices in organotypic culture and found that 5-d exposure of the cultures to BDNF replicated the ‘‘pain footprint’’ remarkably well (Fig. 2C) (Lu et al., 2007; Biggs et al., 2010). In fact, the two ‘‘pain footprints’’ are almost completely superimposed (Fig. 2D), suggesting that the ‘‘compensatory molecule’’ BDNF may be responsible for multiple aspects of the central sensitization process, at least at the level of the substantia gelatinosa. We used 5–6d exposure to BDNF to match the reported time course of BDNF elevation produced by nerve injury (Cho et al., 1997; Zhou et al., 1999; Dougherty et al., 2000; Fukuoka et al., 2001). In other work, we examined long-term actions of interleukin 1b (IL-1b) as a putative harbinger of central sensitization (Gustafson-Vickers et al., 2008). Interestingly the ‘‘pain footprint’’ produced by interleukin 1b is obviously dissimilar from that produced by CCI and BDNF. This argues against a major role for IL-1b in the onset of central sensitization at the level of the substantia gelatinosa yet further underlines the importance of BDNF (Biggs et al., 2010; Ferrini and De Koninck, 2013). We also found that 5–6d exposure of spinal cord organotypic cultures to BDNF increases their overall excitability, as monitored by the amplitude of Ca2+ responses evoked by nerve stimulation or exposure to 35 mM K+ (Lu et al., 2007). Similar effects were seen when the cultures were exposed to activated microgliaconditioned medium but this effect was blocked when any BDNF in the medium was sequestered with TrkBd5 (Banfield et al., 2001; Lu et al., 2009a; Biggs et al., 2010). This adds additional weight to the argument that microglia-derived BDNF is a major mediator of central sensitization (Coull et al., 2005; Beggs and Salter, 2013; Tsuda et al., 2013a). Neither CCI nor long-term BDNF exposure produce changes in passive or active membrane properties of substantia gelatinosa neurons. Thus input resistance, current–voltage relationships, action potential threshold and rheobase, as well as repetitive discharge characteristics, examined by current ramps or depolarizaing commands are essentially unchanged (Balasubramanyan et al., 2006; Lu et al., 2007, 2009a; Chen et al., 2009). Thus, BDNF-induced alterations in synaptic processing likely play a major role in the onset of dorsal horn excitability that underlies central sensitization. As will be discussed below, BDNF-induced central sensitization may involve; (1) Decreased inhibition in the spinal dorsal horn (section ‘BDNF and decreased inhibition in the spinal dorsal horn’), (2) Increased excitation in the spinal dorsal horn (section ‘BDNF and


393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453

NSC 15446


5 June 2014

6


Fig. 2. Neuron types and injury footprints produced by CCI and BDNF. (A) Firing patterns of tonic, delay, irregular, phasic and transient neurons in response to depolarizing current commands. (B) ‘‘Pain footprint’’ produced by CCI. Neuron types are listed across the top of the scheme and four indices of excitatory synaptic transmission are listed to the left. Neuron-specific parameters increased ("; such as sEPSC amplitude in delay neurons) are coded green. Neuron-specific parameters decreased (;; such as sEPSC amplitude in tonic neurons) are coded red. nd = not determined. (C) ‘‘Pain footprint’’ produced by BDNF. Neuron types are listed across the top of the scheme and four indices of excitatory synaptic transmission are listed to the left. Neuron-specific parameters increased ("; such as sEPSC amplitude in delay neurons) are coded green. Neuronspecific parameters decreased (;; such as sEPSC amplitude in tonic neurons) are coded red. (D) Overlay of the injury footprints from B and C, similarities between the actions of CCI and BDNF treatment show up as clear green or red squares. Yellow squares illustrate the few parameters which appear to be altered in a different way by BDNF compared to CCI. Two out of 20 squares (10%) are yellow. This analysis indicates that the many aspects of the effects of CCI are mimicked by BDNF. Reproduced with permission and slightly modified from Fig. 3 in Biggs et al. (2010). 454 455 456 457 458

459 460 461 462

increased excitation in the spinal dorsal horn’), (3) actions in the periphery (section ‘Actions of BDNF in the periphery’) and (4) possible alterations in descending control mechanisms (section ‘BDNF and alterations in descending control mechanisms’).

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).This straightforward observation is of great significance as allodynia is highly characteristic of neuropathic pain. More recently, pharmacological potentiation of GABA signaling though GABAA receptors has been shown to reverse signs


463 464 465 466 467 468 469 470 471 472 473

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 474 475 476 477

of neuropathic pain in animal models (Knabl et al., 2008; Zeilhofer et al., 2012a,b; Besson et al., 2013; Paul et al., 2014). There is also evidence to implicate attenuated GABAB signaling in neuropathic pain (Laffray et al., 2012).

478

Altered chloride gradients in dorsal horn neurons

479

Although multiple pre- and postsynaptic mechanisms undoubtedly contribute to attenuated spinal inhibition in neuropathic pain, considerable attention has been paid to the involvement of alterations in chloride gradients (Coull et al., 2003; Prescott and De Koninck, 2005; Keller et al., 2007; Ferrini and De Koninck, 2013; Beggs and Salter, 2013). This is brought about by a trans-synaptic reduction in the activity of the potassium–chloride exporter, KCC2, in output neurons of lamina I as well as in nociceptive-specific deep spinothalamic tract neurons but not in wide dynamic range neurons (Lavertu et al., 2014). The resulting accumulation of intracellular chloride shifts the chloride equilibrium potential (ECl) to a less negative value. Activation of GABAA receptors thus produces less hyperpolarization and less inhibition (Prescott and De Koninck, 2005; Prescott et al., 2006). If ECl is sufficiently displaced, GABA may exert an excitatory effect in the dorsal horn of nerve-injured animals. Other work from this group (Coull et al., 2005), identified microglial-derived BDNF as the mediator of this effect. In addition to decreasing KCC2 expression, BDNF may exert more rapid alterations in its function by phosphorylation and decreased trafficking to the cell surface (Ferrini and De Koninck, 2013). Coull et al. (2005) also found that ATP evokes the release of BDNF from microglia and that intrathecal injection of ATP-stimulated microglia caused a depolarizing shift in chloride reversal potential in spinal lamina I neurons in a similar fashion to BDNF. Blocking signaling between BDNF and TrkB reversed nerve injury-induced allodynia and the shift in ECl that follows both nerve injury and administration of ATP-stimulated microglia. Interestingly, as will be discussed below, this BDNF–KCC2–GABA attenuation sequence may operate in pain centralization at other levels; notably in the midbrain raphe magnus, where it may impact descending modulation of nociceptive processing (Zhang et al., 2013).

480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515

516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531

Decreased excitatory drive to inhibitory neurons in Substantia gelatinosa Another mechanism that could lead to attenuated inhibition in the dorsal horn during central sensitization involves lessening of excitatory synaptic drive to inhibitory substantia gelatinosa neurons (Balasubramanyan et al., 2006; Leitner et al., 2013). Since BDNF and CCI exert similar changes in sEPSCs and mEPSCs in putative inhibitory neurons (Fig. 3A, C, D and F), this is consistent with a causal relationship (Biggs et al., 2010). This similarity is reflected at the microphysiological level where both BDNF and CCI caused a 35% reduction in the mean time constant for mEPSC decay and a similar percentage decrease in mEPSC amplitude (Biggs et al., 2010). Because both the amplitude and frequency of mEPSC were reduced, attenuation of excitatory synaptic

7

transmission by 5–6d exposure to BDNF (or CCI) likely engages both pre- and postsynaptic changes (Lu et al., 2007). Some of these may correspond to loss of terminals on islet neurons seen with nerve injury (Bailey and Ribeiro-da-Silva, 2006). Current–clamp recording showed a significant decrease in the frequency of spontaneous action potentials in putative inhibitory neurons after BDNF (Lu et al., 2007). This change likely reflects decreased synaptic drive, as the inherent excitability of neurons, as determined by their response to depolarizing current commands, was unchanged. The most recent analysis of this effect suggests that release of excitatory neurotransmitter from presynaptic terminals in dorsal horn is reduced as a result of a retrograde signal from postsynaptic inhibitory neurons (Leitner et al., 2013). Since, as mentioned above, long-term (5–6d) application of BDNF reduces mEPSC frequency in tonic-firing inhibitory neurons in a similar fashion to peripheral nerve injury (Lu et al., 2009a; Biggs et al., 2010), this raises the intriguing possibility that neuron-derived BDNF may act as retrograde signal to impair excitation of inhibitory dorsal horn neurons. This parallels the suggestion, that retrograde signaling via neuron-derived BDNF (or proBDNF) may be involved in hippocampal long-term depression (Woo et al., 2005). While the augmentation of excitatory transmission by BDNF to be described in section ‘BDNF and increased excitation in the spinal dorsal horn’ depends on TrkB signaling, it is possible, again by analogy with findings in hippocampus, that depression of transmission may be mediated by the p75NTR (Woo et al., 2005).

