Neurofibromas in NF1: Schwann cell origin and role of tumor environment.
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Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly inherited genetic diseases of the nervous system. NF1 encodes a tumor suppressor whose functional loss results in the development of benign neurofibromas that can progress to malignancy. Neurofibromas are complex tumors composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. Through use of a conditional (cre/lox) allele, we show that loss of NF1 in the Schwann cell lineage is sufficient to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in non-neoplastic cells. The requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers. (+info)
Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.
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Although injury-induced afferent discharge declines significantly over time, experimental neuropathic pain persists unchanged for long periods. These observations suggest that processes that initiate experimental neuropathic pain may differ from those that maintain such pain. Here, the role of descending facilitation arising from developing plasticity in the rostral ventromedial medulla (RVM) in the initiation and maintenance of experimental neuropathic pain was explored. Tactile and thermal hypersensitivity were induced in rats by spinal nerve ligation (SNL). RVM lidocaine blocked SNL-induced tactile and thermal hypersensitivity on post-SNL days 6-12 but not on post-SNL day 3. Lesion of RVM cells expressing mu-opioid receptors with dermorphin-saporin did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Similarly, lesions of the dorsolateral funiculus (DLF) did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Lesions of the DLF also blocked the SNL-induced increase in spinal dynorphin content, which has been suggested to promote neuropathic pain. These data distinguish mechanisms that initiate the neuropathic state as independent of descending supraspinal influences and additional mechanism(s) that require supraspinal facilitation to maintain such pain. In addition, the data indicate that these time-dependent descending influences can underlie some of the SNL-induced plasticity at the spinal level. Such time-dependent descending influences driving associated spinal changes, such as the upregulation of dynorphin, are key elements in the maintenance, but not initiation, of neuropathic states. (+info)
Effects of MK-801 and morphine on spinal C-Fos expression during the development of neuropathic pain.
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The purpose of this study was to investigate the expression of c-fos in the spinal cord during the development of allodynia, induced by peripheral nerve injury. Following tight ligation of the left L5 and L6 spinal nerves of Sprague- Dawley rat, the lumbar spinal cord was postfixed following perfusion. Frontal frozen sections of 40 microm were immunostained according to the peroxidase-antiperoxidase method. The allodynic threshold was checked with 8 calibrated von Frey filaments. MK-801 (0.3 mg/kg), morphine (3 mg/kg) and saline (as a placebo) were administered subcutaneously 30 min before, and 24 and 48 hrs after surgery. The tactile threshold decreased below 3 g since 2 days after surgery in the saline and morphine groups, but delayed a little in the MK-801 group. In the superficial layer the number of Fos-like immunoreactive neurones (Fos-LI) peaked at 2 hours and decreased thereafter, and reached normal levels 24 hrs following operation, for all groups. In the deep layer they were biphasic, - peaking at 2 and 24 hrs - in the saline group, but were suppressed in the morphine and MK-801 groups until 7 days following operation. The above discrepancy between the number of Fos-LI and the allodynic threshold showed that central sensitizations are not critically involved in the development of nerve injury induced tactile allodynia. (+info)
Role of adenosine receptors in spinal G-protein activation after peripheral nerve injury.
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BACKGROUND: Spinally injected adenosine induces antinociception in animal models of neuropathic but not acute pain. The reasons for this discrepancy remain unclear. Adenosine receptors are coupled to G proteins, and increased efficiency of adenosine-induced G-protein activity in neuropathic pain could contribute to the antinociceptive effect of adenosine. In this study the authors used [(35)S]guanosine-5'-O-(3-thiotriphosphate) ([(35)S]GTP gamma S) autoradiography in rat spinal cord sections to test this possibility. METHODS: The spinal cords of normal animals and those that underwent left L5 and L6 spinal nerve ligation (SNL) were removed and immediately frozen. Horizontal spinal cord sections were cut and mounted on chrom-alum gelatin-subbed slides. Sections were incubated with guanosine diphosphate, [(35)S]GTP gamma S, the adenosine A1 agonist R-N6-phenylisopropyladenosine, and various other drugs, apposed to films, and analyzed. RESULTS: Baseline and R-N6-phenylisopropyladenosine-stimulated [(35)S]GTP gamma S binding was predominantly localized to the superficial dorsal horns of both normal and SNL animals. This binding was significantly increased in SNL compared with normal animals. In contrast, no difference in R-N6-phenylisopropyladenosine-stimulated [(35)S]GTP gamma S binding was observed between SNL and normal animals. Blockade of adenosine A1 receptors by 1,3-dipropyl-8-cyclopentylxanthine, or adenosine destruction by added adenosine deaminase, reduced the increased basal activity in SNL to baseline levels of normal dorsal horns, whereas atropine and naloxone had no effect. CONCLUSION: This study shows an increased basal G-protein activity in lumbar spinal cords during conditions of SNL. The data suggest that increased adenosine release during conditions of SNL results in an increased basal activity of G proteins in the spinal cord during neuropathic pain. (+info)
Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry.
