Peripheral Nerve Growth Factor Research Articles

Role of tear size and tendon degeneration for development of pain in rat models of rotator cuff tear

BackgroundRotator cuff tear (RCT) is a frequent etiology of shoulder pain and disability; however, the triggers for the onset and aggravation of pain remain obscure. In this study, we established novel rat RCT models to examine the impact of tear size and tendon degeneration on pain. MethodsFifty-five adult male Sprague-Dawley rats were allocated into 4 study groups: large tear (L group, n=10); small tear (S group, n=15); small tear with scratching (S+ group n=15); sham surgery (sham group, n=15). Pain-related behaviors were evaluated by weight distribution of forelimbs during a 5-minute free gait using a dynamic weight-bearing apparatus at 2, 4, 6 and 8 weeks. Calcitonin gene-related peptide (CGRP) expressions in ipsilateral dorsal root ganglion (DRG) neurons of C4/5/6 were evaluated at 4 and 8 weeks. The area of scar tissues around the torn tendon, infiltration of inflammatory cells, and severity of tendon degeneration (modified Bonar score) were histologically assessed at 4 and 8 weeks. Additionally, enzyme-linked immunosorbent assay (ELISA) was conducted to evaluate the levels of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) expression in torn tendons and surrounding tissues at 4 weeks. ResultsThe weight distribution ratio (ipsilateral /contralateral side) was significantly decreased in the L and S+ group compared with its baseline and sham group (P<0.05), but the S group showed no significant difference compared with the Sham. The ratio of CGRP-immunoreactive neurons in the DRGs was significantly higher in the L and S+ groups than in the S and sham groups. The histological assessment indicated that scar tissue formation was more extensive in the L group than in the S and S+ groups. Still, there was no significant difference between the S and S+ groups. The Modified Bonar Score was considerably higher in the S+ group than in the S group. Furthermore, ELISA analysis demonstrated no significant disparity in COX-2 levels between the groups; however, NGF levels were substantially higher in the S+ group than in the S and sham groups. ConclusionThe present study provides compelling evidence that large RCT is strongly associated with heightened pain severity in a rat mode. Nevertheless, even a small tear can significantly aggravate pain when the torn tendon is degenerated. CGRP upregulation driven by peripheral NGF possibly played a pivotal role in the genesis and exacerbation of pain in small RCT.

Neuroprotective factors in schizophrenia: BDNF, NGF, NT3, GDNF and their connection to the pathogenesis of schizophrenia. A narrative review

Introduction: There are several hypotheses of schizophrenia pathogenesis, including the neurodegenerative theory, which is supported by evidence for the decrease of neuroprotective factors’ serum levels. The proteins, that exert a protective effect on neurons and are researched concerning schizophrenia pathogenesis, include the brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and glial cell line-derived neurotrophic factor (GDNF). This review aims to discuss the role of neuroprotective factors in the development of schizophrenia and their relevance in clinical trials. Material and methods: This review was performed by search of the PubMed, Google Scholar, and Science Direct databases from December 25th, 2022, through January 31st, 2023, using keywords: ‘schizophrenia’, ‘schizophrenia pathogenesis’, ‘neuroprotection’, ‘neurodegeneration’, ‘BDNF’, ‘NGF’, ‘NT3’, and ‘GDNF’. We considered original research papers and systematic reviews published in English or Polish. Additionally, clinical trials, which included the assessment of neuroprotective factors’ levels in schizophrenia as outcome measures, were searched for on clinicaltrials.gov. Results: Lower levels of serum BDNF have been linked to cognitive impairment in schizophrenia. In clinical trials, the assessment of serum BDNF is used as a clinical outcome measure for novel schizophrenia therapies. Schizophrenia has also been associated with reduced peripheral NGF levels. During remission, lower NGF levels correlate with higher severity of negative symptoms. Decreased NT3 and GDNF levels can also be seen, but literature reports are inconsistent. Conclusions: Neuroprotective factors are most likely related to the pathogenesis of schizophrenia. Assessing the serum level of these proteins may prove to be an invaluable element of schizophrenia management. Keywords: schizophrenia, brain-derived neurotrophic factor, nerve growth factor,neurotrophin 3, glial cell line-derived neurotrophic factor

Nerve growth factor serum levels in treatment-resistant schizophrenic patients following electroconvulsive therapy.

