Change in mRNAs for neuropeptides and the GABAA receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model

Fukuoka, Tetsuo; Tokunaga, Atsushi; Kondo, Eiji; Miki, Kenji; Tachibana, Tetsuya; Noguchi, Koichi

doi:10.1016/s0304-3959(98)00111-0

Cited by 159 publications

(99 citation statements)

References 89 publications

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“…1 D), but there were few NPY-IR neurons in the naive and ipsilateral L4 DRG (Fig. 1C), consistent with previous studies (Fukuoka et al, 1998;Ossipov et al, 2002). There was also no evidence of an upregulation of galanin immunoreactivity in the ipsilateral L4 DRG after the L5 SNL (data not shown).…”

Section: Resultssupporting

confidence: 90%

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Obata¹,

Yamanaka²,

Kobayashi³

et al. 2004

J. Neurosci.

290

208

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To investigate whether activation of mitogen-activated protein kinase (MAPK) in damaged and/or undamaged primary afferents participates in neuropathic pain after partial nerve injury, we examined the phosphorylation of extracellular signal-regulated protein kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) in the L4 and L5 dorsal root ganglion (DRG) in the L5 spinal nerve ligation (SNL) model. We first confirmed, using activating transcription factor 3 and neuropeptide Y immunoreactivity, that virtually all L4 DRG neurons are spared from axotomy in this model. In the injured L5 DRG, the L5 SNL induced the activation of ERK, p38, and JNK in different populations of DRG neurons. In contrast, in the uninjured L4 DRG, the L5 SNL induced only p38 activation in tyrosine kinase A-expressing small-to medium-diameter neurons. Intrathecal ERK, p38, and JNK inhibitor infusions reversed SNL-induced mechanical allodynia, whereas only p38 inhibitor application attenuated SNL-induced thermal hyperalgesia. Furthermore, the L5 dorsal rhizotomy did not prevent SNL-induced thermal hyperalgesia. We therefore hypothesized that p38 activation in the uninjured L4 DRG might be involved in the development of heat hypersensitivity in the L5 SNL model. In fact, the treatment of the p38 inhibitor and also anti-nerve growth factor reduced SNL-induced upregulation of brain-derived neurotrophic factor and transient receptor potential vanilloid type 1 expression in the L4 DRG. Together, our results demonstrate that the L5 SNL induces differential activation of MAPK in injured and uninjured DRG neurons and, furthermore, that MAPK activation in the primary afferents may participate in generating pain hypersensitivity after partial nerve injury.

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Section: Resultssupporting

confidence: 90%

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Obata¹,

Yamanaka²,

Kobayashi³

et al. 2004

J. Neurosci.

290

208

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“…In previous studies [25], the expression of calcitonin gene-related peptide (CGRP) mRNA and preprotachykinin (PPT; a gene encoding substance P) mRNA increased in large DRG neurons (which do not transmit pain under physiological conditions) in rat lumbar neuropathic pain models.…”

Section: Discussionmentioning

confidence: 95%

“…ATF3 is a commonly used marker of DRG neuron activation, and it is also known that ATF3 regulates neurite outgrowth [22][23][24][25][26][27]. Lindwall reported that ATF3 is a c-Jun dimerization partner and that JNK-mediated c-Jun activation is associated with axonal outgrowth following axotomy of adult rat sensory neurons [25].…”

Section: Discussionmentioning

confidence: 99%

Expression of activating transcription factor 3 (ATF3) in uninjured dorsal root ganglion neurons in a lower trunk avulsion pain model in rats

et al. 2013

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Purpose Clinically, neuropathic pain is frequent and intense following brachial plexus injury. It is thought that brachial plexus pain is not generated by avulsed roots, but rather by non-avulsed roots, since the avulsed root could not possibly transmit action potentials to central nerves. The aim of this study was to evaluate pain behavior and activation of sensory neurons in a brachial plexus avulsion (BPA) model in rats. Methods Fifteen male Wistar rats were used. In the BPA group, the C8-T1 roots were avulsed from the spinal cord with forceps at the lower trunk level (n = 5). In the naïve group, rats did not receive any procedures (n = 5). In the sham-operated group, the lower trunk was simply exposed (n = 5). Mechanical hyperalgesia of forelimbs corresponding to C6 and C7 dermatomes was measured using von Frey filaments every third day for 3 weeks. Activation of DRG neurons was immunohistochemically examined using anti-ATF3 (a marker for neuron activation) antibodies 21 days after surgery. Von Frey and immunohistochemical data between groups were analyzed using a Kruskal-Wallis test, followed by Mann-Whitney U tests. Bonferroni corrections were performed. Results Animals in the BPA group displayed significant mechanical hyperalgesia at the dermatome innervated by uninjured nerves continuing through day 21 compared with animals in the sham-operated group. ATF3-immunoreactive small and large DRG neurons were significantly activated in the BPA group (10.6 ± 9.5 and 5.2 ± 4.1 %, 39.7 ± 6.7 and 25.2 ± 10.3 %, 78.0 ± 9.1 and 53.7 ± 29.3 %) compared with the sham-operated group (0.7 ± 0.9 and 0 ± 0 %, 2.8 ± 2.0 and 1.0 ± 2.0 %, 3.9 ± 2.7 and 8.6 ± 10.1 %) at every level of C5, 6, and 7. In the naïve group, no DRG neurons were activated. ATF3-immunoreactive small and large DRG neurons were significantly activated at the level of C7 compared with C6 and C5, and significantly activated at the level of C6 compared with C5 in the BPA group. Conclusions Expression of ATF3 in uninjured DRG neurons may contribute to pain following brachial plexus avulsion injury. Consequently, spared spinal sensory nerves may represent therapeutic targets for treatment of this pain.