532

Some unexpected changes in inhibitory synaptic transmission in Substantia gelatinosa

563

Somewhat surprisingly, some of the observed actions of BDNF on GABA and glycinergic transmission in lamina II run contrary to its perceived role as a universal excitatory influence in the onset of central sensitization (Biggs et al., 2010; Ferrini and De Koninck, 2013). For example, acute intrathecal injection of BDNF has been reported to increase GABA release and to promote a transient increase in hindpaw threshold to noxious thermal stimulation (Pezet et al., 2002a). Other work suggests that nerve injury-induced, chronic neuropathic pain can be ameliorated by intrathecal BDNF injection (Lever et al., 2003) or by adeno-associated viral (AAV) vectormediated over-expression of BDNF in the rat spinal cord (Eaton et al., 2002). Although these behavioral observations are consistent with the finding that acute application of BDNF increases the frequency of TTX-resistant, glycine and GABA-mediated mIPSCs in dorsal horn, stimulation-evoked IPSCs are depressed (Bardoni et al., 2007). Other data suggest that long-term (5–6d) application BDNF decreases mIPSC frequency yet increases mIPSC amplitude (Lu et al., 2009b, 2012). The long-term effects of BDNF on action potential-dependent sIPSCs seem to be cell-type dependent, with amplitude and frequency of events increasing in putative excitatory neurons while decreasing in putative inhibitory neurons (Lu et al., 2009b, 2012).

565


533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562

564

566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590

NSC 15446


5 June 2014

8


Fig. 3. Bar graphs to illustrate similarity of effects of CCI and BDNF on excitatory transmission to putative inhibitory, tonic islet-central (TIC) and to

Q12 putative excitatory radial-delay neurons (RD). Data sets were obtained from Lu et al. (2009a,b). ⁄P < 0.001 (Student’s t test). In some cases, error bars are too small to be visible on this figure size. For clarity of comparison of interevent interval (IEI) values for data from organotypic cultures are divided by 10 as IEI were much smaller in culture compared to acutely isolated slices. (A) Comparison of mean IEI for sEPSCs in tonic inhibitory central (putative inhibitory) neurons in slices from sham and CCI animals as well as those in control or BDNF treated cultures. (B) Comparison of mean IEI in sham and CCI radial irregular delay (presumed excitatory) neurons in acute slices and control and BDNF-treated RD neurons in organotypic slice culture. (C) Comparison of percentage changes in IEI calculated (without error bars) from data in A and B. Note that both BDNF and CCI produce the same types of changes in IEI both TIC and RID/RD neurons. (D) Comparison of sEPSC amplitude for TIC neurons in slices from sham and CCI animals and in control or BDNF-treated cultures. (E) Comparison of mean sEPSC amplitude in sham, CCI, control and BDNFtreated RID/RD neurons. (F) Comparison of percentage changes in sEPSC amplitude calculated (without error bars) from data in D and E. Note that both BDNF and CCI produce the same types of changes in sEPSC amplitude in both TIC and RD neurons. Legend in A applies also to B, D and E. Legend in C also applies to F. Reproduced with permission and slightly modified from Fig. 5 in Lu et al. (2009a,b).

591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615

A possible explanation for these divergent findings comes from recent work in hippocampal neurons which underlined how cellular responses to BDNF differ markedly depending on how it is delivered (Ji et al., 2010). Acute increases in BDNF concentration elicited transient activation of TrkB, neurite elongation and spine head enlargement and enhancement of basal transmission. By contrast, more gradual changes in BDNF levels led to sustained TrkB activation, facilitation of neurite branch and spine neck elongation and enhancement of long-term potentiation. The type of cellular response generated may thus be critically dependent on the kinetics of TrkB activation. This may help to explain disparate findings with BDNF actions on inhibitory synaptic transmission in dorsal horn. Thus, acute intrathecal injection in vivo (Pezet et al., 2002a), acute application (Bardoni et al., 2007) or long-term treatment with BDNF in vitro (Lu et al., 2009b, 2012) may elicit differential effects on inhibitory transmission. Notwithstanding the possibility that BDNF may, under certain circumstances augment inhibitory transmission, there is little doubt that it increases overall dorsal horn excitability (Lu et al., 2007, 2009a). This implies that the ability of BDNF to augment excitatory processes at the

spinal level over rides its ability to enhance processes that appear to augment inhibition. This idea is further supported by the observation that the frequency of mEPSCs and sEPSCs in all neuron types in the dorsal horn is far greater than that of sIPSC and mIPSCs (Lu et al., 2012) and with the suggestion that the substantia gelatinosa is primarily an excitatory network (Santos et al., 2007). It should also be noted that the work done in our laboratory (Lu et al., 2009b, 2012) and others (Bardoni et al., 2007) were done with whole-cell recording in substantia gelatinosa neurons. Under these conditions, the concentration of intracellular chloride is determined by the concentration in the recording pipette (Pusch and Neher, 1988). If BDNF reverses the chloride gradient in lamina II as it does in lamina I (Coull et al., 2005; Miletic and Miletic, 2008), any increase in the frequency or amplitude of GABAergic events may translate into an increased excitability. Alternatively, since neurons were exposed to BDNF for 5–6d, the observed enhancement of GABAergic transmission (Lu et al., 2009b, 2012) may reflect some yet to be understood homeostatic adjustment to an earlier decrease in transmission. This may relate to a recent report that BDNF exerts both rapid and slower homeostatic regulations of AMPA receptor expression in nucleus accumbens neurons (Reimers et al., 2014).


616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 641 642 643 644 645 646 647 648 649 650 651 652 653 654

655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677

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 postsynaptic neurons (Merighi et al., 2008a). These authors did not however subcategorize postsynaptic neurons into putative inhibitory and putative inhibitory subtypes.

BDNF and increased excitatory drive to excitatory Substantia gelatinosa neurons In view of reports that nerve-injury increases BDNF levels for several days (Cho et al., 1997; Zhou et al., 1999; Dougherty et al., 2000; Fukuoka et al., 2001), we elected to study the effects of 5–6d exposure to neurotrophin as this may be more relevant to understanding its role in central sensitization. This duration of exposure to BDNF of dorsal horn neurons in organotypic cultures increased excitatory drive to excitatory neurons in a similar fashion to CCI in vivo (Balasubramanyan et al., 2006; Lu et al., 2007, 2009a; Chen et al., 2009; Biggs et al., 2010). Both pre- and postsynaptic mechanisms appear to contribute to BDNF-induced augmentation of excitatory drive to ‘‘delay’’ or ‘‘delay radial’’ neurons which likely display an excitatory phenotype (Yasaka et al., 2010; Punnakkal et al., 2014). BDNF and CCI both increase mean sEPSC and mEPSC amplitude and frequency in putative excitatory neurons (Figs. 2B–D and 3B, E, C and F). More detailed comparison of their effects show that both manipulations reveal a new population of large mEPSCs that is absent in both sham-operated animals and in control organotypic cultures (Biggs et al., 2010).

678

Other excitatory actions of BDNF in spinal cord

679

Unlike other brain regions, notably the hippocampus, where the molecular mechanisms underlying BDNF potentiation of synaptic transmission have been extensively investigated (Elmariah et al., 2004; Alder et al., 2005; Woo et al., 2005; Jiang et al., 2008; Crozier et al., 2008; Fortin et al., 2012; Park and Poo, 2013), rather less is known about mechanisms operating in the dorsal horn. Acute excitatory spinal actions of BDNF likely require NMDA receptor activation (Kerr et al., 1999; Garraway et al., 2003; Alder et al., 2005) but it remains to be determined whether such mechanisms contribute to its longer term effects. We have found that while long-term exposure to BDNF increases the amplitude of AMPA-induced changes in intracellular Ca2+, postsynaptic responses to NMDA are unchanged (Kim, 2011). There is also evidence that BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals (Chen et al., 2014).

