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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of intralesion grafts of serotonergic precursors on locomotor recovery and development of chronic pain were assessed after chronic spinal cord hemisection injury (SCI) in rats. Serotonin- and brain-derived neurotrophic factor-secreting (RN46A-B14) and RN46A-vector-only cells were transplanted into the site of T13 lateral hemisection 10 days following injury in immunosuppressed animals, and locomotor and pain related behaviors were assessed weekly for 28 days. There were significant improvements in the degree of spontaneous locomotor recovery, but no significant difference was found in the magnitude of development of mechanical allodynia or thermal hyperalgesia in any transplant group. From these results, we conclude that intraparenchymal engraftment of RN46A-B14 cells is largely ineffective in influencing somatosensory outcomes after SCI, in contrast with the efficacy of dorsal intrathecal placement.
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PMID:Intralesion transplantation of serotonergic precursors enhances locomotor recovery but has no effect on development of chronic central pain following hemisection injury in rats. 1200 28

A variety of molecules released by inflammatory reactions in the dorsal root and dorsal root ganglion (DRG) may play important roles in the pathology of neuronal abnormalities in lumbar disc herniation. In order to elucidate the pathophysiological mechanisms of painful radiculopathy, secondary to lumbar disc herniation, we evaluated pain-related behavior and the change of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG and dorsal root using a rat model of lumbar disc herniation. In the nucleus pulposus (NP) group, the left L4/5 nerve roots were exposed after hemilaminectomies and autologous intervertebral discs, which were obtained from coccygeal intervertebral discs, were implanted on each of the exposed nerve roots without mechanical compression. Rats in the NP group, but not the sham-operated rats, developed mechanical allodynia on the ipsilateral hind paw for 1 day after surgery and showed a significant increase in the number of NGF-immunoreactive (IR) cells in the nerve root and DRG. NGF-IR cells in the nerve root and DRG included macrophages and Schwann cells, because these cells were labeled for NGF and ED-1 or glial fibrillary acid protein by dual immunostaining. A significant increase in the percentage of BDNF-IR neurons in the DRG was observed in the NP group at 3 days after surgery and the increase in BDNF mRNA expression was confirmed using in situ hybridization histochemistry and reverse transcription-polymerase chain reaction. We also injected NGF into the endoneurial space of the normal rat spinal nerve root and found that the NGF injection produced dose-dependent mechanical allodynia on the ipsilateral hind paw at 1 day after surgery and an increase in the percentage of BDNF-IR neurons in the DRG at 3 days after surgery compared to the group receiving saline injection. These findings suggest that in the lumbar disc herniation model, i.e. neuritis of the nerve root, increased NGF produced by the inflammatory responses in the dorsal root and DRG tissues may affect the production of BDNF in the DRG and may play important roles in the modulation of the dorsal horn neurons. These changes in neurotrophic factors in the primary afferents may be involved in the pathophysiological mechanisms of neuropathic pain produced by lumbar disc herniation.
Pain 2002 Sep
PMID:Expression of neurotrophic factors in the dorsal root ganglion in a rat model of lumbar disc herniation. 1223 90

Changing the levels of neurotrophins in the spinal cord micro-environment after nervous system injury has been proposed to recover normal function, such that behavioral response to peripheral stimuli does not lead to chronic pain. We have investigated the effects of recombinant adeno-associated viral (rAAV)-mediated over-expression of brain-derived neurotrophic factor (BDNF) in the spinal cord on chronic neuropathic pain after unilateral chronic constriction injury (CCI) of the sciatic nerve. The rAAV-BDNF vector was injected into the dorsal horn at the thirteenth thoracic spinal cord vertebra (L(1) level) 1 week after CCI. Allodynia and hyperalgesia induced by CCI in the hindpaws were permanently reversed, beginning 1 week after vector injection, compared with a similar injection of a control rAAV-GFP vector (green fluorescent protein) or saline. In situ hybridization for BDNF demonstrated that both dorsal and ventral lumbar spinal neurons contained an intense signal for BDNF mRNA, at 1 to 8 weeks after vector injection. There was no similar BDNF mRNA over-expression associated with either injections of saline or rAAV-GFP. These data suggest that chronic neuropathic pain is sensitive to early spinal BDNF levels after partial nerve injury and that rAAV-mediated gene transfer could potentially be used to reverse chronic pain after nervous system injuries in humans.
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PMID:Amelioration of chronic neuropathic pain after partial nerve injury by adeno-associated viral (AAV) vector-mediated over-expression of BDNF in the rat spinal cord. 1236 4

