Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor

Verge, Valerie M. K.; Richardson, P. M.; Benoit, Robert; Riopelle, Richard J.

doi:10.1007/bf01187079

Cited by 161 publications

(89 citation statements)

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“…NTR DRG neurons had been reported to express TrkA acting as a high affinity receptor for NGF (19,28,29), and a low affinity NGF receptor, p75 NTR (21). At first, we examined whether the expression of these NGF receptors was maintained in cultured sensory neurons isolated from adult rats.…”

Section: Cultured Adult Rat Drg Neurons Express Trka and P75mentioning

confidence: 99%

“…Heat-polished glass electrodes with a 2-to 3-MΩ tip resistance were used. The pipette solution contained (mM): 151.6 K-methansulfonic acid; 3.4 KCl; 5 Na-methansulfonic acid; 2 MgCl 2 ; 1.3 CaCl 2 ; 10 ethylene glycol-bis (β-aminoethylether)-N, N, N', N'-tetraacetic acid (EGTA, Sigma); 10 N- [2- (19,28,29) and p75 NTR (21) as receptors for NGF, and can be potential targets of the action of NGF. Therefore, cultured DRG neurons isolated from healthy adult rats were chronically treated with NGF by adding it into culture medium, and chronic effects of NGF on electrophysiological activity of neurons were examined.…”

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Nerve growth factor-induced hyperexcitability of rat sensory neuron in culture

et al. 2005

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Abnormal spontaneous firing of primary sensory neurons is considered to be a cause of neuropathic pain. However, pathogenic mechanisms of hyperexcitable sensory neurons in neuropathic model animals are unclear. We examined effects of chronic treatment of nerve growth factor (NGF), one of candidate mediators for the pathogenesis, on excitability of sensory neurons by voltage-clamped recording in a cell-attached configuration. From rat dorsal root ganglion (DRG) neurons cultured without NGF, only stable holding currents without spontaneous firing activity were recorded. On the other hand, more than 20% neurons cultured in the presence of NGF for more than 3 days showed spontaneous current spikes at frequencies between 0.1 and 5 Hz. Each spikes had an initial inward phase followed by the outward phase, resulted from spontaneous transient depolarization followed by transient hyperpolarization. These spontaneous spikes were abolished by tetrodotoxin, lidocaine and reduction of extracellular concentration of Na + from 154 mM to 100 mM, in all-or-none fashion, suggesting that spontaneous current spikes reflected spontaneous action potentials. From these results, it became evident that DRG neurons of adult rats had a nature to respond to NGF and obtained the abnormal hyperexcitability to fire spontaneously.Peripheral nerve injury frequently results in severe chronic pain, neuropathic pain that is poorly responsive to general analgesic therapy, and remains as an unsolved problem in health. Experimental injury of the peripheral nerve in experimental animals induces hyperalgesia and allodynia (2,5,13,22,31,32). Although primary sensory neurons of healthy animals are "silent" in electrophysiology without excitatory inputs from other neurons or sensational inputs, abnormal spontaneous firing was observed in sensory neurons of animals with nerve injury (6,11,12,18). Such abnormal firing is considered to be a cause of neuropathic pain. Such spontaneous firing was observed at the local injured site and also at the soma of the dorsal root ganglion (DRG) neurons (30). Subthreshold membrane potential oscillation and the spontaneously generated action potentials were recorded in DRG neurons freshly isolated from nerveinjured rats by the intracellular microelectrode method (1,17,26) and the whole-cell patch clamp method in the current clamp mode (20,27). Nevertheless, the pathogenic mechanisms of the abnormal hyperexcitability of the primary sensory neurons are unclear. Concentration of nerve growth factor (NGF) in DRG was reported to increase after the artificial nerve injury (9), and injection of exogenous NGF into healthy rats induced hyperalgesia (16). These reports suggest that NGF correlates with the pathogenesis of neuropathic pain. Small DRG neurons, which respond to noxious sensation, express TrkA

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Section: Cultured Adult Rat Drg Neurons Express Trka and P75mentioning

confidence: 99%

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confidence: 99%

Nerve growth factor-induced hyperexcitability of rat sensory neuron in culture

et al. 2005

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“…The signals regulating these responses are complex and include the promotion of thermal hyperalgesia and nociceptor phenotype by the neurotrophin nerve growth factor (NGF) through activation of its receptor, tropomyosin-related kinase A (trkA) (Verge et al, 1989b(Verge et al, , 1995Lewin and Mendell, 1993;Jongsma Wallin et al, 2001. Recently, it has been shown that the upregulation of NGF after peripheral inflammation leads to the activation of the mitogen-activated protein kinase (MAPK) p38 (Ji et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Neurotrophin-3 Suppresses Thermal Hyperalgesia Associated with Neuropathic Pain and Attenuates Transient Receptor Potential Vanilloid Receptor-1 Expression in Adult Sensory Neurons

