BDNF in sensory neurons and chronic pain

Neuroscience Research 55 (2006) 1–10 www.elsevier.com/locate/neures

Update article

BDNF in sensory neurons and chronic pain Koichi Obata, Koichi Noguchi * Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan Received 11 November 2005; accepted 31 January 2006 Available online 3 March 2006

Abstract Neurotrophic factors, which support neuronal survival and growth during development of the nervous system, have been shown to play significant roles in the transmission of physiologic and pathologic pain. Brain-derived neurotrophic factor (BDNF), synthesized in the primary sensory neurons, is anterogradely transported to the central terminals of the primary afferents in the spinal dorsal horn, where it is involved in the modulation of painful stimuli. In models of inflammatory and neuropathic pain, BDNF synthesis is greatly increased in different populations of dorsal root ganglion (DRG) neurons. Furthermore, it is now known that the activation of mitogen-activated protein kinases occurs in these sensory neurons and contributes to persistent inflammatory and neuropathic pain by regulating BDNF expression. The recent discovery that BDNF upregulation in the DRG and spinal cord contributes to chronic pain hypersensitivity indicates that blocking BDNF in sensory neurons could provide a fruitful strategy for the development of novel analgesics. # 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords: Dorsal rhizotomy; Dorsal root ganglion; Extracellular signal-regulated protein kinase; Inflammatory pain; Neuropathic pain; P38 mitogen-activated protein kinase; Spinal cord; Ventral rhizotomy

1. Introduction Using several animal models of chronic pain, the pathophysiologic mechanisms underlying the increased neuronal excitability and the resultant behavioral abnormality have been extensively examined. Neurotrophic factors, which were originally known to have developmental and regenerative roles in the nervous system, have attracted attention because of their important roles in pathological situations, including many chronic pain conditions (Shu and Mendell, 1999; Apfel, 2000; Bennett, 2001; Sah et al., 2003; McMahon and Cafferty, 2004). They include nerve growth factor (NGF) and brain-derived

Abbreviations: BDNF, brain-derived neurotrophic factor; CCI, chronic constriction injury; CFA, complete Freund’s adjuvant; CGRP, calcitonin gene-related peptide; DR, dorsal rhizotomy; DRG, dorsal root ganglion; ERK, extracellular signal-regulated protein kinase; IR, immunoreactive; ISHH, in situ hybridization histochemistry; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NT-3, neurotrophin 3; NT-4/5, neurotrophin 4/5; p75NTR, p75 neurotrophin receptor; p-ERK, phosphorylatedERK; PPT, preprotachykinin; Raf, MAPK kinase kinase; SNT, spinal nerve transection; TRP, transient receptor potential; VR, ventral rhizotomy * Corresponding author. Tel.: +81 798 45 6415; fax: +81 798 45 6417. E-mail address: [email protected] (K. Noguchi).

neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). The neurotrophins interact with two categories of cell surface receptors, the trk family of highaffinity tyrosine kinase receptors and the low-affinity p75 neurotrophin receptor (p75NTR). Whereas, all neurotrophins bind the p75NTR receptor, NGF binds trkA receptors, BDNF and NT-4/5 bind trkB receptors, and NT-3 binds trkC receptors (Patapoutian and Reichardt, 2001; Chao, 2003; Huang and Reichardt, 2003). BDNF is expressed in small- and medium-sized sensory neurons that also express trkA and calcitonin gene-related peptide (CGRP). BDNF, synthesized in the dorsal root ganglion (DRG), is transported to the central terminals of the primary afferents (Zhou and Rush, 1996; Michael et al., 1997; Li et al., 1999), is released into the spinal dorsal horn, and binds to trkB receptors on second-order sensory neurons. It has been suggested to function as a neuromodulator of synaptic transmission and spinal nociception (Kerr et al., 1999; Mannion et al., 1999; Thompson et al., 1999; Lever et al., 2001; Pezet et al., 2002c; Garraway et al., 2003). For example, exogenous BDNF enhances N-methyl-D-aspartate (NMDA) receptorinduced depolarizations in the spinal cord in vitro, a mechanism of central sensitization of spinal neurons (Kerr et al., 1999). Expressions of BDNF mRNA and protein are dramatically

