Growth Factors and Neuropathic Pain

Ossipov, Michael H.

doi:10.1007/s11916-011-0183-5

Cited by 47 publications

(36 citation statements)

References 57 publications

(86 reference statements)

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“…The spontaneous discharges trigger APs, which in turn cause the fluctuation of the cytosolic Ca 2+ in nociceptive neurons as previously reported (16). Since NGF concentration was reported to increase in the DRG after inflammation or nerve injury (24), NGF-induced hyperexcitability of nociceptive neurons may be an underlying mechanism of the chronic pain following to the inflammation or nerve injury. Generally, DRG neurons extend dendrites and axons during culture.…”

Section: Discussionsupporting

confidence: 57%

“…One of the neurotrophic factors, nerve growth factor (NGF), has been reported to induce hyperalgesia in rats (4,19,39). Therefore, trials to use anti-NGF agents to cure neuropathic pains have been made (22,24). In spite of a pronociceptive action of NGF on neuropathic and inflamatory pains, trials to use neurotrophic factors as a therapeutic tool for neuropathic pain have also been made (28).…”

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confidence: 99%

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Chronic NGF treatment induces somatic hyperexcitability in cultured dorsal root ganglion neurons of the rat

et al. 2013

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Adult rat dorsal root ganglion (DRG) neurons cultured in the presence of 100-ng/mL NGF were reported to show spontaneous action potentials in the cell-attached recording. In this study, underlying mechanisms were examined in the whole-cell and outside-out voltage clamp recording. In 75% neurons with on-cell firing, transient inward current spikes were repetitively recorded in the voltage clamp mode at −50 mV in the whole-cell configuration (named "I sp "). I sp with stable amplitudes occurred in an all-or-none fashion, and was abolished by TTX (< 100 nM), lidocaine (< 1 mM) and a reduction of extracellular Na + (154 to 100 mM) in an all-or-none fashion, suggesting that I sp reflects spontaneous dicharges occurring at the loosely voltage-clamped regions. I sp was also observed in the excised outside-out patches and the kinetics and the sensitivity to TTX and lidocaine resembled those in the whole-cell. Spontaneous action potentials were also recorded in the current clamp mode. Small subthreshold spikes often preceded the action potentials. When the localized discharge affected a whole-somatic membrane potential to overcome a threshold, the action potential generated. These results indicate that the triggering sources of the action potential exist in the somatic membrane itself in NGF-treated DRG neurons.Peripheral nerve injury frequently results in neuropathic pain, e.g. hyperalgesia and allodynia. Since neuropathic pain is poorly responsive to general analgesic therapy, it is difficult to improve patients' quality of life. Artificial injury of peripheral nerves in rats induces neuropathic symptoms (5-7, 17, 29, 36, 37). Abnormal spontaneous firing was observed in sensory neurons of some animal model with nerve injury (8,15). Such abnormal firing is considered to cause spontaneous pain. Moreover, neither the pathogenic mechanisms of hyperexcitablity nor mechanisms triggering spontaneous discharges in dorsal root ganglion (DRG) neurons are completely understood. This seems to be a cause why neuropathic pain remains as an unsolved therapeutic problem. One of the neurotrophic factors, nerve growth factor (NGF), has been reported to induce hyperalgesia in rats (4,19,39). Therefore, trials to use anti-NGF agents to cure neuropathic pains have been made (22,24). In spite of a pronociceptive action of NGF on neuropathic and inflamatory pains, trials to use neurotrophic factors as a therapeutic tool for neuropathic pain have also been made (28). The action of NGF in pathogenesis of neuropathic pains is complicated: it is not restricted to the peripheral tissues, and NGF seems to have effects on the central

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Section: Discussionsupporting

confidence: 57%

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confidence: 99%

Chronic NGF treatment induces somatic hyperexcitability in cultured dorsal root ganglion neurons of the rat

et al. 2013

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“…Delivery of neurotrophic factors has been considered a potential strategy for the treatment of a variety of neurological disorders, including neuropathic pain (33). GFLs exhibited great promise in animal models, but have yet to yield any approved human therapies (34).…”