Wilson-Gerwing

Dmyterko²,

Zochodne³

et al. 2005

J. Neurosci.

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Neurotrophin-3 (NT-3) negatively modulates nerve growth factor (NGF) receptor expression and associated nociceptive phenotype in intact neurons, suggesting a beneficial role in treating aspects of neuropathic pain mediated by NGF. We report that NT-3 is effective at suppressing thermal hyperalgesia associated with chronic constriction injury (CCI); however, NT-3 does not alter the mechanical hypersensitivity that also develops with CCI. Thermal hyperalgesia is critically linked to expression and activation of the capsaicin receptor, transient receptor potential vanilloid receptor-1 (TRPV1). Thus, its modulation by NT-3 after CCI was examined. CCI results in elevated TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons, with the percentage of neurons expressing TRPV1 remaining unchanged at ϳ56%. Attenuation of thermal hyperalgesia mediated by NT-3 correlates with decreased TRPV1 expression such that only ϳ26% of neurons ipsilateral to CCI expressed detectable TRPV1 mRNA. NT-3 effected a decrease in expression of the activated component of the signaling pathway linked to regulation of TRPV1 expression, phospho-p38 MAPK (Ji et al., 2002), in neurons ipsilateral to CCI. Exogenous NT-3 could both prevent the onset of thermal hyperalgesia and reverse established thermal hyperalgesia and elevated TRPV1 expression 1 week after CCI. Continuous infusion is required for suppression of both thermal hyperalgesia and TRPV1 expression, because removal of NT-3 resulted in a prompt reestablishment of the hyperalgesic state and corresponding CCI-associated TRPV1 phenotype. In conclusion, although NGF drives inflammation-associated thermal hyperalgesia via its regulation of TRPV1 expression, NT-3 is now identified as a potent negative modulator of this state.

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“…The NGF-responsive population of lumbar dorsal root ganglion (DRG) neurons includes those with calcitonin gene-related peptide immunoreactivity and substance P immunoreactivity but not those with somatostatin immunoreactivity (Verge et al, 1989b). Little is known about genetic and developmental influences that determine which 40% of sensory neurons in the adult animal come to have functional high-affinity NGF receptors.…”

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Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF

et al. 1992

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The distributions of mRNAs for the protooncogene trk and the low- affinity NGF receptor (LNGFR) were studied by hybridization with oligonucleotide probes on sections of adult rat primary sensory and sympathetic ganglia. For comparison with high-affinity binding sites, adjacent sections were processed for NGF receptor radioautography. Among neurons in lumbar dorsal root ganglia and trigeminal ganglia, trk mRNA and NGF-binding sites were closely colocalized; this finding together with previous direct evidence in other cell types is taken to indicate that trk protein is an essential component of the high- affinity NGF receptor in adult sensory neurons. In lumbar dorsal root ganglia and trigeminal ganglia, abundant LNGFR mRNA was found in all neurons with strong 125I-NGF labeling and on additional neurons lacking high-affinity NGF-binding sites. The presence of abundant LNGFR in neurons with high-affinity receptors could be the cause and/or consequence of their ability to respond to NGF. Neurons with abundant LNGFR mRNA but few high-affinity NGF-binding sites may have receptors for other members of the neurotrophin family. In nodose ganglia, neurons with high concentrations of LNGFR mRNA greatly outnumbered the small percentage with abundant trk mRNA. Following intrathecal infusion of NGF to otherwise normal dorsal root ganglia, the concentrations of LNGFR mRNA but not those of trk mRNA and NGF-binding sites were increased in NGF-responsive neurons. The usual single normal pattern of frequency histograms of LNGFR labeling indices became bimodal in response to NGF. Concentrations of NGF-binding sites, LNGFR mRNA, and trk mRNA were all decreased by peripheral nerve transection and restored by exogenous NGF, the restoration being complete for LNGFR mRNA and partial for trk mRNA and NGF-binding sites. The data indicate that NGF can regulate both LNGFR and trk mRNAs but do not clarify the possible contribution of the LNGFR protein to high-affinity binding sites.

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Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor

Cited by 161 publications

References 43 publications

Nerve growth factor-induced hyperexcitability of rat sensory neuron in culture

Nerve growth factor-induced hyperexcitability of rat sensory neuron in culture

Neurotrophin-3 Suppresses Thermal Hyperalgesia Associated with Neuropathic Pain and Attenuates Transient Receptor Potential Vanilloid Receptor-1 Expression in Adult Sensory Neurons

Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF

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