0168-0102/$ – see front matter # 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2006.01.005

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changed in the DRG after peripheral inflammation and nerve injury. This review will mainly focus on the DRG neurons and will review the roles of BDNF in nociceptive pathways for chronic pain. 2. BDNF upregulation in DRG neurons after inflammation and nerve injury Peripheral inflammation and nerve injury lead to altered gene transcription and protein synthesis in DRG neurons (Hokfelt et al., 1994; Noguchi et al., 1995; Alvares and Fitzgerald, 1999; Woolf and Salter, 2000). BDNF synthesis is known to increase in small- and medium-sized DRG neurons following inflammation (Cho et al., 1997a,b; Lee et al., 1999; Mannion et al., 1999; Ha et al., 2000; Kim et al., 2001; Ohtori et al., 2002; Obata et al., 2002, 2003b, 2004b). On the other hand, NGF is suggested to be a major contributor to the production of inflammatory pain (Lewin and Mendell, 1993; Andreev et al., 1995; Bennett et al., 1998). NGF concentration is increased in inflamed tissue (McMahon et al., 1995; Woolf et al., 1996, 1997) and an enhanced retrograde transport of NGF to the DRG from target tissues increases the production of preprotachykinin (PPT), CGRP and BDNF at the level of gene expression, mainly in trkA-expressing small- and medium-sized neurons (Donnerer et al., 1992; Apfel et al., 1996; Michael et al., 1997; Kerr et al., 1999; Thompson et al., 1999; Lever et al., 2001; Karchewski et al., 2002). Indeed, NGF has been shown to mediate the increased expression of BDNF in the DRG after inflammation induced by complete Freund’s adjuvant (CFA), because intraplantar

injection of anti-NGF antibodies blocked the increase of BDNF mRNA in the DRG (Cho et al., 1997a). In addition to the inflammation-induced increase in DRG neurons, BDNF synthesis is greatly increased following damage to the central or peripheral process of DRG neurons (Cho et al., 1998; Tonra et al., 1998; Kashiba and Senba, 1999; Li et al., 1999; Michael et al., 1999; Shen et al., 1999; Zhou et al., 1999; Ha et al., 2001; Kim et al., 2001; Karchewski et al., 2002; Onda et al., 2003; Obata et al., 2003a,b, 2004a,c,d). To determine the relative importance of injury site (proximal or distal to the DRG) and injury type (motor or sensory), we examined the pain-related behaviors and the changes of BDNF expression in the L5 DRG in the L5 dorsal rhizotomy (DR) and/or ventral rhizotomy (VR), and further, the spinal nerve transection (SNT) models (Obata et al., 2006) (Fig. 1). We found that in the DR and DR + VR groups, the increase in BDNF mRNA/protein expression was observed mainly in medium- and large-size neurons (Fig. 2). Furthermore, L5 SNT upregulated BDNF expression, mainly in medium- and large-size L5 DRG neurons, whereas, in the VR group, the increase in BDNF was detected in small- and medium-size neurons, as reported previously (Ha et al., 2001; Obata et al., 2004a). It has been reported that L5 VR increases the expression of NGF in small sensory neurons in the L5 DRG (Li et al., 2003). Because NGF increases the expression of BDNF, mainly in trkA-containing small neurons, we believe that NGF might contribute to the upregulation of BDNF expression in small DRG neurons in this L5 VR model (Obata et al., 2004a). In contrast, the mechanisms underlying upregulation of BDNF expression in