680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696

9

An additional excitatory spinal action of BDNF may be mediated via enhancement of function of acid-sensing ion channels (ASIC1a) currents via the phosphoinositide 3-kinase and Akt cascade (Duan et al., 2012). Interestingly, these authors found that manipulations that attenuated ASIC1a function attenuated mechanical hyperalgesia produced by intrathecal BDNF injection. Lastly, injury-induced generation of BDNF may promote sprouting of descending serotonergic fibers which augment nociceptive transmission at the spinal level (Ramer, 2012).

697

Initiation of oscillatory activity by BDNF

708

Oscillatory activity in neuronal networks is monitored as spontaneous intracellular calcium transients (Ruscheweyh and Sandkuhler, 2005; Fabbro et al., 2007) and/or as extracellular field potential recordings. Oscillatory activity occurs in spinal dorsal horn following brief or long-term exposures to BDNF (Lu et al., 2007; Merighi et al., 2008a) and this may relate to any of the variety of mechanisms capable of initiating oscillatory activity in the spinal cord. For example, ventral horn interneurons in about 33% of spinal cord organotypic cultures exhibit oscillatory activity that is suppressed in a calcium-free medium or one containing extracellular solution or by application of cobalt but is unaffected following blockade of network activity with TTX, CNQX, APV, strychnine or bicuculline. Rather than involving altered synaptic transmission, these oscillations may instead involve the dynamics of mitochondrial Ca2+ buffering as they are blocked by CCCP, that selectively collapses the mitochondrial electrochemical gradient (Fabbro et al., 2007). Oscillatory activity has also been observed in the dorsal horn of acutely isolated spinal cord slices when neuronal excitability is increased following treatment with 4-aminopyridine (Ruscheweyh and Sandkuhler, 2005). Because they were blocked by APV and TTX but not by AMPA/kainate blockers and arose in the dorsal horn rather than the ventral horn, these oscillations are likely mediated by a different mechanism than those described by Fabbro et al. (2007). Oscillatory activity described by Ruscheweyh and Sandkuhler (2005) may relate to NMDA-mediated spontaneous inward currents in lamina II neurons that appear to be activated by astrocyte-derived glutamate (Bardoni et al., 2010). Spontaneous, synchronous oscillations in dorsal horn slices in organotypic culture following 5–6d exposure to BDNF occur once every 7s or so (Lu et al., 2007). Oscillations are monitored by confocal Ca2+ imaging and are correlated with extracellular recordings of spontaneous electrical activity. Preliminary analysis of these oscillations shows that they are blocked by 1 lM TTX, removal of extracellular calcium or by 200 lM Cd2+. The amplitude but not the frequency of the oscillations is reduced by 50 lM APV and the responses are eliminated by 10 lM NBQX (Lu, 2007). This suggests that BDNFinduced oscillatory activity results from altered function of AMPA receptors rather than NMDA receptors and may therefore engage a different mechanism to those described by others (Ruscheweyh and Sandkuhler, 2005; Fabbro et al., 2007; Bardoni et al., 2010).

709


698 699 700 701 702 703 704 705 706 707

710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756

NSC 15446


5 June 2014

10 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775


BDNF-induced oscillatory activity has also been described in cultured hippocampal neurons (Sakai et al., 1997) and this may relate to possible pro-convulsant actions (Gill et al., 2013) and may parallel the presence of convulsive activity in mice strains that over express BDNF (Heyden et al., 2011). The presence of unprovoked, stimulus-independent, shooting or electric shock-like pains is a major cause of morbidity in neuropathic pain patients. Spontaneous bursts of action potentials have also been described in lamina I neurons in vivo following intrathecal injection of activated microglia (Keller et al., 2007). We have also noticed oscillations in intracellular Ca2+ concentration in spinal cord slices acutely-isolated from nerve-injured rats. These were not usually seen in slices from uninjured animals. While it is tempting to speculate that BDNF-induced oscillations in the dorsal horn may underlie this activity, other types of oscillatory activity as described above may also contribute.

776

ACTIONS OF BDNF IN THE PERIPHERY

777

The observation by Pitcher and Henry (2008) that application of lidocaine to injured peripheral nerves in vivo reduced the elevated discharge rate of single, secondorder 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 horn brought about by BDNF and or peripheral nerve injury but Pitcher and Henry’s work showed that this synaptic activity must be driven by increased afferent activity. In addition to actions in the CNS, peripheral actions of BDNF therefore need to be considered as a contributing factor in pain centralization. It is well-established that BDNF synthesis is increased in lesioned peripheral nerve (Meyer et al., 1992) and acute application of BDNF to capsaicin-sensitive dorsal root ganglion neurons increases excitability as monitored by the number of action potentials generated by a depolarizing current ramp command (Zhang et al., 2008). This results, in part, from an increase in tetrodotoxin-resistant sodium current and to suppression of a delayed rectifierlike K+ current. These actions of BDNF occur via the p75 neurotrophin–sphingomyelin pathway (Zhang et al., 2008). Lasting increases in various types of voltage-gated Na+ currents (Waxman et al., 1999; Everill et al., 2001; Abdulla and Smith, 2002; Dib-Hajj et al., 2010), decreases in K+ currents (Abdulla and Smith, 2001b; Kim et al., 2002; Tan et al., 2006; Rose et al., 2011) and augmented excitability of peripheral neurons (Govrin-Lippmann and Devor, 1978; Wall and Devor, 1983; Liu et al., 2000, 2001; Abdulla and Smith, 2001a) are well known to be associated with the initiation and persistence of neuropathic pain, but it remains to be determined whether there is a causal relationship between this and the BDNF-induced increases in peripheral neuron excitability observed by Zhang et al. (2008). Whereas interlukin-1b is much less likely than BDNF to be involved in

778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815

microglia–neuron interactions in the dorsal horn (Biggs et al., 2010), its role in the periphery as a mediator of injury-induced neuronal hyperactivity is well-established (Binshtok et al., 2008; Stemkowski and Smith, 2012a). As mentioned above, BDNF does not seem to affect postsynaptic voltage-gated ion channels in the spinal cord as intrinsic neuronal excitability is unchanged (Lu et al., 2007, 2009a). It is of course possible that some of the increases in sEPSC frequency observed in excitatory neurons in substantia gelatinosa (Lu et al., 2009a) result from altered expression of Na+ channels in primary afferent terminals (Black et al., 2012). This possibility is supported by the observation that BDNF-induced increases in sEPSC frequency in dorsal horn neurons in an inflammatory pain model has been attributed to an action on presynaptic TTX-resistant Na+ channels (Matayoshi et al., 2005). Elsewhere in the CNS however, BDNF has been reported to impair excitability by increasing inactivation of Nav1.2 channels (Ahn et al., 2007). In a similar fashion to spinal cord, where BDNF is released from microglia during central sensitization (Coull et al., 2005; Trang et al., 2012; Ferrini and De Koninck, 2013), peripherally derived BDNF may also originate from immuno-competent cells such as activated T cells or B cells, monocytes (Kerschensteiner et al., 1999), macrophages (Batchelor et al., 2000) and mast cells (Zochodne and Cheng, 2000) as well as from blood platelets (Yamamoto and Gurney, 1990). The peripheral and dorsal horn aspects of BDNF’s role in central sensitization were elegantly brought together in a recent report that showed that transection of either the gastrocnemius–soleus nerve which innervates skeletal muscle or tibial nerve, which supplies both muscle and skin, but not of the sural nerve, which only innervates the skin, produced a lasting mechanical allodynia and thermal hyperalgesia in adult rats. These differences were correlated with the ability of selective stimulation of the three different nerve types to generate long-term potentiation in the dorsal horn. Stimulation of the tibial nerve induced long-term potentiation of C-fiber responses evoked by the stimulation of the sural nerve and this was prevented by spinal application of the BDNF scavenger, TrkB-Fc. Furthermore, spinal application of low-dose BDNF (10 pg/ml) enabled sural nerve to generate long-term potentiation. Because injury of the gastrocnemius– soleus nerve but not that of the sural nerve up-regulated BDNF in DRG neurons, and that the up-regulation of BDNF occurred not only in injured neurons but also in many uninjured ones, it was concluded, that the inability of sural nerve injury to produce neuropathic pain may be due to the nerve containing insufficient BDNF under both physiological and pathological conditions (Zhou et al., 2010).