Electroconvulsive Therapy (ECT) has been widely applied to treat schizophrenia (SCZ) in the presence of resistance to pharmacotherapy. The mechanism of action of ECT in schizophrenia has not been fully clarified, though its intrinsic mechanism presents analogies with some neurobiological processes mediated by nerve growth factor (NGF). The aim of this study was to investigate in patients with treatment-resistant schizophrenia (TRS) the effect of ECT on acute and long-term NGF serum levels and the association with the clinical outcomes. Twelve male inpatients with TRS underwent eight sessions of ECT. Blood samples were collected during the first and the eighth ECT at the following time points: 5 minutes before the induction of seizure and then at 0, 5, 15 and 30 minutes after seizure. Following ECT treatment, a substantial clinical improvement in symptom severity was indicated by a significant reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscales scores. Even though the baseline NGF levels showed an increase over time, there were no statistical differences in NGF at time 0 at the first and the eighth ECT session. Furthermore, no correlation was observed between the severity of schizophrenic symptoms and NGF levels. This is the first study addressing peripheral NGF during ECT treatment in TRS, as well as the first study in which NGF has been evaluated in different ECT sessions at various time points. These findings may potentiate the knowledge about the neurotrophic effects of ECT and the role of NGF in synaptic plasticity related to possible mechanisms of schizophrenia treatment.

Transcranial direct current stimulation did not revert the increased central and peripheral NGF levels induced by neuropathic pain in rats

ABSTRACT BACKGROUND AND OBJECTIVES: The expression of nerve growth factor (NGF) in the large-size neurons may represent a key role in the neuronal synaptic plasticity and re-organization of neuronal function after a nerve injury. Transcranial direct current stimulation (tDCS) is a non-invasive method of cerebral stimulation and represents a promising tool to pain management since it promotes neuroplasticity in the central system, and it can be combined with other interventions. The aim was to investigate the effects of tDCS in the NGF levels in central and peripheral nervous system structures of rats submitted to a neuropathic pain (NP) model. METHODS: The chronic constriction injury (CCI) of sciatic nerve was used for the induction of NP. For sham surgery, the sciatic nerve was exposed, but without any ligation. The control group did not undergo surgical procedure. After the establishment of NP, treated groups were subjected to tDCS treatment 0.5 mA/20min/day/8 days. NGF levels in cerebral cortex, spinal cord and sciatic nerve were determined by sandwich-ELISA at 48 hours and 7 days after the end of treatment. RESULTS: The CCI model increased NGF levels in all three structures analyzed at long-lasting time, evidencing the importance of this neurotrophin in neuropathic pain condition. On the other hand, there was no tDCS effect in the central and peripheral NGF levels discarding the participation of this neurotrophin in the analgesic tDCS effect. CONCLUSION: tDCS modulation effects of nociceptive pathways seem not to be linked to the NGF signaling in this chronic pain model.

The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V.