Fig. 1. Surgical microscopic photographs showing the five experimental groups included in this study. (A) Group 1 (sham) served as the sham group and had an exposure of the L5 nerve root and DRG after L5 hemilaminectomy. (B) Group 2 (DR) had an L5 dorsal rhizotomy (2–3 mm proximal to the DRG). The L5 ventral root can be seen underlying the transected dorsal root segments. (C) Group 3 (VR) had an L5 ventral rhizotomy. The arrow indicates the intact L5 dorsal root. (D) Group 4 (DR + VR) had both an L5 dorsal rhizotomy and an L5 ventral rhizotomy. (E) Group 5 (SNT) had an L5 spinal nerve transection (2–3 mm distal to the DRG) after the L6 transverse process was partially removed. (F) Group 6 (ganglionectomy) had an L5 dorsal root ganglionectomy. In this group, the left L5 dorsal root was lifted and the DRG was dissected out in one piece, as indicated by the arrow. The bottom schematic diagrams indicate the six different nerve lesion paradigms.

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Table 1 Summary of effects of different nerve lesions on degeneration of motor and sensory fibers and the changes in BDNF expression in the L4 DRG Nerve lesions

Wallerian degeneration Motor fibers

Sham L5 DR L5 DR + VR L5 VR L5 SNT L5 Ganglionectomy



+ + +


BDNF expression in the L4 DRG Sensory fibers Distal branch

Proximal branch





+ +


+ +

+

large neurons in the L5 DRG after the L5 DR, DR + VR, and SNT, are not clear at this point. One possible interpretation is that withdrawal of growth factors, such as NGF and NT-3, may increase the expression of BDNF, which could underlie the negative regulation (Ohara et al., 1995; Verge et al., 1995; Shadiack et al., 2001; Karchewski et al., 2002; Kato et al., 2002; Obata et al., 2003b, 2004d). Alternatively, positive factors, such as the cytokine interleukin-6 and tumor necrosis factor-alpha, might regulate BDNF expression (Murphy et al., 2000; Onda et al., 2004). Furthermore, there is a possibility that BDNF itself could act in a paracrine or autocrine manner (Acheson and Lindsay, 1996; Lee et al., 1999; Kim et al., 2001). There is compelling evidence for the changes in the molecular phenotype of intact L4 DRG neurons in the L5 SNT model (Gold, 2000; Ha et al., 2001; Hudson et al., 2001). For example, we have demonstrated the upregulation in mRNAs for PPT, CGRP, transient receptor potential ion channel TRPV1, TRPA1, and BDNF in the ipsilateral L4 DRG neurons in the L5 SNT model (Fukuoka et al., 1998, 2001, 2002; Obata et al., 2004c, 2005). A degenerating fiber initiates a cascade of cellular and molecular events that ultimately leads to an accumulation of chemokines, cytokines and growth factors (Myers et al., 1996; Ramer et al., 1997; Sommer and Schafers, 1998; Cui et al., 2000; Shamash et al., 2002). Therefore, we speculate that the products of Wallerian degeneration of L5 nerve fibers induce phenotypic changes in the L4 DRG (Fukuoka and Noguchi, 2002). We recently demonstrated that L5 SNT, but not DR + VR, increased the expression of BDNF in the L4 DRG (Obata et al., 2006) (Fig. 2). Considering that L5 SNT produces degeneration of L5 motor fibers and sensory fibers distal to the DRG, whereas, L5 DR + VR produces degeneration of L5 motor and sensory fibers proximal to the DRG, these data suggest that Wallerian degeneration of L5 sensory fibers distal, but not proximal, to the L5 DRG may influence the neighboring intact L4 nerve fibers in the sciatic nerve and induce phenotypic changes in the L4 DRG neurons (Table 1). Indeed, we have shown that L5 ganglionectomy, producing a selective lesion of sensory fibers, produced not only heat hypersensitivity but also an increase in BDNF expression in the L4 DRG (Obata et al., 2004a), indicating that BDNF increase in the L4 DRG might be involved in neuropathic pain (Table 2).