816

BDNF AND ALTERATIONS IN DESCENDING CONTROL MECHANISMS

870

As well as actions in the periphery and spinal cord, there is evidence that BDNF augments nociceptive transmission at the level of descending control

872


817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869

871

873 874

NSC 15446


5 June 2014

11

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915

916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931

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 periaqueductal gray and increases TrkB phosphorylation in rostral mediolateral medulla neurons. Microinjection of BDNF into the rostral mediolateral medulla facilitates nociception by a mechanism that is dependent on NMDA receptors. But most importantly, sequestration of BDNF or knockdown of TrkB by RNA interference in the rostral mediolateral medulla attenuates thermal hyperalgesia associated with inflammatory pain. Additional evidence for actions of BDNF in the midbrain was provided from a recent study of neurons in the nucleus raphe magnus (Zhang et al., 2013). Like the rostral mediolateral medulla, this is a critical relay in the brain’s descending pain-modulating system. Persistent inflammatory pain induced by complete Freund’s adjuvant decreased the protein level of the K+-Cl cotransporter (KCC2) in the nucleus raphe magnus. Persistent pain also shifted the equilibrium potential of evoked GABAergic IPSCs to a more positive level thus attenuating inhibition and increasing the firing of evoked action potentials selectively in mu-opioid receptor (MOR)-expressing raphe neurons, but not in neurons that did not express MOR. Microinjection of BDNF reduced KCC2 protein level, and both BDNF administration and KCC2 inhibition by furosemide mimicked the effects of peripheral inflammation on IPSC amplitude and on the excitability in MOR-expressing neurons. Furthermore, inhibiting BDNF signaling or blocking KCC2 with furosemide prevented changes provoked by peripheral inflammation in MOR-expressing neurons. These findings, together with observations at the spinal level (Coull et al., 2003, 2005) again underline the general significance of the BDNF–KCC2–GABA impairment sequence in the development of chronic pain (Beggs et al., 2012b; Beggs and Salter, 2013; Ferrini and De Koninck, 2013).

CONCLUSIONS

932

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 maladaptive mechanisms including those associated with chronic and neuropathic pain. At the spinal level, primary afferent-derived BDNF is thought to be involved in chronic inflammatory pain whereas microglia-derived BDNF is involved in neuropathic pain (Zhao et al., 2006). Although it may be possible to selectively evoke these two types of pain in animal models, this distinction is unlikely to be obtained in clinical situations where pain can result from complex injury or disease states. Nevertheless, there is compelling evidence that BDNF is a ubiquitous pain mediator at many levels of the nervous system. In very general terms, this may relate to the ability of BDNF to increase neuronal activity in most brain regions and to the tenet of the Hebbian theory where an increase in synaptic efficacy arises from the presynaptic cell’s repeated and persistent stimulation of the postsynaptic cell. In fact, parallels between a role for BDNF in pain centralization and learning phenomena have long been recognized (Malcangio and Lessmann, 2003). Another point which emerges is that BDNF engages multiple molecular and cellular mechanisms that are largely complementary (i.e. increased excitation and reduced inhibition) in spinal, midbrain and peripheral structures associated with nociceptive processing. In view of this, and the special association of BDNF with both chronic inflammatory and neuropathic pain it is difficult to conclude that the generation of BDNF in the injured nervous system is truly compensatory.

933

BDNF AND OTHER PAIN-RELATED PHENOMENA

REFERENCES

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 antinociception nor tolerance was affected. There is however evidence to suggest that BDNF may be involved in the development of opioid tolerance within the ventral tegmental–nucleus accumbens system (Vargas-Perez et al., 2009).

934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969

Acknowledgements—Supported by Canadian Institutes of Health Q8 970 Research (CIHR) MOP 81089. We thank Dr. Nataliya Bukhanova Q13971 972 for the artwork in Fig. 1.

973

Abbadie C, Bhangoo S, De KY, Malcangio M, Melik-Parsadaniantz S, Q9 974 975 White FA (2009) Chemokines and pain mechanisms. Brain Res 976 Rev 60:125–134. 977 Abdulla FA, Smith PA (2001a) Axotomy and autotomy-induced 978 changes in the excitability of rat dorsal root ganglion neurons. J 979 Neurophysiol 85:630–643. 980 Abdulla FA, Smith PA (2001b) Axotomy- and autotomy-induced 981 changes in Ca2+and K+ channel currents of rat dorsal root 982 ganglion neurons. J Neurophysiol 85:644–658. 983 Abdulla FA, Smith PA (2002) Changes in Na+ channel currents of rat 984 dorsal root ganglion neurons following axotomy and axotomy985 induced autotomy. J Neurophysiol 88:2518–2529. 986 Ahn M, Beacham D, Westenbroek RE, Scheuer T, Catterall WA 987 (2007) Regulation of NaV1.2 channels by brain-derived 988 neurotrophic factor, TrkB, and associated Fyn kinase. J 989 Neurosci 27:11533–11542.


NSC 15446


5 June 2014

12 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008Q10 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059


Alder J, Thakker-Varia S, Crozier RA, Shaheen A, Plummer MR, Black IB (2005) Early presynaptic and late postsynaptic components contribute independently to brain-derived neurotrophic factor-induced synaptic plasticity. J Neurosci 25:3080–3085. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S, Wiffen P (2006) EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 13:1153–1169. Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238–258. Bailey AL, Ribeiro-da-Silva A (2006) Transient loss of terminals from non-peptidergic nociceptive fibers in the substantia gelatinosa of spinal cord following chronic constriction injury of the sciatic nerve. Neuroscience 138:675–690. Baj G, Carlino D, Gardossi L, Tongiorgi E (2013) Towards a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking. Front Neurosci 7. Balasubramanyan S, Stemkowski PL, Stebbing MJ, Smith PA (2006) Sciatic chronic constriction injury produces cell-type specific changes in the electrophysiological properties of rat substantia gelatinosa neurons. J Neurophysiol 96:579–590. Balkowiec A, Katz DM (2000) Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci 20:7417–7423. Banfield MJ, Naylor RL, Robertson AG, Allen SJ, Dawbarn D, Brady RL (2001) Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure 9:1191–1199. Bannister K, Dickenson AH (2010) Opioid hyperalgesia. Curr Opin Support Palliat Care 4:1–5. Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1:549–553. Bardoni R, Ghirri A, Salio C, Prandini M, Merighi A (2007) BDNFmediated modulation of GABA and glycine release in dorsal horn lamina II from postnatal rats. Dev Neurobiol 67:960–975. Bardoni R, Ghirri A, Zonta M, Betelli C, Vitale G, Ruggieri V, Sandrini M, Carmignoto G (2010) Glutamate-mediated astrocyte-to-neuron signalling in the rat dorsal horn. J Physiol (Lond) 588:831–846. Bardoni R, Merighi A (2009) BDNF and TrkB mediated mechanisms in the spinal cord. In: Malcangio M, editor. Synaptic plasticity in pain. Springer Science & Business Media. Barker PA (2009) Whither proBDNF? Nat Neurosci 12:105–106. Batchelor PE, Liberatore GT, Porritt MJ, Donnan GA, Howells DW (2000) Inhibition of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression reduces dopaminergic sprouting in the injured striatum. Eur J Neurosci 12:3462–3468. Beggs S, Currie G, Salter MW, Fitzgerald M, Walker SM (2012a) Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain 135:404–417. Beggs S, Liu XJ, Kwan C, Salter MW (2010) Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood–brain barrier. Mol Pain 6:74. Beggs S, Salter MW (2010) Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0. Curr Opin Neurobiol 20:474–480. Beggs S, Salter MW (2013) The known knowns of microglia-neuronal signalling in neuropathic pain. Neurosci Lett 557PA:37–42. Beggs S, Trang T, Salter MW (2012b) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15:1068–1073. Besson M, Daali Y, Di LA, Dayer P, Zeilhofer HU, Desmeules J (2013) Antihyperalgesic effect of the GABA(A) ligand clobazam in a neuropathic pain model in mice: a pharmacokinetic– pharmacodynamic study. Basic Clin Pharmacol Toxicol 112:192–197. Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K (2011) Neuronal CCL21

