Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Distinct classes of primary sensory neurons in dorsal root ganglia subserve different sensory modalities, terminate in different dorsoventral locations in the spinal cord, and display different neurotrophin response profiles. Large diameter muscle afferents that terminate in the ventral spinal cord are NT-3 responsive, whereas small diameter afferents subserving pain and temperature are NGF responsive and terminate in the dorsal spinal cord. Previous in vitro studies showed that the developing ventral spinal cord secretes a diffusible factor that inhibits the growth of sensory axons. Here we show that this factor repels NGF-responsive axons but has little effect on NT-3-responsive axons. We also provide evidence implicating semaphorin III/collapsin, a diffusible guidance molecule expressed by ventral spinal cord cells, in mediating this effect. These results suggest that semaphorin III functions to pattern sensory projections by selectively repelling axons that normally terminate dorsally.
 ...
PMID:Semaphorin III can function as a selective chemorepellent to pattern sensory projections in the spinal cord. 774 62

There is a stereotypical pattern of primary afferent terminations within the mature spinal cord; however, this pattern is not immutable. Peripheral axotomy causes A fibers to sprout into lamina II, a region from which they are normally excluded. We have investigated the role of neurotrophins in this response. Rats which had undergone sciatic axotomy were treated intrathecally with NGF, BDNF, or NT-3. A fibers were visualized using transganglionic labeling with cholera toxin B subunit; small fibers were visualized using CGRP immunostaining. NGF (12 microg/day for 2 weeks), but not NT-3 or BDNF, prevented both the axotomy-induced reduction in CGRP staining within lamina II and the sprouting of A fibers into this region. It is likely that the prevention of A fiber sprouting is a secondary consequence of NGF rescuing small fibers. This effect of NGF on dorsal horn sprouting has implications both for our understanding of the maintenance of CNS connectivity and for the treatment of neuropathic pain states.
 ...
PMID:NGF but not NT-3 or BDNF prevents the A fiber sprouting into lamina II of the spinal cord that occurs following axotomy. 900 Apr 37

During development, semaphorins (collapsin, fasciclin) mediate repulsive and inhibitory guidance of neurons. Semaphorin III, a secretable member of this family, is expressed by the ventral spinal cord at the time corresponding to projection of sensory afferents from the dorsal root ganglion (DRG) into the spinal cord. The inhibitory effect of E14 ventral cord is active only on nerve growth factor (NGF)-responsive sensory afferents (small-diameter A-delta and C fibers subserving sensations of temperature and pain). Similarly, COS cells secreting recombinant semaphorin III are able to selectively repel DRG afferents whose growth is stimulated by NGF and not NT-3. However, it is not known whether these molecules can exert a functional role in the fully developed adult peripheral nervous system. In this study, we demonstrated that gene gun transfection and production of semaphorin III in corneal epithelial cells in adult rabbits in vivo can cause repulsion of established A-delta and C fiber trigeminal sensory afferents. In addition, it is shown that, following epithelial wounding and denervation, semaphorin III is able to inhibit collateral nerve sprouts from innervating the reepithelialized tissue. These findings are significant in that they provide direct evidence that small-diameter adult sensory neurons retain the ability to respond to semaphorin III. In addition, the corneal gene gun technique may be generally used to study the in vivo effects of neural growth modulators by quantifying the amount of sensory nerve growth.
 ...
PMID:Semaphorin III can repulse and inhibit adult sensory afferents in vivo. 939 12