Although known primarily for its role in neuronal development, brain-derived neurotrophic factor (BDNF) has also recently been implicated in processes mediated by the adult nervous system, such as spinal nociception. Peripheral inflammation increases expression of BDNF preferentially in dorsal root ganglion cells that contain substance P and/or calcitonin gene-related peptide, known nociceptive transmitters for which synthesis is also increased during inflammatory states. Expression of the tyrosine kinase receptor that selectively binds BDNF, trkB, is increased in the spinal dorsal horn during inflammation as well. Additionally, intrathecal (i.t.) administration of the BDNF-scavenging protein trkB-IgG attenuates inflammation-induced behavioral responses. Collectively, this evidence implicates BDNF in spinal nociceptive processes. Here we show that, in normal mice, i.t. BDNF produces an acute, dose-dependent thermal hyperalgesic response. Selective inhibition of BDNF expression by i.t. antisense oligodeoxynucleotide treatment produces antinociception in normal mice and attenuates carrageenan-induced hyperalgesia. Further, we demonstrate that i.t. antisense treatment directed against the full-length trkB receptor (trkB.FL) attenuates carrageenan-induced hyperalgesia. Consistent with a trkB.FL-mediated mechanism, the i.t. administration of another trkB ligand, neurotrophin-4/5, also produces hyperalgesia while the trkC agonist neurotrophin-3, which weakly cross-reacts with trkB, has little effect. Finally, with the accumulating evidence linking BDNF to synaptic plasticity, we investigated whether BDNF-induced hyperalgesia in normal mice involves the N-methyl-D-aspartate (NMDA) receptor. Interestingly, i.t. co-administration of the NMDA receptor antagonist D(-)-2-amino-5-phosphonovaleric acid (D-APV) with BDNF dose-dependently inhibits BDNF-induced hyperalgesia, suggesting that BDNF induces acute hyperalgesic responses and affects central sensitization in a process dependent on NMDA receptor activation.
Pain 2002 Nov
PMID:Spinal brain-derived neurotrophic factor (BDNF) produces hyperalgesia in normal mice while antisense directed against either BDNF or trkB, prevent inflammation-induced hyperalgesia. 1243 70

Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a thermal stimulus only on the ipsilateral side. This thermal hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of thermal hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, thermal hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse thermal hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like thermal hyperalgesia induced by nerve injury in mice.
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PMID:Involvement of a spinal brain-derived neurotrophic factor/full-length TrkB pathway in the development of nerve injury-induced thermal hyperalgesia in mice. 1247 Aug 70

Several lines of evidence suggest that the brain-derived neurotrophic factor (BDNF) acts as central pain neuromodulator. We examined the ability of different types of peripheral stimulation to activate the BDNF high-affinity receptor, TrkB, in the spinal cord. We found that noxious chemical, mechanical, or thermal stimuli, but not innocuous stimuli, caused Trk phosphorylation in the spinal cord. These changes were rapid and transient and restricted to somatotopically appropriate spinal segments. We observed, both in vitro and in vivo, that exogenous BDNF induced a rapid activation of ERK, a signaling kinase important in the development of acute pain. Finally, we found that sequestering BDNF in vivo with a TrkB-IgG fusion molecule significantly reduced the activation of ERK evoked by noxious stimulation. These data suggest that BDNF, once released with activity from primary afferent nociceptors, exerts a neuromodulatory role in pain processing through stimulation of postsynaptic TrkB receptors and subsequent activation of ERK.
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PMID:Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. 1250

Neuropathic pain models, such as the chronic constriction injury (CCI) model, are partial nerve injury models where there exist both intact and injured peripheral axons. Recent studies suggested that dorsal root ganglion (DRG) neurons with intact axons also show the alteration of excitability and gene expression and might have some role in the pathophysiological mechanisms of neuropathic pain. The incidence of pain-related behavior after the CCI is unstable and variable. In the present study, we used activating transcription factor 3 (ATF3) expression as a neuronal injury marker, and analyzed a relationship between the number of axotomized neurons and the incidence of pain-related behavior. We divided all rats into three groups according to the percentage of ATF3-immunoreactive (IR) neurons, group 1 (<12.5%), group 2 (12.5-25%), and group 3 (>25%). We found that rats in groups 2 and 3 showed thermal hyperalgesia, whereas only the rats in group 2 developed tactile allodynia from the third day to the fourteenth day after surgery. Rats in group 1 did not show thermal hyperalgesia or tactile allodynia. The DRG neurons in group 2 contained ATF3-IR neurons mainly in medium- and large-sized neurons. In order to investigate brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid(A)-receptor (GABA(A)-R) regulation in both intact and injured primary afferent neurons after the CCI, we used a double-labeling method with immunohistochemistry and in situ hybridization, as well as double immunofluorescent staining. The CCI induced an increased number of BDNF-labeled neurons in the ipsilateral DRG and the increase in BDNF expression was observed mainly in small- and medium-sized neurons that were mainly ATF3-negative. On the other hand, the number of GABA(A)-Rgamma2 subunit mRNA-positive neurons decreased in the ipsilateral DRG and GABA(A)-R- and ATF3-labeled neurons rarely overlapped. These changes in molecular phenotype in intact and injured primary afferents may be involved in the pathophysiological mechanisms of neuropathic pain produced by partial nerve injury.
Pain 2003 Jan
PMID:Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. 1250 1