up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J 30:1864–1873. Biggs JE, Lu VB, Stebbing MJ, Balasubramanyan S, Smith PA (2010) Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain 6:44. Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22:123–131. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, Brenner GJ, Ji RR, Bean BP, Woolf CJ, Samad TA (2008) Nociceptors are interleukin-1{beta} sensors. J Neurosci 28:14062–14073. Black JA, Frezel N, Dib-Hajj SD, Waxman SG (2012) 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 8:82. Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307. Chen W, Walwyn W, Ennes HS, Kim H, McRoberts JA, Marvizoń JC (2014) BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals. Eur J Neurosci 39:1439–1454. Chen Y, Balasubramanyan S, Lai AY, Todd KG, Smith PA (2009) Effects of sciatic nerve axotomy on excitatory synaptic transmission in rat substantia gelatinosa. J Neurophysiol 102:3203–3215. Cho HJ, Kim JK, Park HC, Kim JK, Kim DS, Ha SO, Hong HS (1998) Changes in brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia, spinal cord, and gracile nuclei following cut or crush injuries. Exp Neurol 154:224–230. Cho HJ, Kim JK, Zhou XF, Rush RA (1997) Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res 764:269–272. Clark AK, D’Aquisto F, Gentry C, Marchand F, McMahon SB, Malcangio M (2006) Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J Neurochem 99:868–880. Clark AK, Staniland AA, Marchand F, Kaan TKY, McMahon SB, Malcangio M (2010) P2X7-dependent release of interleukin1{beta} and nociception in the spinal cord following lipopolysaccharide. J Neurosci 30:573–582. Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, Barrett L, Brenner GJ, Vardeh D, Woolf CJ, Fitzgerald M (2009a) T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 29:14415–14422. Costigan M, Scholz J, Woolf CJ (2009b) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1–32. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, de Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, de Koninck Y (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942. Craig AD, Dostrovsky J (1999) Medulla to thalamus. In: Wall PD, Melzack R, editors. Textbook of pain. Toronto: Churchill Livingstone. p. 183–214. Crozier RA, Bi C, Han YR, Plummer MR (2008) BDNF modulation of NMDA receptors is activity dependent. J Neurophysiol 100:3264–3274. Dalal A, Tata M, Alle`gre G, Gekiere F, Bons N, Albe-Fessard D (1999) Spontaneous activity of rat dorsal horn cells in spinal segments of sciatic projection following transection of sciatic nerve or of corresponding dorsal roots. Neuroscience 94:217–228.


1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199

Dalal R, Djakiew D (1997) Molecular characterization of neurotrophin expression and the corresponding tropomyosin receptor kinases (trks) in epithelial and stromal cells of the human prostate. Mol Cell Endocrinol 134:15–22. de Jong EK, de Haas AH, Brouwer N, van Weering HR, Hensens M, Bechmann I, Pratley P, Wesseling E, Boddeke HW, Biber K (2008a) Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. J Neurochem 105:1726–1736. de Jong EK, Dijkstra IM, Hensens M, Brouwer N, van AM, Liem RS, Boddeke HW, Biber K (2005) Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. J Neurosci 25:7548–7557. de Jong EK, Vinet J, Stanulovic VS, Meijer M, Wesseling E, Sjollema K, Boddeke HW, Biber K (2008b) Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles. FASEB J 22:4136–4145. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG (2010) Sodium channels in normal and pathological pain. Annu Rev Neurosci 33:325–347. Dougherty KD, Dreyfus CF, Black IB (2000) Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis 7:574–585. Duan B, Liu DS, Huang Y, Zeng WZ, Wang X, Yu H, Zhu MX, Chen ZY, Xu TL (2012) PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity. J Neurosci 32:6351–6363. Eaton MJ, Blits B, Ruitenberg MJ, Verhaagen J, Oudega M (2002) Amelioration of chronic neuropathic pain after partial nerve injury by adeno-associated viral (AAV) vector-mediated overexpression of BDNF in the rat spinal cord. Gene Ther 9:1387–1395. Elmariah SB, Crumling MA, Parsons TD, Balice-Gordon RJ (2004) Postsynaptic TrkB-mediated signaling modulates excitatory and inhibitory neurotransmitter receptor clustering at hippocampal synapses. J Neurosci 24:2380–2393. Everill B, Cummins TR, Waxman SG, Kocsis JD (2001) Sodium currents of large (Abeta-type) adult cutaneous afferent dorsal root ganglion neurons display rapid recovery from inactivation before and after axotomy. Neuroscience 106:161–169. Fabbro A, Pastore B, Nistri A, Ballerini L (2007) Activity-independent intracellular Ca2+ oscillations are spontaneously generated by ventral spinal neurons during development in vitro. Cell Calcium 41:317–329. Ferrini F, De Koninck Y (2013) Microglia control neuronal network excitability via BDNF signalling. Neural Plast 2013:429815. Ferrini F, Trang T, Mattioli TA, Laffray S, Del’Guidice T, Lorenzo LE, Castonguay A, Doyon N, Zhang W, Godin AG, Mohr D, Beggs S, Vandal K, Beaulieu JM, Cahill CM, Salter MW, De KY (2013) Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat Neurosci 16:183–192. Fortin DA, Srivastava T, Dwarakanath D, Pierre P, Nygaard S, Derkach VA, Soderling TR (2012) Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors. J Neurosci 32:8127–8137. Fouad K, Bennett DJ, Vavrek R, Blesch A (2013) Long-term viral brain-derived neurotrophic factor delivery promotes spasticity in rats with a cervical spinal cord hemisection. Front Neurol 4:187. Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K (2001) Brainderived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci 21:4891–4900. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29:4096–4108.