Nerve growth factor (NGF) is a key mediator of nociception, acting during the development and differentiation of dorsal root ganglion (DRG) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF also has central actions in the brain, where it regulates the phenotypic maintenance of cholinergic neurons. The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), caused by the 661C>T transition in the Ngf gene, resulting in the R100W missense mutation in mature NGF. Homozygous HSAN V patients present with congenital pain insensitivity, but are cognitively normal. This led us to hypothesize that the R100W mutation may differentially affect the central and peripheral actions of NGF. To test this hypothesis and provide a mechanistic basis to the HSAN V phenotype, we generated transgenic mice harboring the human 661C>T mutation in the Ngf gene and studied both males and females. We demonstrate that heterozygous NGFR100W/wt mice display impaired nociception. DRG neurons of NGFR100W/wt mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGFR100W protein has reduced capability to activate pain-specific signaling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGFR100W/wt mice, unlike heterozygous mNGF+/- mice, show no learning or memory deficits, despite a reduction in secretion and brain levels of NGF. The results exclude haploinsufficiency of NGF as a mechanistic cause for heterozygous HSAN V mice and demonstrate a specific effect of the R100W mutation on nociception.SIGNIFICANCE STATEMENT The R100W mutation in nerve growth factor (NGF) causes Hereditary Sensory and Autonomic Neuropathy type V, a rare disease characterized by impaired nociception, even in apparently clinically silent heterozygotes. For the first time, we generated and characterized heterozygous knock-in mice carrying the human R100W-mutated allele (NGFR100W/wt). Mutant mice have normal nociceptor populations, which, however, display decreased activation of pain transduction pathways. NGFR100W interferes with peripheral and central NGF bioavailability, but this does not impact on CNS function, as demonstrated by normal learning and memory, in contrast with heterozygous NGF knock-out mice. Thus, a point mutation allows neurotrophic and pronociceptive functions of NGF to be split, with interesting implications for the treatment of chronic pain.

Systemic L-Buthionine -S-R-Sulfoximine Treatment Increases Plasma NGF and Upregulates L-cys/L-cys2 Transporter and γ-Glutamylcysteine Ligase mRNAs Through the NGF/TrkA/Akt/Nrf2 Pathway in the Striatum.

Glutathione (GSH) is the most abundant intracellular antioxidant. GSH depletion leads to oxidative stress and neuronal damage in the central nervous system (CNS). In mice, the acute systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO) triggers a protective response and a subsequent increase in the CNS GSH content. This response might be modulated by a peripheral increment of circulating nerve growth factor (NGF). NGF is an important activator of antioxidant pathways mediated by tropomyosin-related kinase receptor A (TrkA). Here, we report that peripheral administration of BSO increased plasma NGF levels. Additionally, BSO increased NGF levels and activated the NGF/TrkA/Akt pathway in striatal neurons. Moreover, the response in the striatum included an increased transcription of nrf2, gclm, lat1, eaac1, and xct, all of which are involved in antioxidant responses, and L-cys/L-cys2 and glutamate transporters. Using antibody against NGF confirmed that peripheral NGF activated the NGF/TrkA/Akt/Nrf2 pathway in the striatum and subsequently increased the transcription of gclm, nrf2, lat1, eaac1, and xct. These results provide evidence that the reduction of peripheral GSH pools increases peripheral NGF circulation that orchestrates a neuroprotective response in the CNS, at least in the striatum, through the NGF/TrkA/Akt/Nrf2 pathway.

Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice.Chronic neuropathic mechanical and cold hyperalgesia after partial sciatic nerve ligation (PSL) were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate.Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any changes. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of wildtype, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion.We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research.

A meta-analysis of peripheral blood nerve growth factor levels in patients with schizophrenia.

Neurotrophins particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are crucial modulators in the neurodevelopment and maintenance of central and peripheral nervous systems. Neurotrophin hypothesis of schizophrenia (SCZ) postulated that the changes in the brains of SCZ patients are the result of disturbances of developing processes involving neurotrophic factors. This hypothesis was mainly supported by the abnormal regulation of BDNF in SCZ, especially the decreased peripheral blood BDNF levels in SCZ patients validated by several meta-analyses. However, the regulation of NGF in SCZ remains unclear because of the inconsistent findings from the clinical studies. Therefore, we undertook, to the best of our knowledge, the first systematic review with a meta-analysis to quantitatively summarize the peripheral blood NGF data in SCZ patients compared with healthy control (HC) subjects. A systematic search of Pubmed, PsycINFO and Web of Science identified 13 articles encompassing a sample of 1693 individuals for the meta-analysis. Random-effects meta-analysis showed that patients with SCZ had significantly decreased peripheral blood levels of NGF when compared with the HC subjects (Hedges's g=-0.633, 95% confidence interval (CI)=-0.948 to -0.318, P<0.001). Subgroup analyses revealed reduced NGF levels both in serum (Hedges's g=-0.671, 95% CI=-1.259 to -0.084, P=0.025) and plasma (Hedges's g=-0.621, 95% CI=-0.980 to -0.261, P<0.001) of the patients, and in drug-free (Hedges's g=-0.670, 95% CI=-1.118 to -0.222, P=0.003) and medicated (Hedges's g=-0.357, 95% CI=-0.592 to -0.123, P=0.003) patients with SCZ. Furthermore, meta-regression analyses showed that age, gender and sample size had no moderating effects on the outcome of the meta-analysis, whereas disease severity might be a confounding factor for the meta-analysis. These results demonstrated that patients with SCZ are accompanied by the decreased peripheral blood NGF levels, strengthening the clinical evidence of an abnormal neurotrophin profile in the patients with SCZ.

