Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: Evidence for a regulatory function of nerve growth factor in vivo

Donnerer, Josef; Schuligoi, Rufina; Amann, Rainer; Stein, Christoph

doi:10.1016/0143-4179(92)90384-9

Cited by 123 publications

(167 citation statements)

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“…Furthermore, NGF has been shown to be an important mediator of hyperalgesia in inflammatory pain states. NGF levels in the skin increase after an inflammatory insult (Weskamp and Otten, 1987;Donnerer et al, 1992;Woolf et al, 1994), and administration of either an anti-NGF antiserum or a TrkA-IgG fusion protein prevents the development of inflammatory hyperalgesia and nociceptor activation without changing the amount of tissue inflammation (Donnerer et al, 1992;Woolf et al, 1994;McMahon et al, 1995;Koltzenburg et al, 1999).The present results support a pronociceptive role for NGF in primary sensory neurons by demonstrating its ability to attenuate opioid-mediated inhibition of VGCC in sensory neurons. Sites where this regulation of opioid action may occur include both the peripheral and central terminals of the nociceptive neuron.…”

supporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

“…A large number of nociceptive neurons remain sensitive to NGF postnatally, and in adult animals NGF plays a role in both physiological and pathological pain conditions. In the resting state, low levels of NGF are needed for the expression of nociceptor markers such as the neuropeptides substance P and calcitonin-gene-related peptide (CGRP; Molliver and Snider, 1997;Patel et al, 2000), and for nociceptive afferents to retain their ability to respond to noxious stimuli (Ritter et al, 1991;Lewin and Mendell, 1994;McMahon et al, 1995;Bennett et al, 1998 (Donnerer et al, 1992;Woolf et al, 1994;McMahon et al, 1995;Koltzenburg et al, 1999).…”

Section: Abstract Neurotrophins; Drg Neurons; G Proteins; Patch Clampmentioning

confidence: 99%

“…sensitization and hyperalgesia (Donnerer et al, 1992;Woolf et al, 1994;McMahon et al, 1995;Koltzenburg et al, 1999).…”

mentioning

confidence: 99%

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Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

McDowell

2004

Neuroscience

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Nerve growth factor (NGF) promotes the survival of embryonic sensory neurons and maintains the phenotypic characteristics of primary nociceptive neurons postnatally. NGF also contributes to nociceptor activation and hyperalgesia during inflammatory pain states. The purpose of this study was to determine whether NGF might have an additional pronociceptive action by interfering with opioid-mediated analgesia in primary nociceptive neurons. Sensory neurons were isolated from the dorsal root ganglia of weanling rats and kept in standard culture conditions either with or without exogenous NGF (50 ng/ml). Currents through voltage-gated calcium channels were recorded from individual neurons using the whole cell patch clamp technique with Ba 2+ as the charge carrier (I Ba ). The μ-opioid agonist fentanyl (1 μM) and the GABA B agonist baclofen (50 μM) were used to test G protein-dependent inhibition of I Ba . Fentanyl inhibited I Ba by an average of 38±4% in untreated cells vs. 25±2% in NGF-treated cells (P<0.01). NGF had no effect on I Ba current magnitude or kinetics. The NGF-induced attenuation of opioid action was observed as early as 4 h after exposure, but was not seen when NGF was applied by bath perfusion for up to 40 min, suggesting that the effect was not mediated by a rapid phosphorylation event. The effect of NGF was prevented by K-252a (100 nM), an inhibitor of TrkA autophosphorylation. Baclofen-induced inhibition of I Ba , on the other hand, was not affected by NGF treatment, suggesting that NGF modulation of opioid-mediated inhibition occurred upstream from the G protein. This was supported by the finding that GTP-γ-S, an agonist independent G protein activator, inhibited I Ba similarly in both untreated and NGF treated cells. The results show that NGF selectively attenuated opioid-mediated inhibition of I Ba via TrkA receptor activation, possibly by altering opioid receptor function. Keywords neurotrophins; DRG neurons; G proteins; patch clampNerve growth factor (NGF) is a neurotrophin required for the survival of most primary nociceptive neurons during embryonic development. A large number of nociceptive neurons remain sensitive to NGF postnatally, and in adult animals NGF plays a role in both physiological and pathological pain conditions. In the resting state, low levels of NGF are needed for the expression of nociceptor markers such as the neuropeptides substance P and calcitonin-gene-related peptide (CGRP; Molliver and Snider, 1997;Patel et al., 2000), and for nociceptive afferents to retain their ability to respond to noxious stimuli (Ritter et al., 1991;Lewin and Mendell, 1994;McMahon et al., 1995;Bennett et al., 1998 (Donnerer et al., 1992;Woolf et al., 1994;McMahon et al., 1995;Koltzenburg et al., 1999).NGF may sensitize nociceptors in several ways. NGF has been shown to upregulate the TRPV1 channel, one of the molecular transducers of noxious heat which is also activated by capsaicin, and to increase capsaicin-induced currents in nociceptors (Nicholas et al., 1999;Shu and Mendell, 2001;J...