Nerve-growth factor (NGF), a member of the neurotrophin family, plays an important role in nociceptor function. Prompted by a previous uinexpected finding that NT-4/5, as well as NGF sensitizes single nociceptors to noxious heat, we have explored the relative potency of all neurotrophins in eliciting thermal hyperalgesia. NGF, brain-derived neurotrophic factor (BDNF), NT-4/5 and NT-3 were injected locally into the hind paw of rats, and the behavioral response to noxious heat was compared with that from the other paw that received an identical injection of vehicle. Like NGF, agonists of tyrosine kinaseB (trkB) receptors (NT-4/5 and BDN F) induced thermal hyperalgesia in the first 5 h after treatment (NT-4/5 > BDNF) but the effect had worn off by 24 h. In contrast, the trkC agonist NT-3 had no effect on the response to noxious heat. Electrophysiological recordings from single C-fibres in the in vitro skin-saphenous nerve preparation revealed sensitization to noxious heat stimuli after direct application of BDNF to the receptive field, as previously noted for NT-4/5, and in parallel with the behavioral findings. NT-3 was ineffective as in the behavioral studies. These results suggest that trkB agonists BDNF and NT-4/5 as well as the trkA agonist NGF can regulate nociceptive responses to noxious heat.
Pain 1999 Apr
PMID:Effects of trkB and trkC neurotrophin receptor agonists on thermal nociception: a behavioral and electrophysiological study. 1034 8

It is now well established that neurotrophins play a crucial role in the development of the nervous system. However, there is increasing evidence that the function of neurotrophins persists throughout adulthood. The broad scope of neurotrophin action is well documented in the case of nerve growth factor (NGF) and its effect on nociceptors and nociception. Here, we review the evidence for these multiple roles for NGF. Two manipulations influencing NGF levels are discussed in detail. The first involves the use of transgenic mice that overexpress or underexpress neurotrophins. A second strategy involves administration of NGF or its antibody in vivo to increase or decrease its level. During prenatal development, NGF is required for survival of nociceptors. In the early postnatal period, NGF is required for expression of the appropriate nociceptor phenotype. In adults, NGF acts as an important intermediate in inflammatory pain, contributing to both peripheral and central sensitization. The sensitization of peripheral nociceptors can be very rapid and can involve non-neural cells such as mast cells, neutrophils, fibroblasts, and macrophages. Recent evidence indicates that other neurotrophins also play key supporting roles in the development of nociceptors (e.g., NT-3) and in inflammatory pain (e.g., BDNF, NT-4/5). Furthermore, molecules from other superfamilies (e.g., GDNF) also are required to assure survival of certain classes of nociceptors. The diverse effects of neurotrophins on nociceptive processing emphasize their broad importance in the development and function of the nervous system.
 ...
PMID:Neurotrophins, nociceptors, and pain. 1038 18

This brief review explores the action of neurotrophins on sensory neurons in adults. Neutralization of neurotrophins in adults does not cause sensory neurons to die as it does in prenatal animals. Thus they are not required as survival factors in adults. However, neurotrophins continue to play important roles in the postnatal development of sensory neurons. They also exert strong effects on the anatomy and physiology of these fibers after axotomy in adults. Here we review of the effects of NT-3 on spindle afferent fibers and NGF on nociceptive afferents and consider possible extension of the neurotrophic hypothesis to adults.
Pain 1999 Aug
PMID:Neurotrophin action on sensory neurons in adults: an extension of the neurotrophic hypothesis. 1049 81

Peripheral ganglion neurons confer sensory information including touch, pain, temperature, and proprioception. Sensory modality is linked to specific neurotrophin (NTF) requirements. NT-3 supports survival of neurons that differentiate primarily into proprioceptors whereas nerve growth factor and brain-derived neurotrophic factor (BDNF) support subpopulations that transmit nociception and mechanoreception, respectively. We examined sensory neurons of gene-targeted mouse mutants at the NT-4, BDNF, NT-3, and TrkA loci. We show that NT-4 functions early in gangliogenesis, upstream of BDNF. In the absence of NT-4 function, BDNF-dependent, TrkB-expressing neurons fail to appear. The results are consistent with the model that precursor cells intended to become BDNF-dependent mechanoreceptors instead differentiate into NT-3-dependent proprioceptive neurons.
 ...
PMID:Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice. 1068 61