NC NC NC NC " "

3. MAPK activation and BDNF expression in DRG neurons Mitogen-activated protein kinases (MAPK) transduce diverse extracellular stimuli to mitogenic and differentiation signals (Lewis et al., 1998; Widmann et al., 1999). The MAPK family includes extracellular signal-regulated protein kinases (ERK), p38 MAPK, c-Jun N-terminal kinase (JNK), and ERK5. ERK is involved in cellular growth and differentiation, whereas, p38 and JNK participate in injury responses and cell death. The ERK pathway involvement in neurotrophin-dependent survival and differentiation of developing peripheral neurons has been characterized in detail (Klesse and Parada, 1999; Miller and Kaplan, 2001; Patapoutian and Reichardt, 2001). For example, the high-affinity receptor for NGF, trkA, can signal through at least six different pathways, a major one of which is a MAPK pathway (i.e., the ERK pathway; Finkbeiner, 2000; Chang and Karin, 2001). In this pathway, activated receptors induce GTP loading and activation of the small G-protein Ras. In turn, RasGTP recruits a three-tiered enzyme cascade in which a MAPK kinase kinase (Raf) phosphorylates MAPK/ERK kinase (MEK), which phosphorylates and activates ERK (English et al., 1999). Recent reports showed that following NGF treatment, the ERK pathway is activated in DRG neurons in vivo (Averill et al., 2001; Delcroix et al., 2003; Zhuang et al., 2004; Dina et al., 2005; Malik-Hall et al., 2005). However, very little is known about the ERK pathway, responsible for the maintenance of the nociceptive phenotype of adult sensory neurons and the changes after peripheral inflammation and nerve injury. Furthermore, it is not clear what role these changes play in generating pain hypersensitivity (Woolf and Table 2 Summary of effects of different nerve lesions on pain-related behaviors and the changes in BDNF expression in the L4/5 DRG and spinal cord at 7 days after the surgery Nerve lesions

Pain-related behavior

Sham L5 DR L5 DR + VR L5 VR L5 SNT




+ +

NC, no change.

BDNF expression L4 DRG

L5 DRG

SC

NC NC NC NC "

NC " " " "

NC # # " "

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Fig. 2. (A, D, G, J, M) Photomicrographs showing the BDNF-IR in the ipsilateral L5 DRG in the sham (A), DR (D), DR + VR (G), VR (J), and SNT (M) groups at 7 days after surgery. Arrowheads indicate large-size sensory neurons labeled for BDNF-IR, whereas, arrows indicate small-to-medium diameter neurons. (B, E, H, K, N) Expression of BDNF mRNA in the ipsilateral L5 DRG by darkfield photomicrographs of ISHH in the sham (B), DR (E), DR + VR (H), VR (K), and SNT (N) groups at 7 days after surgery. Arrowheads indicate large-size sensory neurons positive for BDNF, whereas, arrows indicate small-to-medium diameter neurons. (C, F, I, L, O) Photomicrographs showing the BDNF-IR in the lumber spinal cord on the ipsilateral side in the sham (C), DR (F), DR + VR (I), VR (L), and SNT (O)

