Mutations in dynein link motor neuron degeneration to defects in retrograde transport.
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Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein. (+info)
Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy.
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Microglia, the intrinsic macrophages of the central nervous system, have previously been shown to be activated in the spinal cord in several rat mononeuropathy models. Activation of microglia and subsequent release of proinflammatory cytokines are known to play a role in inducing a behavioral hypersensitive state (hyperalgesia and allodynia) in these animals. The present study was undertaken to determine whether minocycline, an inhibitor of microglial activation, could attenuate both the development and existing mechanical allodynia and hyperalgesia in an L5 spinal nerve transection model of neuropathic pain. In a preventive paradigm (to study the effect on the development of hypersensitive behaviors), minocycline (10, 20, or 40 mg/kg intraperitoneally) was administered daily, beginning 1 h before nerve transection. This regimen produced a decrease in mechanical hyperalgesia and allodynia, with a maximum inhibitory effect observed at the dose of 20 and 40 mg/kg. The attenuation of the development of hyperalgesia and allodynia by minocycline was associated with an inhibitory action on microglial activation and suppression of proinflammatory cytokines at the L5 lumbar spinal cord of the nerveinjured animals. The effect of minocycline on existing allodynia was examined after its intraperitoneal administration initiated on day 5 post-L5 nerve transection. Although the postinjury administration of minocycline significantly inhibited microglial activation in neuropathic rats, it failed to attenuate existing hyperalgesia and allodynia. These data demonstrate that inhibition of microglial activation attenuated the development of behavioral hypersensitivity in a rat model of neuropathic pain but had no effect on the treatment of existing mechanical allodynia and hyperalgesia. (+info)
p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain.
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The possible involvement of p38 mitogen-activated protein kinase activation in spinal cord and dorsal root ganglion (DRG) cells in the development of peripheral neuropathic pain has been explored. Ligation of the L5 spinal nerve (SNL) on one side in adult rats produces an early onset and long-lasting mechanical allodynia. This lesion results in activation of p38 in the L5 segment of the spinal cord, most prominently in the ipsilateral dorsal horn, starting soon after the lesion (<1 d) and persisting for >3 weeks. The activated p38 in the spinal cord is restricted entirely to microglia; phospho-p38 colocalizes only with the microglial marker OX-42 and not with either the neuronal marker neuronal-specific nuclear protein or the astrocyte marker GFAP. In contrast, SNL induces a delayed (>3 d) activation of p38 in the L5 DRG that occurs predominantly in neurons. Continuous injection of the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) via the intrathecal route, starting before the SNL surgery, reduces SNL-induced mechanical allodynia from day 1 to day 10, with maximal effects at early time points. Post-treatment with SB203580 starting on day 1 or on day 10 after surgery also reduces established mechanical allodynia. Because the reduction in neuropathic pain by p38 inhibition occurs before the appearance of p38 activation in DRG neurons, p38 activation in spinal cord microglia is likely to have a substantial role in the earliest phase of neuropathic pain. Coactivation of p38 in DRG neurons and spinal microglia may contribute to later phases of neuropathic pain. (+info)
Intraspinal adenosine induces spinal cord norepinephrine release in spinal nerve-ligated rats but not in normal or sham controls.
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BACKGROUND: Intrathecal adenosine is antinociceptive under conditions of central sensitization, but not in response to acute stimuli in normals. The reasons for this selective circumstance of action remain unclear, but some evidence links adenosine's antinociceptive effects to release of norepinephrine by terminals in the spinal cord. The purpose of this study was to test whether spinal adenosine induces norepinephrine release selectively in settings of hypersensitivity. METHODS: Rats randomly assigned to spinal nerve ligation, sham operation, or no operation were anesthetized. A microdialysis fiber was implanted in the spinal cord dorsal horn at the L5-L6 level and perfused with artificial cerebrospinal fluid. After washout and a baseline sample period, adenosine at various concentrations was infused through the fiber for 150 min, and samples were collected every 15 min. RESULTS: In ligated, but not in sham or normal animals, adenosine perfusion increased norepinephrine in spinal cord microdialysates in a concentration-dependent manner. The effects of adenosine plateaued after 75 min and remained stable until the end of the experiment. Intravenous injection of selective adenosine A1 and A2 receptor antagonists revealed that adenosine's effect on spinal norepinephrine release was A1 receptor mediated. CONCLUSIONS: This is the first study to provide direct evidence that adenosine is able to release norepinephrine in spinal cord dorsal horns in living animals. However, this effect was only seen in animals after spinal nerve ligation. These data are consistent with behavioral studies demonstrating that adenosine's antinociceptive effects in rats after spinal nerve ligation is totally dependent on intact spinal noradrenergic terminals and can be blocked by spinal alpha 2-adrenergic receptor antagonists. (+info)
Spinal neuronal responses to urinary bladder stimulation in rats with corticosterone or aldosterone onto the amygdala.