Peripheral blood nerve growth factor levels in major psychiatric disorders

Nerve growth factor (NGF) plays crucial roles in promoting neural growth and survival, and mediating synaptic and morphological plasticity. Several studies investigated the correlation between peripheral NGF levels and major psychiatric disorders, including schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BPD); however, the findings were inconsistent. This meta-analysis sought to investigate blood NGF levels in patients with psychiatric disorders compared with healthy subjects and examined potential effects of blood fraction, medication and disease status. A total of 21 eligible studies, encompassing 1342 patients suffering from psychiatric disorders and 1225 healthy subjects, were enrolled in the present meta-analysis. No obvious publication bias was observed either for SCZ, MDD or BPD by the Begg's test (P > 0.05). Random-effects meta-analysis showed that SCZ (Z = 2.14, P = 0.033, SMD = −1.08, 95% CI = −2.07 to −0.09) and MDD (Z = 2.57, P = 0.010, SMD = −0.61, 95% CI = −1.08 to −0.14) patients had significantly reduced NGF levels, compared with healthy controls. Notably, this decrease was enhanced in un-medicated patients of SCZ (P = 0.004) and medicated or chronic patients of MDD (P < 0.001). No significant difference of NGF levels was observed between BPD patients and controls (P > 0.05). These results supported an association between the reduction of NGF levels and psychiatric disorders. It remains unclear whether the change of NGF levels is a prerequisite for its function in psychiatric disorders development or merely an epiphenomenon unrelated to the pathophysiologic mechanisms.

Significantly lower nerve growth factor levels in patients with major depressive disorder than in healthy subjects: a meta-analysis and systematic review.

IntroductionSince its discovery several decades ago, nerve growth factor (NGF) has been found to play roles in different areas, such as neurology, endocrinology, and immunology. There is some evidence linking NGF and psychiatry, including the role of NGF in subjects’ response to stress, the alteration of NGF in different emotional states, and the penetration of NGF across the blood–brain barrier under specific conditions. There are many inconsistent findings regarding the differences in NGF in patients with major depressive disorder (MDD) at the present time. The aim of our study was to clarify whether NGF levels are different in MDD compared with healthy controls (HCs).MethodsWe conducted a thorough literature search and compared peripheral NGF levels between MDD and HC through meta-analysis, and investigated possible confounding variables through meta-regression.ResultsSeven studies were brought into the current meta-analysis comparing peripheral NGF in MDD and HCs. The main result was that the NGF levels were significantly lower in MDD than in HCs and that this had an inverse correlation with mean age and disease severity. In addition, meta-analysis of four articles found that the peripheral NGF levels did not change significantly before and after treatment.ConclusionOur study highlights the significant differences in peripheral NGF levels in patients with MDD. However, further exploration of the dynamic changes in peripheral NGF along with the disease course, and specific studies investigating the correlation of NGF in the peripheral and CNS environments are still needed.