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BACKGROUND: Neurons in the dorsal spinal cord play important roles in nociception and pain. These neurons receive input from peripheral sensory neurons and then transmit the signals to the brain, as well as receive and integrate descending control signals from the brain. Many molecules important for pain transmission have been demonstrated to be localized to the dorsal horn of the spinal cord. Further understanding of the molecular interactions and signaling pathways in the dorsal horn neurons will require a better knowledge of the molecular neuroanatomy in the dorsal spinal cord. RESULTS: A large scale screening was conducted for genes with enriched expression in the dorsal spinal cord using DNA microarray and quantitative real-time PCR. In addition to genes known to be specifically expressed in the dorsal spinal cord, other neuropeptides, receptors, ion channels, and signaling molecules were also found enriched in the dorsal spinal cord. In situ hybridization and immunohistochemistry revealed the cellular expression of a subset of these genes. The regulation of a subset of the genes was also studied in the spinal nerve ligation (SNL) neuropathic pain model. In general, we found that the genes that are enriched in the dorsal spinal cord were not among those found to be up-regulated in the spinal nerve ligation model of neuropathic pain. This study also provides a level of validation of the use of DNA microarrays in conjunction with our novel analysis algorithm (SAFER) for the identification of differences in gene expression. CONCLUSION: This study identified molecules that are enriched in the dorsal horn of the spinal cord and provided a molecular neuroanatomy in the spinal cord, which will aid in the understanding of the molecular mechanisms important in nociception and pain. (+info)
Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents.
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We demonstrated recently that uninjured C-fiber nociceptors in the L4 spinal nerve develop spontaneous activity after transection of the L5 spinal nerve. We postulated that Wallerian degeneration leads to an alteration in the properties of the neighboring, uninjured afferents from adjacent spinal nerves. To explore the role of degeneration of myelinated versus unmyelinated fibers, we investigated the effects of an L5 ventral rhizotomy in rat. This lesion leads to degeneration predominantly in myelinated fibers. Mechanical paw-withdrawal thresholds were assessed with von Frey hairs, and teased-fiber techniques were used to record from single C-fiber afferents in the L4 spinal nerve. Behavioral and electrophysiological data were collected in a blinded manner. Seven days after surgery, a marked decrease in withdrawal thresholds was observed after the ventral rhizotomy but not after the sham operation. Single fiber recordings revealed low-frequency spontaneous activity in 25% of the C-fiber afferents 8-10 d after the lesion compared with only 11% after sham operation. Paw-withdrawal thresholds were inversely correlated with the incidence of spontaneous activity in high-threshold C-fiber afferents. In normal animals, low-frequency electrocutaneous stimulation at C-fiber, but not A-fiber, strength produced behavioral signs of secondary mechanical hyperalgesia on the paw. These results suggest that degeneration in myelinated efferent fibers is sufficient to induce spontaneous activity in C-fiber afferents and behavioral signs of mechanical hyperalgesia. Ectopic spontaneous activity from injured afferents was not required for the development of the neuropathic pain behavior. These results provide additional evidence for a role of Wallerian degeneration in neuropathic pain. (+info)
cDNA microarray analysis of the differential gene expression in the neuropathic pain and electroacupuncture treatment models.
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Partial nerve injury is the main cause of neuropathic pain disorders in humans. Acupuncture has long been used to relieve pain. It is known to relieve pain by controlling the activities of the autonomic nervous system. Although the mechanism of neuropathic pain and analgesic effects of electroacupuncture (EA) have been studied in a rat model system, its detailed mechanism at the molecular level remains unclear. To identify genes that might serve as either markers or explain these distinct biological functions, a cDNA microarray analysis was used to compare the expression of 8,400 genes among three sample groups. Messenger RNAs that were pooled from the spinal nerves of 7 normal, 7 neuropathic pain, and 7 EA treatment rat models were compared. Sixty-eight genes were differentially expressed more than 2-fold in the neuropathic rat model when compared to the normal, and restored to the normal expression level after the EA treatment. These genes are involved in a number of biological processes, including the signal transduction, gene expression, and nociceptive pathways. Confirmation of the differential gene expression was performed by a dotblot analysis. Dot-blotting results showed that the opioid receptor sigma was among those genes. This indicates that opioid-signaling events are involved in neuropathic pain and the analgesic effects of EA. The potential application of these data include the identification and characterization of signaling pathways that are involved in the EA treatment, studies on the role of the opioid receptor in neuropathic pain, and further exploration on the role of selected identified genes in animal models. (+info)
Selective mediation of nerve injury-induced tactile hypersensitivity by neuropeptide Y.
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Prevention of nerve injury-induced tactile, but not thermal, hypersensitivity is achieved by ipsilateral lesions of the dorsal columns or lidocaine microinjection into the nucleus gracilis (n. gracilis). These and other data support the possibility that tactile hyperresponsiveness after nerve injury may be selectively mediated by a low-threshold myelinated fiber pathway to the n. gracilis. Here we identify a transmitter that might selectively mediate such injury-induced tactile hypersensitivity. Neuropeptide Y (NPY), normally not detected in the dorsal root ganglion (DRG) or in the n. gracilis of rats, became markedly upregulated at both sites and in the spinal cord after spinal nerve injury. Injury-induced NPY-IR occurred predominately in large-diameter DRG cells, and the NPY-IR in the n. gracilis was blocked by dorsal rhizotomy or dorsal column lesion. NPY microinjection into the n. gracilis of uninjured rats elicited reversible tactile, but not thermal, hypersensitivity only in the ipsilateral hindpaw. Administration of anti-NPY antiserum, but not control serum or preabsorbed serum, into the n. gracilis ipsilateral to nerve injury reversed tactile, but not thermal, hypersensitivity. Similarly, microinjection of the NPY antagonists NPY(18-36) and (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininam ide trifluoroacetate, into the n. gracilis ipsilateral to the injury reversed tactile, but not thermal, hypersensitivity. Antagonist administration into the contralateral n. gracilis had no effect on injury-induced hypersensitivity. These data suggest the selective mediation of nerve injury-induced tactile hypersensitivity by upregulated NPY via large fiber input to n. gracilis. Selective reversal of injury-induced tactile allodynia by NPY receptor antagonists would have significant implications for human neuropathic conditions. (+info)