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supporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Abstract Neurotrophins; Drg Neurons; G Proteins; Patch Clampmentioning

confidence: 99%

“…sensitization and hyperalgesia (Donnerer et al, 1992;Woolf et al, 1994;McMahon et al, 1995;Koltzenburg et al, 1999).…”

mentioning

confidence: 99%

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Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

McDowell

2004

Neuroscience

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“…The basis for the hyperalgesic action of NGF appears to include an up-regulation of peptide neurotransmitters expressed by nociceptors, such as calcitonin gene-related peptide (CGRP) and substance P. Both are clearly regulated by the availability of NGF and contained in a subset of NGF-responsive DRG neurons expressing NGF-specific receptors [18]. Also, NGF applied to peripheral targets increases the excitability of spinal cord neurons to activation of the treated afferents.…”

Section: Introductionmentioning

confidence: 99%

Presence of NGF and its receptor TrkA in degenerative lumbar facet joint specimens

Surace¹,

Prestamburgo²,

Campagnolo³

et al. 2009

Eur Spine J

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In a preliminary study, the recurrent presence of nervous terminations was demonstrated with optical microscopy in several slides of degenerative lumbar facet joints and surrounding soft tissues. The purpose of this study was to prove the presence of NGF (nerve growth factor) and its receptor TrkA (tyrosine kinase receptor) with immunofluorescence. The peri/articular tissues were harvested from the lumbar facet joints of ten patients surgically treated for degenerative diseases. There were seven females (one bilateral) and two males whose mean age at surgery was 72 years (range, 67-80 years). The affected levels were L3-L4 in two cases and L4-L5 in seven cases (one bilateral). All specimens were fixed in formalin, dehydrated and enclosed in paraffin. From each specimen, four slides were obtained. Two slides were employed for the search of NGF: one was treated with specific antibodies and marked with FITC (fluorescein isothiocyanate conjugated), and the second slide was for control purposes. It was exposed to FITC, but without prior exposure to the specific antibody. The same procedure was repeated to obtain on two more slides, to repeat the search for Trka with specific antibodies. All the slides were finally studied on a fluoromicroscope. The analysis of these specimens revealed the presence of the neurotrophin (NGF) and its own receptor (TrkA) in all cases: the immunohistochemical reaction between the specimens and the specific antibodies marked with FITC was seen under fluoromicroscopy, but in none of the control cases treated with FITC only. NGF is released by mastocytes, fibroblasts and other cell types involved in the inflammatory processes. The level of peripheral NGF is increased in inflammatory processes, while the administration of exogenous NGF has a hyperalgesic effect on rats and produces muscular pain in humans. Furthermore, NGF produces hypersensitization to heat stimulation in humans and mammals in general. There is considerable evidence showing that the system constituted by the NGF and its high-affinity receptor TrkA plays a fundamental role in the molecular processes underlying the main forms of ''persistent'' pain. This indicates a possible therapeutic area for the antibodies that could block the NGF/ TrkA system, in order to modulate the frequency and the duration of the action potential of nociceptive neurons during chronic inflammation. This study demonstrated the presence of NGF and TrkA in specimens collected from degenerative facet joints, suggesting that specific molecules could be used in order to modulate chronic pain in patients with degenerative lumbar spine.

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Neuropeptides

Schäffer¹,

Beiter²,

Becker³

et al. 1998

Arch Surg

160

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uccessful repair of injured tissues requires diverse interactions between cells, biochemical mediators, and the cellular microenvironment. [1][2][3] Much has been learned about the individual events that are involved in this process, but their integration is clearly far more complex than has been imagined, and the important role of neurogenic stimuli is only recently being recognized.Neurogenic stimuli profoundly affect cellular events that are involved in inflammation, proliferation, and matrix, as well as cytokine and growth factor synthesis. Immune cells regulated by neuropeptides include lymphocyte subsets, macrophages, and mast cells. In addition, neuropeptides may affect the proliferative and synthetic activity of epithelial, vascular, and connective tissue cells. Furthermore, a close interaction between the nervous and the immune systems has become obvious. 4 The peripheral nervous system (PNS), acting through neuropeptides, not only relays sensory information to the central nervous system (CNS) but also plays an effector role in the inflammatory, proliferative, and reparative processes after injury. These effects range from growth factor and cytokine responses to control of local blood flow. Neuropeptides mediate many of the actions important in tissue-nervous system communication.We review the accumulated knowledge about the role of neuropeptides in inflammation as it pertains to tissue repair. NEUROPEPTIDES OF THE PNSNeuropeptides constitute one of the largest families of extracellular messengers, having a long phylogenetic history. They can act as neurotransmitters, hormones, and paracrine factors.

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Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: Evidence for a regulatory function of nerve growth factor in vivo

Cited by 123 publications

References 0 publications

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

Presence of NGF and its receptor TrkA in degenerative lumbar facet joint specimens

Neuropeptides

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