Section: Discussionmentioning

confidence: 99%

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

Hedstrom

Murtie

Albers

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Small-fiber neuropathy (SFN) is a disorder of peripheral nerves commonly found in patients with diabetes mellitus, HIV infection, and those receiving chemotherapy. The complexity of disease etiology has led to a scarcity of effective treatments. Using two models of progressive SFN, we show that overexpression of glial cell line-derived neurotrophic factor (GDNF) in skin keratinocytes or topical application of XIB4035, a reported nonpeptidyl agonist of GDNF receptor α1 (GFRα1), are effective treatments for SFN. We also demonstrate that XIB4035 is not a GFRα1 agonist, but rather it enhances GFRα family receptor signaling in conjunction with ligand stimulation. Taken together, our results indicate that topical application of GFRα/RET receptor signaling modulators may be a unique therapy for SFN, and we have identified XIB4035 as a candidate therapeutic agent.topical drug | pain | thermonociception | sensory | trophic factor S mall-fiber neuropathy (SFN), i.e., damage or dysfunction of small-diameter axons (C fibers) in peripheral nerves, is a prevalent neurological disorder that afflicts an estimated 1.5% of the world's population and millions of people in the United States (1-3). SFN is associated with diabetes, HIV infection, and chemotherapy treatment, but many patients suffer from idiopathic SFN (3-5). SFN patients can exhibit a large variety of symptoms, including loss of sensation and chronic pain. Despite the pervasiveness of SFN, its etiology is poorly understood, resulting in a lack of disease-modifying treatments.Initial stages of SFN commonly involve nerve terminal degeneration before sensory neuron death (6), and reduction in targetderived trophic factor expression has been observed in multiple models of peripheral neuropathy (7,8). Therefore, replenishing or replacing neurotrophic factors promptly after disease onset could potentially be used as a treatment to promote the survival and restore the function of C-fiber neurons (9, 10). One group of trophic factors necessary for development and survival of C fibers is the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (10, 11). Each family member interacts selectively with a different high affinity receptor: GDNF with GDNF receptor α1 (GFRα1), neurturin (NRTN) with GFRα2, artemin (ARTN) with GFRα3, and persephin (PSPN) with GFRα4, although GDNF and NRTN have the capacity to bind and activate GFRα2 and GFRα1, respectively (12). Each ligand/receptor pair forms a complex with the RET receptor tyrosine kinase, resulting in downstream effects that include tyrosine hydroxylase (TH) gene transcription (13,14). GFLs not only play a pivotal role in sensory neuron development, but also appear to be beneficial in the context of peripheral nerve injury. For example, systemic, transgenic, or viral delivery of GFLs has been shown to attenuate neuropathic symptoms in mouse models of nerve injury (15-19). Thus, we hypothesized that topical delivery of GDNF receptor agonists to the skin would be an effective, noninvasive therapeutic approach for t...

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“…Hence, providing a favorable milieu for the injured and adjacent uninjured nerve fibers may ease neuropathic pain. About providing a protective microenvironment, neurotrophic factors are known to induce neuroprotection by maintaining functional integrity, promoting regeneration, regulating neuronal plasticity, and repairing the damaged nerves (20). Furthermore, recent studies have demonstrated that the activation of immune system also contributes to peripheral neuropathic pain pathology (21).…”

Section: Peripheral Nerve Injury-induced Neuropathic Painmentioning

confidence: 99%

Stem Cells for the Treatment of Neuropathic Pain

Xie¹,

Yue²,

Guan³

et al. 2017

J Anesth Perioper Med

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Aim of review:Neuropathic pain induced by injury to the somatosensory system is a great clinical problem. Despite multiple therapeutic strategies, the medical community still faces a challenge to treat neuropathic pain in a complete and definitive way, since the pathogenesis of this hypersensitive state is very complex. Stem cell transplantation may be an important approach for the treatment of neuropathic pain. This article aimed to review important and illustrative results from recent stem cell studies under various neuropathic pain conditions and to interpret their clinical implications for stem cell transplantation. Methods: We reviewed recent articles and literatures about stem cells for the treatment of neuropathic pain, in order to identify the types of stem cells, delivery approaches and the advances of stem cells for the treatment of peripheral nerve injury induced neuropathic pain, painful diabetic peripheral neuropathy and spinal cord injury (SCI) induced chronic pain. Recent findings: Recently, the successful use of stem cell for the treatment of a diverse spectrum of diseases in animals has attracted more attentions from pain scientists. Accumulating evidence has shown that stem cell transplantation has a therapeutic effect on neuropathic pain. Stem cell transplantation can effectively relieve neuropathic pain under different pathological conditions. However, it is interesting to point out that peripheral neuropathic pain seems to be more responsive to stem cell therapy than SCI-induced chronic pain. Moreover, stem cell treatment does not always exert positive results in SCI-induced chronic pain (e.g. aggravating pain above the lesion spinal cord segment). Conclusion:The analgesic effect of stem cells depends on the capacity to offer a multipotent cellular source for replacing injured neural cells and delivering trophic factors to lesion sites. Stem cell researches should focus on both experimental and clinical studies of

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Growth Factors and Neuropathic Pain

Cited by 47 publications

References 57 publications

Chronic NGF treatment induces somatic hyperexcitability in cultured dorsal root ganglion neurons of the rat

Chronic NGF treatment induces somatic hyperexcitability in cultured dorsal root ganglion neurons of the rat

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

Stem Cells for the Treatment of Neuropathic Pain

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