13

1200 Garraway SM, Petruska JC, Mendell LM (2003) BDNF sensitizes the 1201 response of lamina II neurons to high threshold primary afferent 1202 inputs. Eur J Neurosci 18:2467–2476. 1203 Gill R, Chang PK, Prenosil GA, Deane EC, McKinney RA (2013) 1204 Blocking brain-derived neurotrophic factor inhibits injury-induced 1205 hyperexcitability of hippocampal CA3 neurons. Eur J Neurosci 1206 38:3554–3566. 1207 Gilron I, Watson CP, Cahill CM, Moulin DE (2006) Neuropathic pain: 1208 a practical guide for the clinician. CMAJ 175:265–275. 1209 Gold MS, Gebhart GF (2010) Nociceptor sensitization in pain 1210 pathogenesis. Nat Med 16:1248–1257. 1211 Gordon T, Sulaiman O, Boyd JG (2003) Experimental strategies to 1212 promote functional recovery after peripheral nerve injuries. J 1213 Peripher Nerv Syst 8:236–250. 1214 Govrin-Lippmann R, Devor M (1978) Ongoing activity in severed 1215 nerves: source and variation with time. Brain Res 159:406–410. 1216 Groth R, Aanonsen L (2002) Spinal brain-derived neurotrophic factor 1217 (BDNF) produces hyperalgesia in normal mice while antisense 1218 directed against either BDNF or trkB, prevent inflammation1219 induced hyperalgesia. Pain 100:171–181. 1220 Gruber-Schoffnegger D, Drdla-Schutting R, Honigsperger C, 1221 Wunderbaldinger G, Gassner M, Sandkuhler J (2013) Induction 1222 of thermal hyperalgesia and synaptic long-term potentiation in the 1223 spinal cord lamina I by TNF-alpha and IL-1beta is mediated by 1224 glial cells. J Neurosci 33:6540–6551. 1225 Guo W, Robbins MT, Wei F, Zou S, Dubner R, Ren K (2006) 1226 Supraspinal brain-derived neurotrophic factor signaling: a novel 1227 mechanism for descending pain facilitation. J Neurosci 1228 26:126–137. 1229 Gustafson-Vickers SL, Lu VB, Lai AY, Todd KG, Ballanyi K, Smith PA 1230 (2008) Long-term actions of interleukin-1beta on delay and tonic 1231 firing neurons in rat superficial dorsal horn and their relevance to 1232 central sensitization. Mol Pain 4:63. 1233 Ha SO, Kim JK, Hong HS, Kim DS, Cho HJ (2001) Expression of 1234 brain-derived neurotrophic factor in rat dorsal root ganglia, spinal 1235 cord and gracile nuclei in experimental models of neuropathic 1236 pain. Neuroscience 107:301–309. 1237 Hains BC, Waxman SG (2006) Activated microglia contribute to the 1238 maintenance of chronic pain after spinal cord injury. J Neurosci 1239 26:4308–4317. 1240 Heinke B, Ruscheweyh R, Forsthuber L, Wunderbaldinger G, 1241 Sandkuhler J (2004) Physiological, neurochemical and 1242 morphological properties of a subgroup of GABAergic spinal 1243 lamina II neurones identified by expression of green fluorescent 1244 protein in mice. J Physiol 560:249–266. 1245 Herradon G, Ezquerra L, Nguyen T, Wang C, Siso A, Franklin B, 1246 Dilorenzo L, Rossenfeld J, Alguacil LF, Silos-Santiago I (2007) 1247 Changes in BDNF gene expression correlate with rat strain 1248 differences in neuropathic pain. Neurosci Lett 420:273–276. 1249 Herzog KH, Bailey K, Barde YA (1994) Expression of the BDNF gene 1250 in the developing visual system of the chick. Development 1251 120:1643–1649. 1252 Heyden A, Ionescu MC, Romorini S, Kracht B, Ghiglieri V, Calabresi 1253 P, Seidenbecher C, Angenstein F, Gundelfinger ED (2011) 1254 Hippocampal enlargement in Bassoon-mutant mice is 1255 associated with enhanced neurogenesis, reduced apoptosis, 1256 and abnormal BDNF levels. Cell Tissue Res 346:11–26. 1257 Huang J, Zhang Y, Lu L, Hu X, Luo Z (2013) Electrical stimulation 1258 accelerates nerve regeneration and functional recovery in Q111259 delayed peripheral nerve injury in rats. Eur J Neurosci. 1260 Huber LJ, Hempstead B, Donovan MJ (1996) Neurotrophin and 1261 neurotrophin receptors in human fetal kidney. Dev Biol 1262 179:369–381. 1263 Hughes DI, Boyle KA, Kinnon CM, Bilsland C, Quayle JA, Callister 1264 RJ, Graham BA (2013) HCN4 subunit expression in fast-spiking 1265 interneurons of the rat spinal cord and hippocampus. 1266 Neuroscience 237:7–18. 1267 Hughes PE, Alexi T, Walton M, Williams CE, Dragunow M, Clark RG, 1268 Gluckman PD (1999) Activity and injury-dependent expression of 1269 inducible transcription factors, growth factors and apoptosis-


NSC 15446


5 June 2014

14 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339


related genes within the central nervous system. Prog Neurobiol 57:421–450. Inoue K (2006) The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 109:210–226. Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L, Duan S, Lu B (2010) Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 13:302–309. Jiang X, Tian F, Du Y, Copeland NG, Jenkins NA, Tessarollo L, Wu X, Pan H, Hu XZ, Xu K, Kenney H, Egan SE, Turley H, Harris AL, Marini AM, Lipsky RH (2008) BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability. J Neurosci 28:1118–1130. Kang H, Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267:1658–1662. Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28:5189–5194. Keller AF, Beggs S, Salter MW, de Koninck Y (2007) Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol Pain 3:27. Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB, Thompson SW (1999) Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci 19:5138–5148. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells, and monocytes produce brainderived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870. Kim DS, Choi JO, Rim HD, Cho HJ (2002) Downregulation of voltagegated potassium channel alpha gene expression in dorsal root ganglia following chronic constriction injury of the rat sciatic nerve. Brain Res Mol Brain Res 105:146–152. Kim HJ (2011) Effects of long-term inhibition of EAAT2 on the excitability of spinal dorsal horn neurons. Thesis, University of Alberta. Kim KJ, Yoon YW, Chung JM (1997) Comparison of three rodent models of neuropathic pain. Exp Brain Res 113:200–206. Klein R, Nanduri V, Jing SA, Lamballe F, Tapley P, Bryant S, CordonCardo C, Jones KR, Reichardt LF, Barbacid M (1991) The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66:395–403. Knabl J, Witschi R, Hosl K, Reinold H, Zeilhofer UB, Ahmadi S, Brockhaus J, Sergejeva M, Hess A, Brune K, Fritschy JM, Rudolph U, Mohler H, Zeilhofer HU (2008) Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451:330–334. Laffray S, Bouali-Benazzouz R, Papon MA, Favereaux A, Jiang Y, Holm T, Spriet C, Desbarats P, Fossat P, Le FY, Decossas M, Heliot L, Langel U, Nagy F, Landry M (2012) Impairment of GABAB receptor dimer by endogenous 14-3-3zeta in chronic pain conditions. EMBO J 31:3239–3251. Laird JMA, Bennett GJ (1992) Dorsal root potentials and afferent input to the spinal cord in rats with an experimental peripheral neuropathy. Brain Res 584:181–190. Lamy JC, Boakye M (2013) BDNF Val66Met polymorphism alters spinal DC stimulation-induced plasticity in humans. J Neurophysiol 110:109–116. Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926. Lavertu G, Cote SL, De KY (2014) Enhancing K-Cl co-transport restores normal spinothalamic sensory coding in a neuropathic pain model. Brain 137:724–738.

Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341:149–152. Leitner J, Westerholz S, Heinke B, Forsthuber L, Wunderbaldinger G, Jager T, Gruber-Schoffnegger D, Braun K, Sandkuhler J (2013) Impaired excitatory drive to spinal GABAergic neurons of neuropathic mice. PLoS One 8:e73370. Lessmann V (1998) Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol 31:667–674. Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69:341–374. Lever I, Cunningham J, Grist J, Yip PK, Malcangio M (2003) Release of BDNF and GABA in the dorsal horn of neuropathic rats. Eur J Neurosci 18:1169–1174. Lever IJ, Bradbury EJ, Cunningham JR, Adelson DW, Jones MG, McMahon SB, Marvizon JC, Malcangio M (2001) Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. J Neurosci 21:4469–4477. Levine ES, Dreyfus CF, Black IB, Plummer MR (1995a) Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A 92:8074–8077. Levine ES, Dreyfus CF, Black IB, Plummer MR (1995b) Differential effects of NGF and BDNF on voltage-gated calcium currents in embryonic basal forebrain neurons. J Neurosci 15:3084–3091. Lewin GR (1996) Neurotrophins and the specification of neuronal phenotype. Phil Trans R Soc Lond B:405–411. Li WP, Xian C, Rush RA, Zhou XF (1999) Upregulation of brainderived neurotrophic factor and neuropeptide Y in the dorsal ascending sensory pathway following sciatic nerve injury in rat. Neurosci Lett 260:49–52. Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M (2010) Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 330:1400–1404. Lindholm D, Castren E, Hengerer B, Zafra F, Berninger B, Thoenen H (1992) Differential regulation of nerve growth factor (NGF) synthesis in neurons and astrocytes by glucocorticoid hormones. Eur J Neurosci 4:404–410. Liu CN, Michaelis M, Amir R, Devor M (2000) Spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons: relation to neuropathic pain. J Neurophysiol 84:205–215. Liu CN, Raber P, Ziv-Sefer S, Devor M (2001) Hyperexcitability in sensory neurons of rats selected for high versus low neuropathic pain phenotype. Neuroscience 105:265–275. Longo FM, Massa SM (2013) Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov 12:507–525. Loomis CW, Khandwala H, Osmond G, Heffean MP (2001) Coadministration of intrathecal strychnine and bicuculline effects synergistic allodynia in the rat: an isobolographic analysis. J Pharmacol Exp Ther 296:756–761. Lu VB (2007) Role of brain derived neurotrophic factor (BDNF) in the generation of central sensitization and neuropathic pain. Thesis, University of Alberta. Lu VB, Ballanyi K, Colmers WF, Smith PA (2007) Neuron typespecific effects of brain-derived neurotrophic factor in rat superficial dorsal horn and their relevance to ‘central sensitization’. J Physiol 584:543–563. Lu VB, Biggs JE, Stebbing MJ, Balasubramanyan S, Todd KG, Lai AY, Colmers WF, Dawbarn D, Ballanyi K, Smith PA (2009a) BDNF drives the changes in excitatory synaptic transmission in the rat superficial dorsal horn that follow sciatic nerve injury. J Physiol (Lond) 587:1013–1032. Lu VB, Colmers WF, Smith PA (2009b) Long-term effects of brainderived neurotrophic factor on the frequency of inhibitory synaptic