During development, brain-derived neurotrophic factor (BDNF) supports the survival of certain neuronal population in central and peripheral nervous system. In adulthood, BDNF has been suggested to act as an important modulator of synaptic plasticity. This article reviews and discusses its potential role as neuromodulator in the spinal dorsal horn. BDNF is synthesized in the cell body of primary sensory neurons (pre-synaptic neurons) and its expression is regulated in models of inflammatory and neuropathic pain. The high affinity receptor for BDNF, tropomyosine receptor kinase B (TrkB), is expressed by post-synaptic neurons of the dorsal horn. Stimulation of pre-synaptic nociceptive afferent fibres induces BDNF release and consequent activation of TrkB receptors leading to a post-synaptic excitability. Electrophysiological recordings showed that BDNF enhances the ventral root potential induced by C-fibre stimulation in an in vitro preparation. In addition, behavioural data indicate that antagonism of BDNF attenuates the second phase of hyperalgesia induced by formalin (in nerve growth factor-treated animals) and the thermal hyperalgesia induced by carageenan, suggesting that BDNF is involved in some aspects of central sensitisation in conditions of peripheral inflammation. In conclusion, BDNF meets many of the criteria necessary to define it as a neurotransmitter/neuromodulator in small diameter nociceptive neurons.
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PMID:BDNF: a neuromodulator in nociceptive pathways? 1258 22

The purpose of this study was to characterize the impact of tooth injury on the distribution of tyrosine receptor kinase B (TrkB) among trigeminal ganglion neurons and assess the time course for tooth injury-induced TrkB distribution changes. In addition, we sought to further characterize the subpopulation of the afferents expressing TrkB receptors. Fifteen adult male Sprague-Dawley rats were studied. Pulpal inflammation was induced and ganglia were subsequently harvested and processed at different time points. Standard immunohistochemical fluorescence techniques were used to visualize TrkB-like immunoreactivity and isolectin B4 binding. Results indicate that full-length TrkB receptors are present in 36.6% of trigeminal ganglion neurons. This percentage decreases for the first 48 h and then increases to 41% by 7 days after tooth injury. Finally, TrkB appears to be present in a large percentage (54%) of isolectin B4+ neurons, suggesting that it is present in nociceptive afferents. These data highlight the fact that even mild injury results in sustained changes in nociceptive circuitry and raise the possibility that the brain-derived neurotrophic factor/TrkB system may contribute to persistent pain after tooth repair.
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PMID:Changes in TrkB-like immunoreactivity in rat trigeminal ganglion after tooth injury. 1259 15

Hemisection of the rat spinal cord at thoracic level 13 provides a model of spinal cord injury that is characterized by chronic pain attributable to hyperexcitability of dorsal horn neurons. Presuming that this hyperexcitability can be explained in part by interruption of descending inhibitory modulation by serotonin, we hypothesized that intrathecal transplantation of RN46A-B14 serotonergic precursor cells, which secrete serotonin and brain-derived neurotrophic factor, would reduce this hyperexcitability by normalizing the responses of low-threshold mechanoreceptive, nociceptive-specific, and multireceptive dorsal horn neurons. Three groups (n=45 total) of 30-day-old male Sprague-Dawley rats underwent thoracic level 13 spinal hemisection, after which four weeks were allowed for development of allodynia and hyperalgesia. The three groups of animals received transplants of no cells, 10(6) RN46A-V1 (vector-only) or 10(6) RN46A-B14 cells at lumbar segments 2-3. Electrophysiological experiments were done two weeks later. Low-threshold mechanoreceptive, nociceptive-specific, and multireceptive cells (n=394 total) were isolated at depths of 1-300 and 301-1000 micro in the lumbar enlargement. Responses to innocuous and noxious peripheral stimuli were characterized, and analyses of population responses were performed. Compared with normal animals, dorsal horn neurons of all types in hemisected animals showed increased responsiveness to peripheral stimuli. This was true for neurons on both sides of the spinal cord. After hemisection, the proportion of neurons classified as multireceptive cells increased, and interspike intervals of spontaneous discharges became less uniform after hemisection. Transplantation of RN46A-B14 cells restored evoked responses to near-control levels, normalized background activity, and returned the proportion of multireceptive cells to the control level. Restoration of normal activity was reversed with methysergide.These electrophysiological results corroborate anatomical and behavioral studies showing the effectiveness of serotonergic neural precursors in correcting phenomena associated with chronic central pain following spinal cord injury, and provide mechanistic insights regarding mode of action.
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PMID:Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat. 1261 51


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