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Costigan, 1999; Ji and Woolf, 2001; Ji, 2004a,b; Obata and Noguchi, 2004). Recently, we have shown that the activation of ERK regulates gene expression of BDNF in primary afferent neurons after inflammation and nerve injury (Obata et al., 2003b, 2004b,c,d). For example, peripheral inflammation induced an increase in the phosphorylation of ERK, mainly in trkAcontaining small-to-medium diameter DRG neurons 1 day after the CFA injection. The treatment of the MEK inhibitor U0126 reversed the pain hypersensitivity and the increase in phosphorylated-ERK (p-ERK) and BDNF in DRG neurons induced by CFA. In contrast, peripheral axotomy induced the activation of ERK mainly in trkA-expressing medium- and large-sized DRG neurons and in satellite glial cells at 3, 7, and 14 days after the nerve lesion. U0126 suppressed the axotomyinduced autotomy behavior and reversed the increase in p-ERK and BDNF. To elucidate whether alterations of endogenous NGF can trigger changes in both the phosphorylation of ERK and BDNF expression similar to those seen after peripheral inflammation and axotomy, intrathecal injections of rat recombinant ß-NGF or anti-NGF were performed. In this test, the intrathecal application of NGF induced an increase in the number of p-ERK- and BDNF-labeled cells, mainly small neurons, and the application of anti-NGF induced an increase in p-ERK and BDNF in some trkA-expressing medium-to-large diameter DRG neurons. Taken together, these findings suggest that the activation of ERK in the primary afferents occurs in different populations of DRG neurons after peripheral inflammation and axotomy, respectively, through alterations in the target-derived NGF and contributes to persistent inflammatory and neuropathic pain, via transcriptional regulation of BDNF expression (Fig. 3) (Obata et al., in press). A recent report demonstrated that p38 MAPK activation in the DRG is required for NGF-induced increases in TRPV1 expression and contributes to the maintenance of inflammatory pain hypersensitivity (Ji et al., 2002). p38, a MAPK which operates through a separate intracellular cascade, functions as a mediator of cellular stresses such as inflammation and apoptosis (Widmann et al., 1999; Shi and Gaestel, 2002). Although p38 MAPK exerts its effects that oppose those of ERK in the hippocampus (Bolshakov et al., 2000), the contribution of p38 MAPK to nociception and pain hypersensitivity is still under investigation. Recent reports have demonstrated that not only peripheral inflammation but also axotomy induces p38 activation in small DRG neurons (Ji et al., 2002; Kim et al., 2002; Jin et al., 2003; Schafers et al., 2003; Tamura et al., 2005; Zelenka et al., 2005). A p38 inhibitor SB203580 reduces inflammation-induced thermal hyperalgesia and L5 SNT-induced mechanical allodynia (Ji et al., 2002; Jin et al., 2003; Schafers et al., 2003). On the other hand, using the chronic constriction injury (CCI) and L5 SNT models, we have demonstrated that p38, but not ERK and JNK, was activated in the adjacent intact DRG, mainly trkA-containing small neurons (Fig. 3) (Obata et al., 2004c,d). In addition, both p38 inhibitor

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and anti-NGF application reduced the SNT-induced thermal hyperalgesia and upregulation of BDNF expression in the uninjured DRG, indicating that p38 activation by NGF in intact DRG neurons participates in heat hyperalgesia by regulating BDNF expression after partial nerve injury. Although, we cannot deny the possibility that other cytokines and growth factors also may be involved in selective p38 activation in the intact DRG after partial nerve injury, we believe that BDNF expression could be regulated by the activation of distinct MAPK in pain states evoked by several pathological conditions through alterations in the target-derived NGF (Fig. 3) (Obata and Noguchi, 2004). 4. Role of sensory-derived BDNF in the dorsal horn for pain hypersensitivity The dorsal horn is an important point of integration and processing of nociceptive information. BDNF is released from primary afferent terminals within the spinal cord in an activitydependent manner (Lever et al., 2001). Subsequent binding to trkB receptors on second-order sensory neurons could then activate signaling cascades (Pezet et al., 2002b; Garraway et al., 2003). For example, activation of signal transduction pathways, such as MAPK pathways, induces long-term changes in central excitability (Pezet et al., 2002a,b; Lever et al., 2003b; Kawasaki et al., 2004). Furthermore, BDNF release within the spinal cord results in phosphorylation and potentiation of NMDA receptors on spinal neurons (Kerr et al., 1999; Slack and Thompson, 2002; Slack et al., 2004), and this represents a possible mechanism by which BDNF mediates central sensitization (Woolf and Salter, 2000; Ji et al., 2003; Malcangio and Lessmann, 2003). In fact, a growing number of behavioral experiments provide evidence for a neuromodulatory effect of endogenous BDNF, especially in inflammatory pain states. Sequestration of endogenous BDNF has demonstrated that this factor does not contribute to the processing of nociceptive information under normal circumstances, but contributes to the generation of inflammatory pain (Kerr et al., 1999; Mannion et al., 1999; Thompson et al., 1999; Groth and Aanonsen, 2002; Matayoshi et al., in press). Conversely, exogenous BDNF administration induced thermal hyperalgesia and mechanical allodynia (Shu et al., 1999; Miki et al., 2000; Zhou et al., 2000). After nerve injury, the upregulated BDNF in large-diameter neurons is transported to the central terminals of the primary afferents in the deep dorsal horn, and further, that BDNF may modify the excitability of their target neurons and contribute to neuropathic sensations (Cho et al., 1998; Li et al., 1999; Michael et al., 1999; Zhou et al., 1999; Miletic and Miletic, 2002; Miletic et al., 2004; Yajima et al., 2005). Recently, we have found that rats in the L5 DR and DR + VR groups did not develop either mechanical or heat hypersensitivity, although not only L5 SNT, but also DR and DR + VR, increased BDNF expression in medium- and large-size neurons in L5 DRG, as stated above (Obata et al., 2006). Considering that anterograde