There is growing evidence suggesting that neurotrophins have modulating effects on the pain signaling system at spinal levels. In order to determine whether neurotransmitter expression is modulated in response to the elevation of neurotrophins, the changes in c-fos, neuropeptide and glutamic acid decarboxylase (GAD) mRNAs expression was evaluated after BDNF or NT-3 was applied to cultured spinal neurons. Reverse transcription polymerase chain reaction analysis revealed that BDNF induced a significant increase in the expression of preprodynorphin (pDYN), preproenkephalin (pENK), neuropeptide Y (NPY) and GAD mRNAs. In contrast, the pENK, not the pDYN, NPY and GAD, mRNA levels increased after the treatment of NT-3. Both BDNF and NT-3 produced a rapid increase in c-fos mRNA. These results suggest that BDNF and NT-3 have differential neuronal effects on the synthesis of spinal cord neurotransmitters that are involved in the modulation of nociceptive information.
 ...
PMID:Effects of brain-derived neurotrophic factor and neurotrophin-3 on expression of mRNAs encoding c-Fos, neuropeptides and glutamic acid decarboxylase in cultured spinal neurons. 1111 6

The sodium channels SNS/PN3 and NaN/SNS2 are regulated by the neurotrophic factors-nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF), and may play an important role in the development of pain after nerve injury or inflammation. These key molecules have been studied in an amputated causalgic finger and control tissues by immunohistochemistry. There was a marked increase in the number and intensity of SNS/PN3-immunoreactive nerve terminals in the affected finger, while GDNF-immunoreactivity was not observed, in contrast to controls. No differences were observed for NGF, trk A, NT-3 or NaN/SNS2-immunoreactivity. While further studies are required, these findings suggest that accumulation of SNS/PN3 and/or loss of GDNF may contribute to pain in causalgia, and that selective blockers of SNS/PN3 and/or rhGDNF may provide effective novel treatments.
Eur J Pain 2001
PMID:Increased sodium channel SNS/PN3 immunoreactivity in a causalgic finger. 1155 87

Calcium-activated potassium ion channels SK and IK (small and intermediate conductance, respectively) may be important in the pathophysiology of pain following nerve injury, as SK channels are known to impose a period of reduced excitability after each action potential by afterhyperpolarization. We studied the presence and changes of human SK1 (hSK1)- and hIK1-like immunoreactivity in control and injured human dorsal root ganglia (DRG) and peripheral nerves and their regulation by key neurotrophic factors in cultured rat sensory neurones. Using specific antibodies, hSK-1 and hIK-1-like immunoreactivity was detected in a majority of large and small/medium-sized cell bodies of human DRG. hSK1 immunoreactivity was decreased significantly in cell bodies of avulsed human DRG (n = 8, surgery delay 8 h to 12 months). There was a decrease in hIK1-like immunoreactivity predominantly in large cells acutely (<3 weeks after injury), but also in small/medium cells of chronic cases. Twenty-three injured peripheral nerves were studied (surgery delay 8 h to 12 months); in five of these, hIK1-like immunoreactivity was detected proximally but not distally to injury, whereas neurofilament staining confirmed the presence of nerve fibres in both regions. These five nerves, unlike the others, had all undergone Wallerian degeneration previously and the loss of hIK1-like immunoreactivity may therefore reflect reduced axonal transport of this ion channel across the injury site in regenerated fibres, as well as decreased expression in the cell body. In vitro studies of neonatal rat DRG neurones showed that nerve growth factor (NGF) significantly increased the percentage of hSK1-positive cells, whereas neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) failed to show a significant effect. NT-3 stimulated hIK1 expression, while NGF and GDNF were ineffective. As expected, NGF increased expression of the voltage-gated sodium channel SNS1/PN3 in this system. Decreased retrograde transport of these neurotrophic factors in injured sensory neurones may thus reduce expression of these ion channels and increase excitability. Blockade of IK1-like and other potassium channels by aminopyridines (4-AP and 3,4-DAP) may also explain the paraesthesiae induced by these medications. Selective potassium channel openers are likely to represent novel therapies for pain following nerve injury.
 ...
PMID:Calcium-activated potassium channel SK1- and IK1-like immunoreactivity in injured human sensory neurones and its regulation by neurotrophic factors. 1184 26


1 2 3 Next >>