1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479

events in the rat superficial dorsal horn. Neuroscience 161:1135–1143. Lu VB, Colmers WF, Smith PA (2012) Long-term actions of BDNF on inhibitory synaptic transmission in identified neurons of the rat substantia gelatinosa. J Neurophysiol 108:441–452. Lynch G, Kramar EA, Rex CS, Jia Y, Chappas D, Gall CM, Simmons DA (2007) Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J Neurosci 27:4424–4434. Ma C, Shu Y, Zheng Z, Chen Y, Yao H, Greenquist KW, White FA, LaMotte RH (2003) Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol 89:1588–1602. Malcangio M, Lessmann V (2003) A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. Trends Pharmacol Sci 24:116–121. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, Nehama D, Rajadas J, Longo FM (2010) Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest 120:1774–1785. Matayoshi S, Jiang N, Katafuchi T, Koga K, Furue H, Yasaka T, Nakatsuka T, Zhou XF, Kawasaki Y, Tanaka N, Yoshimura M (2005) Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat. J Physiol (Lond) 569:685–695. Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde YA (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11:131–133. Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB (1998) Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur J Neurosci 10:607–621. Merighi A, Bardoni R, Salio C, Lossi L, Ferrini F, Prandini M, Zonta M, Gustincich S, Carmignoto G (2008a) Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of postnatal rat spinal cord. Dev Neurobiol 68:457–475. Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R (2008b) BDNF as a pain modulator. Prog Neurobiol 85: 297–317. Meyer M, Matsuoka I, Wetmore C, Olson L, Thoenen H (1992) Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol 119:45–54. Michael GJ, Averill S, Shortland PJ, Yan Q, Priestley JV (1999) Axotomy results in major changes in BDNF expression by dorsal root ganglion cells: BDNF expression in large trkB and trkC cells, in pericellular baskets, and in projections to deep dorsal horn and dorsal column nuclei. Eur J Neurosci 11:3539–3551. Miletic G, Miletic V (2002) Increases in the concentration of brain derived neurotrophic factor in the lumbar spinal dorsal horn are associated with pain behavior following chronic constriction injury in rats. Neurosci Lett 319:137–140. Miletic G, Miletic V (2008) Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn. Pain 137:532–539. Milligan E, Zapata V, Schoeniger D, Chacur M, Green P, Poole S, Martin D, Maier SF, Watkins LR (2005) An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci 22:2775–2782. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36. Milligan ED, Twining C, Chacur M, Biedenkapp J, O’Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR (2003) Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23:1026–1040.

15

Montalbano A, Baj G, Papadia D, Tongiorgi E, Sciancalepore M (2013) Blockade of BDNF signaling turns chemically-induced long-term potentiation into long-term depression. Hippocampus. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ (2002) Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J Neurosci 22:6724–6731. Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A (2007) Pharmacological management of chronic neuropathic pain – consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 12:13–21. Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10:209–219. O’Leary PD, Hughes RA (2003) Design of potent peptide mimetics of brain-derived neurotrophic factor. J Biol Chem 278:25738–25744. Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14:7–23. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates III JR, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609. Paul J, Yevenes GE, Benke D, Lio AD, Ralvenius WT, Witschi R, Scheurer L, Cook JM, Rudolph U, Fritschy JM, Zeilhofer HU (2014) Antihyperalgesia by alpha2-GABAA receptors occurs via a genuine spinal action and does not involve supraspinal sites. Neuropsychopharmacology 39:477–487. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21:6706–6717. Pezet S, Cunningham J, Patel J, Grist J, Gavazzi I, Lever IJ, Malcangio M (2002a) BDNF modulates sensory neuron synaptic activity by a facilitation of GABA transmission in the dorsal horn. Mol Cell Neurosci 21:51–62. Pezet S, Malcangio M, McMahon SB (2002b) BDNF: a neuromodulator in nociceptive pathways? Brain Res Brain Res Rev 40:240–249. Pezet S, McMahon SB (2006) Neurotrophins: mediators and modulators of pain. Ann Rev Neurosci 29:507–538. Pitcher GM, Henry JL (2008) Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy. Exp Neurol 214:219–228. Prescott SA, Sejnowski TJ, de Koninck Y (2006) Reduction of anion reversal potential subverts the inhibitory control of firing rate in spinal lamina I neurons: towards a biophysical basis for neuropathic pain. Mol Pain 2:32. Prescott SA, De Koninck Y (2005) Integration time in a subset of spinal lamina i neurons is lengthened by sodium and calcium currents acting synergistically to prolong subthreshold depolarization. J Neurosci 25:4743–4754. Punnakkal P, Von SC, Haenraets K, Wildner H, Zeilhofer HU (2014) Morphological, biophysical and synaptic properties of glutamatergic neurons of the mouse spinal dorsal horn. J Physiol. Pusch M, Neher E (1988) Rates of diffusional exchange between small cells and a measuring patch pipette. Pflugers Arch 411:204–211. Ramer MS (2012) Endogenous neurotrophins and plasticity following spinal deafferentation. Exp Neurol 235:70–77. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564. Reimers JM, Loweth JA, Wolf ME (2014) BDNF contributes to both rapid and homeostatic alterations in AMPA receptor surface expression in nucleus accumbens medium spiny neurons. Eur J Neurosci 39:1159–1169. Rodriguez-Tebar A, Dechant G, Barde YA (1990) Binding of brainderived neurotrophic factor to the nerve growth factor receptor. Neuron 4:487–492.


1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549

NSC 15446


5 June 2014

16 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620


Rose K, Ooi L, Dalle C, Robertson B, Wood IC, Gamper N (2011) Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. Pain 152:742–754. Rudge JS, Alderson RF, Pasnikowski E, McClain J, Ip NY, Lindsay RM (1992) Expression of ciliary neurotrophic factor and the neurotrophins-nerve growth factor, brain-derived neurotrophic factor and neurotrophin 3-in cultured rat hippocampal astrocytes. Eur J Neurosci 4:459–471. Ruscheweyh R, Sandkuhler J (2005) Long-range oscillatory Ca2+ waves in rat spinal dorsal horn. Eur J Neurosci 22:1967–1976. Sakai N, Yamada M, Numakawa T, Ogura A, Hatanaka H (1997) BDNF potentiates spontaneous Ca2+ oscillations in cultured hippocampal neurons. Brain Res 778:318–328. Sandkuhler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758. Santos SF, Rebelo S, Derkach VA, Safronov BV (2007) Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat. J Physiol 581:241–254. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192:348–356. Scholz J, Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 10:1361–1368. Sherman SE, Loomis CW (1994) Morphine insensitive allodynia is produced by intrathecal strychnine in the lightly anesthetized rat. Pain 56:17–29. Siuciak JA, Wong V, Pearsall D, Wiegand SJ, Lindsay RM (1995) BDNF produces analgesia in the formalin test and modifies neuropeptide levels in rat brain and spinal cord areas associated with nociception. Eur J Neurosci 7:663–670. Stemkowski PL, Smith PA (2013) An overview of animal models of neuropathic pain. In: Toth C, Moulin DE, editors. Neuropathic pain, causes, management and understanding. Cambridge University Press. p. 33–50. Stemkowski PL, Smith PA (2012a) Long-term IL-1beta exposure causes subpopulation-dependent alterations in rat dorsal root ganglion neuron excitability. J Neurophysiol 107:1586–1597. Stemkowski PL, Smith PA (2012b) Sensory neurons, ion channels, inflammation and the onset of neuropathic pain. Can J Neurol Sci 39:416–435. Stoop R, Poo MM (1996a) Synaptic modulation by neurotrophic factors. Prog Brain Res 109:359–364. Stoop R, Poo MM (1996b) Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor. J Neurosci 16:3256–3264. Tan ZY, Donnelly DF, LaMotte RH (2006) Effects of a chronic compression of the dorsal root ganglion on voltage-gated Na+ and K+ currents in cutaneous afferent neurons. J Neurophysiol 95:1115–1123. Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593–598. Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB (1999) Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci U S A 96:7714–7718. Toyomitsu E, Tsuda M, Yamashita T, Tozaki-Saitoh H, Tanaka Y, Inoue K (2012) CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic Signal 8:301–310. Trang T, Beggs S, Salter MW (2011) Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain. Neuron Glia Biol 7:99–108. Trang T, Beggs S, Salter MW (2012) ATP receptors gate microglia signaling in neuropathic pain. Exp Neurol 234:354–361. Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptormediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogenactivated protein kinase activation. J Neurosci 29:3518–3528. Treede R-D, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J (2008)

Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635. Tsuda M, Beggs S, Salter MW, Inoue K (2013a) Microglia and intractable chronic pain. Glia 61:55–61. Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K (2009a) IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A 106:8032–8037. Tsuda M, Masuda T, Tozaki-Saitoh H, Inoue K (2013b) P2X4 receptors and neuropathic pain. Front Cell Neurosci 7:191. Tsuda M, Toyomitsu E, Kometani M, Tozaki-Saitoh H, Inoue K (2009b) Mechanisms underlying fibronectin-induced up-regulation of P2X4R expression in microglia: distinct roles of PI3K-Akt and MEK-ERK signalling pathways. J Cell Mol Med 13:3251–3259. Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in ‘small’ glia. Trends Neurosci 28:101–107. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783. Tyler WJ, Xl Zhang, Hartman K, Winterer J, Muller W, Stanton PK, Pozzo-Miller L (2006) BDNF increases release probability and the size of a rapidly recycling vesicle pool within rat hippocampal excitatory synapses. J Physiol (Lond) 574:787–803. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F (2008) Upregulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268. Vacca V, Marinelli S, Pieroni L, Urbani A, Luvisetto S, Pavone F (2014) Higher pain perception and lack of recovery from neuropathic pain in females: a behavioural, immunohistochemical, and proteomic investigation on sexrelated differences in mice. Pain 155(2):388–402 (abstract). Vargas-Perez H, Ting A, Walton CH, Hansen DM, Razavi R, Clarke L, Bufalino MR, Allison DW, Steffensen SC, van der Kooy D (2009) Ventral tegmental area BDNF induces an opiatedependent-like reward state in naive rats. Science 324:1732–1734. Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (2004) Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20:1150–1160. Wall PD, Devor M (1983) Sensory afferent impulses result from dorsal root ganglia as well as from the periphery in normal and nerve-injured rats. Pain 17:321–339. Wang X, Ratnam J, Zou B, England PM, Basbaum AI (2009) TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain. J Neurosci 29:5508–5515. Waterhouse EG, Xu B (2009) New insights into the role of brainderived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci 42:81–89. Waxman SG, Dib-Hajj S, Cummins TR, Black JA (1999) Sodium channels and pain. Proc Natl Acad Sci U S A 96:7635–7639. Weishaupt N, Blesch A, Fouad K (2012) BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp Neurol 238:254–264. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8:1069–1077. Woolf CJ (1983) Evidence for a central component of post-injury pain hypersensitivity. Nature 306:686–688. Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964. Wu J, Renn CL, Faden AI, Dorsey SG (2013) TrkB.T1 contributes to neuropathic pain after spinal cord injury through regulation of cell cycle pathways. J Neurosci 33:12447–12463.


1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691

NSC 15446


5 June 2014

P. A. Smith / Neuroscience xxx (2014) xxx–xxx 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1762 1763 1764

Xu H, Wu LJ, Wang H, Zhang X, Vadakkan KI, Kim SS, Steenland HW, Zhuo M (2008) Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci 28:7445–7453. Yajima Y, Narita M, Narita M, Matsumoto N, Suzuki T (2002) Involvement of a spinal brain-derived neurotrophic factor/fulllength TrkB pathway in the development of nerve injury-induced thermal hyperalgesia in mice. Brain Res 958:338–346. Yajima Y, Narita M, Usui A, Kaneko C, Miyatake M, Narita M, Yamaguchi T, Tamaki H, Wachi H, Seyama Y, Suzuki T (2005) Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice. J Neurochem 93:584–594. Yamamoto H, Gurney ME (1990) Human platelets contain brainderived neurotrophic factor. J Neurosci 10:3469–3478. Yang J, Siao CJ, Nagappan G, Marinic T, Jing D, McGrath K, Chen ZY, Mark W, Tessarollo L, Lee FS, Lu B, Hempstead BL (2009) Neuronal release of proBDNF. Nat Neurosci 12:113–115. Yasaka T, Tiong SY, Hughes DI, Riddell JS, Todd AJ (2010) Populations of inhibitory and excitatory interneurons in lamina II of the adult rat spinal dorsal horn revealed by a combined electrophysiological and anatomical approach. Pain 151:475–488. Yoshii A, Constantine-Paton M (2010) Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70:304–322. Yuan H, Zhu X, Zhou S, Chen Q, Zhu X, Ma X, He X, Tian M, Shi X (2010) Role of mast cell activation in inducing microglial cells to release neurotrophin. J Neurosci Res 88:1348–1354. Zeilhofer HU, Benke D, Yevenes GE (2012a) Chronic pain states: pharmacological strategies to restore diminished inhibitory spinal pain control. Annu Rev Pharmacol Toxicol 52:111–133. Zeilhofer HU, Wildner H, Yevenes GE (2012b) Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 92:193–235.

17

Zhang J, de Koninck Y (2006) Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 97:772–783. Zhang J, Shi XQ, Echeverry S, Mogil JS, De KY, Rivest S (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 27:12396–12406. Zhang YH, Chi XX, Nicol GD (2008) Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway. J Physiol (Lond) 586:3113–3127. Zhang Z, Wang X, Wang W, Lu YG, Pan ZZ (2013) Brain-derived neurotrophic factor-mediated downregulation of brainstem K+Cl- cotransporter and cell-type-specific GABA impairment for activation of descending pain facilitation. Mol Pharmacol 84:511–520. Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, Morenilla-Palao C, Stirling C, Fitzgerald M, McMahon SB, Rios M, Wood JN (2006) Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci 31:539–548. Zhou LJ, Ren WJ, Zhong Y, Yang T, Wei XH, Xin WJ, Liu CC, Zhou LH, Li YY, Liu XG (2010) Limited BDNF contributes to the failure of injury to skin afferents to produce a neuropathic pain condition. Pain 148(1):148–157 (abstract). Zhou XF, Chie ET, Deng YS, Zhong JH, Xue Q, Rush RA, Xian CJ (1999) Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat. Neuroscience 92:841–853. Zochodne DW, Cheng C (2000) Neurotrophins and other growth factors in the regenerative milieu of proximal nerve stump tips. J Anat 196:279–283. Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5:311–322.

(Accepted 21 May 2014) (Available online xxxx)


1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761

No pain, more gain.

Honesty & hope (a.k.a. no pain, no gain).

No pain, no gain: lack of exercise obstructs neurogenesis.

The role of pain modulators in esophageal disorders - no pain no gain.

Transradial approach: Do we have gain without excessive pain?

Aerobic exercise in muscular dystrophy: gain without pain.

No pain, no gain: the affective valence of congruency conditions changes following a successful response.

No pain no gain: The positive impact of punishment on the strategic regulation of accuracy.

No pain, functional gain: the importance of pain management in older adults with cognitive impairment.

Colon cancer surveillance in inflammatory bowel disease: unclear gain but no psychological pain?

Pneumothorax after endobronchial valve treatment: no drain, no gain?

Nopaine no gain: recreational ethylphenidate toxicity.

No transformation without reconciliation.

No smoke without fire.

Wounds give no pain.

'Without contraries is no progression'.

No impact without data access.

No effects without side effects!

No Health Without Mental Health.

Endurance exercise: more pain, more metabolic gain.

Gain for space station; pain for NSF.

Translumbar aortography without pain.

Stress and Protists: No life without stress.

No indication for DSA without prior ultrasound.