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Elevating glucocorticoids in the amygdala produces colorectal hypersensitivity through activation of lumbosacral spinal neurons. The aim of this study was to determine if descending modulation from the amygdala affects spinal processing of input from urinary bladder afferents. Fischer-344 rats received cholesterol (inactive control)-, corticosterone-, or aldosterone-containing micropellets placed stereotaxically on the dorsal margin of the left and right amygdala (n = 10 for each group). Seven days after amygdaloid implantation, extracellular potentials of single L6-S1 spinal neurons were examined for the responses to graded (0.5-2.0 ml, 20 s) urinary bladder distension (UBD). Spontaneous activity of neurons with excitatory responses to UBD in aldosterone-implanted rats [11.0 +/- 1.7 (SE) imp/s], but not in corticosterone-implanted rats, was higher than in the cholesterol-implanted group (6.6 +/- 1.1 imp/s, P < 0.05). Noxious UBD (1.5 ml) produced a greater excitatory response (21.6 +/- 2.6 imp/s) in aldosterone-implanted rats compared with cholesterol- or corticosterone-implanted rats (15.1 +/- 1.5 and 13.6 +/- 1.4 imp/s; P < 0.05). In contrast, the duration of excitatory responses to UBD in corticosterone-implanted rats (38.5 +/- 3.4 imp/s) was significantly longer than those in the aldosterone or control groups (26.8 +/- 1.8 and 24.7 +/- 1.5 imp/s). Neurons with low thresholds for excitatory responses to UBD were seen more frequently in aldosterone-implanted rats than in corticosterone or cholesterol treated rats (74 vs. 44% and 39%, P < 0.05). No difference in somatic field properties of spinal neurons responsive or nonresponsive to UBD was found among the three groups. These findings suggest that both mineralocorticoid- and glucocorticoid-mediated mechanisms in the amygdala are involved in descending modulation to lumbosacral spinal neurons receiving inputs from the urinary bladder; and this mechanism may play a role in the activation and maintenance of primary central sensitization to noxious visceral stimuli. (+info)
P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.
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Pain after nerve damage is an expression of pathological operation of the nervous system, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X4R expression increased strikingly in the ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X4Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury. (+info)
Reconstruction of the inferior alveolar nerve by autologous graft: a retrospective study of 20 cases examining donor nerve length.
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The purpose of this study was to confirm the length and kind of donor nerves used in nerve grafts for reconstruction of inferior alveolar nerve defects. The authors conducted a retrospective study of surgeries that were performed between 1977 and 1996. A total of 20 patients underwent nerve grafting procedures during this period. The greater auricular nerve was selected as the donor nerve in 16 cases, while the sural nerve was selected in 4. Mean lengths of donor nerves were 7.28 +/- 1.6 cm and 11.5 +/- 3.4 cm for the greater auricular and sural nerves, respectively. As indicated, the sural nerves were significantly longer (p < 0.01). Mean lengths of donor nerves grafted for partial resection and hemi-mandibulectomy were 7.23 +/- 1.6 cm and 10.8 +/- 3.4 cm, respectively. Statistical analysis indicated that grafts used in the hemi-mandibulectomy group were significantly longer (p < 0.05). In terms of types of donor nerve used in mandibulectomies, the greater auricular nerve was used in the majority of partial resections, and the sural nerve was employed for hemi-mandibulectomy. (+info)
Nerve injury-induced afferent discharge is thought to elicit spinal sensitization and consequent abnormal pain. Experimental neuropathic pain, however, also depends on central changes, including descending facilitation arising from the rostral ventromedial medulla (RVM) and upregulation of spinal dynorphin. A possible intersection of these influences at the spinal level was explored by measuring evoked, excitatory transmitter release in tissues taken from nerve-injured animals with or without previous manipulation of descending modulatory systems. Spinal nerve ligation (SNL) produced expected tactile and thermal hyperesthesias. Capsaicin-evoked calcitonin gene-related peptide (CGRP) release was markedly enhanced in lumbar spinal tissue from SNL rats when compared with sham-operated controls. Enhanced, evoked CGRP release from SNL rats was blocked by anti-dynorphin A(1-13) antiserum; this treatment did not alter evoked release in tissues from sham-operated rats. Dorsolateral funiculus lesion (DLF) or destruction of RVM neurons expressing mu-opioid receptors with dermorphin-saporin, blocked tactile and thermal hypersensitivity, as well as SNL-induced upregulation of spinal dynorphin. Spinal tissues from these DLF-lesioned or dermorphin-saporin-treated SNL rats did not exhibit enhanced capsaicin-evoked CGRP-IR release. These data demonstrate exaggerated release of excitatory transmitter from primary afferents after injury to peripheral nerves, supporting the likely importance of increased afferent input as a driving force of neuropathic pain. The data also show that modulatory influences of descending facilitation are required for enhanced evoked transmitter release after nerve injury. Thus, convergence of descending modulation, spinal plasticity, and afferent drive in the nerve-injured state reveals a mechanism by which some aspects of nerve injury-induced hyperesthesias may occur. (+info)