groups at 7 days after surgery. (P) Quantification of the percentage of BDNF-IR neurons in the ipsilateral L4 DRG at 7 days after surgery (mean  S.D.). *p < 0.05 compared with the sham-operated rats. Scale bar: 100 mm. (A)-(O) were reproduced from Obata et al. (2004a) and Obata et al. (2006).

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transport of BDNF was blocked by dorsal rhizotomy (Zhou and Rush, 1996; Li et al., 1999), we believe that after the L5 DR and DR + VR, the increased expression of BDNF protein in mediumto-large neurons was not anterogradely transported into the axon terminals in the spinal dorsal horn, because of dorsal rhizotomy itself, and therefore, rats in the L5 DR and DR + VR groups did not show pain-related behaviors. In fact, several reports demonstrated that BDNF-immunoreactive (IR) terminals in the dorsal horn increased not only in the sciatic nerve injury model, but also in the L5 SNT and VR models (Fig. 2) (Ha et al., 2001; Obata et al., 2004a). On the other hand, not only inflammation but also nerve injury induces an increase in trkB expression in the dorsal horn (Mannion et al., 1999; Narita et al., 2000; Yajima et al., 2002). Therefore, we believe that the BDNF/ trkB receptor-mediated signaling pathway in the dorsal horn via an intact dorsal root is likely to be required for the development of neuropathic pain behaviors (Obata et al., 2006) (Table 2). Although the role of BDNF in the spinal cord in inflammatory pain conditions is well established, the involvement of BDNF in neuropathic pain states is still to be ascertained, as previous reports have described both pronociceptive and antinociceptive effects produced by BDNF. For example, most studies have reported that intrathecal injection of trkB-IgG and anti-BDNF prevents the development of thermal hyperalgesia and mechanical allodynia in the neuropathic pain models (Theodosiou et al., 1999; Deng et al., 2000; Zhou et al., 2000; Fukuoka et al., 2001; Zhao et al., 2003; Yajima et al., 2005). On the other hand, central infusions of BDNF result in analgesia, associated with alternations in neuropeptide expression in the brain and spinal cord (Siuciak et al., 1994, 1995; Cirulli et al., 2000; Guo et al., 2006). Furthermore, there is also evidence suggesting that chronic spinal delivery of BDNF alleviates allodynia and hyperalgesia in neuropathic pain (Cejas et al., 2000; Miki et al., 2000; Eaton et al., 2002). It has been demonstrated that acute application of BDNF to the spinal cord in the microgram dose range, could exert an antinociceptive effect, possibly due to release of GABA from intrinsic interneurons (Pezet et al., 2002a). In fact, in models of neuropathic pain, no release of BDNF could be measured in the dorsal horn after sensory neuron stimulation, and this reduced availability of sensory neuron-derived BDNF might contribute to the reduced GABAergic tone in the dorsal horn of neuropathic rats (Lever et al., 2003a). Therefore, the action of sensory-derived BDNF in the dorsal horn is likely to be complex and dependent on a model used, a mode of