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“…After SNL, expression of various neuroactive agents, receptors, and channels implicated in nociceptive transmission is increased. These include neuropeptides (Fukuoka et al, 1998), neurotrophins , sodium channels (Porreca et al, 1999), and vanilloid-receptor 1 (Hudson et al, 2001;Fukuoka et al, 2002). Exogenous TNF may stimulate injured DRG by triggering one or more cascades, e.g., stimulating production of neurotrophins (Lindholm et al, 1987;Yoshida and Gage, 1992;Hattori et al, 1996,), which in turn may trigger sensitizing neuropeptides or further enhance DRG neuronal responses to capsaicin (Nicol et al, 1997).…”

Section: Sensitization Of Injured Primary Afferents To Tnfmentioning

confidence: 99%

“…The relative contributions of injured and neighboring uninjured afferent fibers, which share nerve trunks or DRGs, to pain generation is controversial. Nevertheless, several points are relevant: (1) phenotypic changes in expression of neuropeptides and neurotransmitters are reported not only for injured (Noguchi et al, 1995;Tsuzuki et al, 2001), but also for nearby uninjured DRG neurons (Fukuoka et al, 1998(Fukuoka et al, , 2000Ma and Bisby, 1998a,b;Porreca et al, 1999;Xie et al, 2001), (2) development of ectopic activity is described for injured (Woolf, 1992;Devor and Seltzer, 1999) and uninjured (Sato and Perl, 1991;Ali et al, 1999;Wu et al, 2001) DRG neurons, and (3) injured as well as uninjured DRG neurons display TNF upregulation after peripheral nerve injury .…”

Section: Introductionmentioning

confidence: 99%

Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation

Schäfers¹,

et al. 2003

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Tumor necrosis factor-␣ (TNF) is upregulated after nerve injury, causes pain on injection, and its blockade reduces pain behavior resulting from nerve injury; thus it is strongly implicated in neuropathic pain. We investigated responses of intact and nerve-injured dorsal root ganglia (DRG) neurons to locally applied TNF using parallel in vivo and in vitro paradigms. In vivo, TNF (0.1-10 pg/ml) or vehicle was injected into L5 DRG in naive rats and in rats that had received L5 and L6 spinal nerve ligation (SNL) immediately before injection. In naive rats, TNF, but not vehicle, elicited long-lasting allodynia. In SNL rats, subthreshold doses of TNF synergized with nerve injury to elicit faster onset of allodynia and spontaneous pain behavior. Tactile allodynia was present in both injured and adjacent uninjured (L4) dermatomes. Preemptive treatment with the TNF antagonist etanercept reduced SNL-induced allodynia by almost 50%. In vitro, the electrophysiological responses of naive, SNL-injured, or adjacent uninjured DRG to TNF (0.1-1000 pg/ml) were assessed by single-fiber recordings of teased dorsal root microfilaments. In vitro perfusion of TNF (100 -1000 pg/ml) to naive DRG evoked shortlasting neuronal discharges. In injured DRG, TNF, at much lower concentrations, elicited earlier onset, markedly higher, and longerlasting discharges. TNF concentrations that were subthreshold in naive DRG also elicited high-frequency discharges when applied to uninjured, adjacent DRG. We conclude that injured and adjacent uninjured DRG neurons are sensitized to TNF after SNL. Sensitization to endogenous TNF may be essential for the development and maintenance of neuropathic pain.

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Change in mRNAs for neuropeptides and the GABAA receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model

Cited by 159 publications

References 89 publications

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation

Expression of activating transcription factor 3 (ATF3) in uninjured dorsal root ganglion neurons in a lower trunk avulsion pain model in rats

Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation

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