Fig. 3. Schematic representation of the expression of ERK, p38, and JNK after peripheral inflammation and nerve injury. (A) The p-ERK-IR is present in a few neurons and in surrounding satellite glial cells, whereas, the p-p38-IR is located in small-sized neurons, as well as in some surrounding satellite glial cells. (B) After peripheral inflammation, ERK, as well as p38, is activated in small sized neurons, due to the increase of target-derived NGF. (C) After partial nerve

injury, ERK is activated in injured large-sized neurons and regulates BDNF expression, whereas, p38 and JNK are activated in injured small sized neurons, due to the loss of target-derived NGF. Furthermore, the increase in both p-ERKand p-p38-IR is seen in satellite glial cells, surrounding injured large-sized neurons. (C0 ) After partial nerve injury, p38 is activated in intact small sized neurons and regulates BDNF expression due to the increase of target-derived NGF. (D–L) Immunohistochemical colocalization of green reaction product for p-p38 (D, G, J) and red product for NF200 (E) or GFAP (H) or trkA (K) in the ipsilateral L4 DRG at 7 days after L5 SNL surgery. Double labeling study indicates that p38 is predominantly expressed in trkA-containing small sensory neurons, but not satellite glial cells in the uninjured L4 DRG after L5 SNL. Arrows indicate double-labeled neurons for p-p38 and trkA. Scale bar: 50 mm. (D)-(L) were reproduced from Obata et al. (2004c).

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application, a range of doses used, and a specific site within nociceptive pathways (Malcangio and Lessmann, 2003; Pezet and Malcangio, 2004; Guo et al., 2006). 5. Concluding remarks In conclusion, the expression of BDNF is dramatically increased in the DRG neurons, and could be regulated by distinct activation of MAPK in pain states evoked by several different mediators and pathological conditions. It is certain that a number of pathophysiological changes in spinal cord and the higher central nervous system might occur and participate in producing inflammatory and neuropathic pain. These include microglia activation, degeneration of inhibitory interneurons, and altered modulation of sensory transmission by pathways descending from the brain stem. For example, a very recent report showed that ATP-stimulated spinal microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signaling molecule between microglia and neurons (Coull et al., 2005). However, these pathological changes in the central nervous system are secondary to pathophysiological changes in first-order sensory neurons and require altered afferent input for their maintenance. We believe that the changes of BDNF expression in the DRG neurons and spinal cord play important roles in the pathophysiological mechanisms of chronic pain, and therefore, blocking BDNF in sensory neurons could represent a new approach to effectively treat clinical inflammatory and neuropathic pain. Acknowledgments This work was supported in part by grants-in-aid for scientific research and a grant from the Open Research Center, Hyogo College of Medicine, from the Japanese Ministry of Education, Science, and Culture. This work was also supported by grant-in-aid for Researchers, Hyogo College of Medicine. We thank Yuka Obata and Nobumasa Ushio for technical assistance. We thank Dr. D.A. Thomas for correcting the English usage. References Acheson, A., Lindsay, R.M., 1996. Non target-derived roles of the neurotrophins. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 351, 417–422. Alvares, D., Fitzgerald, M., 1999. Building blocks of pain: the regulation of key molecules in spinal sensory neurones during development and following peripheral axotomy. Pain Suppl. 6, S71–S85. Andreev, N.Yu., Dimitrieva, N., Koltzenburg, M., McMahon, S.B., 1995. Peripheral administration of nerve growth factor in the adult rat produces a thermal hyperalgesia that requires the presence of sympathetic postganglionic neurones. Pain 63, 109–115. Apfel, S.C., Wright, D.E., Wiideman, A.M., Dormia, C., Snider, W.D., Kessler, J.A., 1996. Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system. Mol. Cell. Neurosci. 7, 134–142. Apfel, S.C., 2000. Neurotrophic factors and pain. Clin. J. Pain 16, S7–S11. Averill, S., Delcroix, J.D., Michael, G.J., Tomlinson, D.R., Fernyhough, P., Priestley, J.V., 2001. Nerve growth factor modulates the activation status

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