The p75NTR signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw

Nerve growth factor (NGF) augments the excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75NTR) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical protein-kinase C (aPKC), protein-kinase M zeta (PKMζ), are key mediators. Here we examined these same receptor-pathways in vivo for their role in mechanical hyperalgesia from exogenous NGF. Mechanical sensitivity was tested by the number of paw withdrawals in response to 10 stimuli (PWF=n/10) by a 4-g von Frey hair (VFH, testing “allodynia”) and by 10 and 15g VFHs (testing “hyperalgesia”). NGF (500ng/10μL) injected into the male rat’s plantar hind paw induced long-lasting ipsilateral mechanical hypersensitivity. Mechano-hypersensitivity, relative to baseline responses and to those of the contralateral paw, developed by 0.5–1.5h and remained elevated at least for 21–24h, Acute intraplantar pre-treatment with nSMase inhibitors, glutathione (GSH) or GW4869, prevented the acute hyperalgesia from NGF (at 1.5h) but not that at 24h. A single injection of N-acetyl sphingosine (C2-ceramide), simulating the ceramide produced by nSMase activity, induced ipsilateral allodynia that persisted for 24h, and transient hyperalgesia that resolved by 2h. Intraplantar injection of hydrolysis-resistant mPro-NGF, selective for the p75NTR over the tyrosine kinase (TrkA) receptor, gave very similar results to NGF and was susceptible to the same inhibitors. Hyperalgesia from both NGF and mPro-NGF was prevented by paw pre-injection with blocking antibodies to rat p75NTR receptor. Finally, intraplantar (1day before NGF) injection of mPSI, the myristolated pseudosubstrate inhibitor of PKCζ/PKMζ, decreased the hyperalgesia resulting from NGF or C2-ceramide, although scrambled mPSI was ineffective. The findings indicate that mechano-hypersensitivity from peripheral NGF involves the sphingomyelin signaling cascade activated via p75NTR, and that a peripheral aPKC is essential for this sensitization.

Peripheral contribution of NGF and ASIC1a to colonic hypersensitivity in a rat model of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with idiopathic colonic hypersensitivity (CHS). However, recent studies suggest that low-grade inflammation could underlie CHS in IBS. The pro-inflammatory mediator nerve growth factor (NGF) plays a key role in the sensitization of peripheral pain pathways and several studies have reported its contribution to visceral pain development. NGF modulates the expression of Acid-Sensing Ion Channels (ASICs), which are proton sensors involved in sensory neurons sensitization. This study examined the peripheral contribution of NGF and ASICs to IBS-like CHS induced by butyrate enemas in the rat colon. Colorectal distension and immunohistochemical staining of sensory neurons were used to evaluate NGF and ASICs contribution to the development of butyrate-induced CHS. Systemic injection of anti-NGF antibodies or the ASICs inhibitor amiloride prevented the development of butyrate-induced CHS. A significant increase in NGF and ASIC1a protein expression levels was observed in sensory neurons of rats displaying butyrate-induced CHS. This increase was specific of small- and medium-diameter L1+S1 sensory neurons, where ASIC1a was co-expressed with NGF or trkA in CGRP-immunoreactive somas. ASIC1a was also overexpressed in retrogradely labeled colon sensory neurons. Interestingly, anti-NGF antibody administration prevented ASIC1a overexpression in sensory neurons of butyrate-treated rats. Our data suggest that peripheral NGF and ASIC1a concomitantly contribute to the development of butyrate-induced CHS NGF-ASIC1a interplay may have a pivotal role in the sensitization of colonic sensory neurons and as such, could be considered as a potential new therapeutic target for IBS treatment.

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

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.

Possible Role of Nerve Growth Factor in the Pathogenesis of Alcohol Dependence

Recent studies have raised the possibility that nerve growth factor (NGF) is abnormally regulated in the central nervous system (CNS) of animal models of chronic ethanol treatment. The goals of this study were to determine whether prolonged alcohol consumption is associated with the plasma NGF levels and to assess the effect of a positive family history of alcohol dependence on plasma NGF levels in the alcohol-dependent patients. We used the enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of peripheral NGF in patients with alcohol dependence and in a control group. The plasma NGF concentrations in the alcohol-dependent patients were significantly lower than in the controls (71.9 vs 110.5 pg/mL, respectively). Moreover, the alcohol-dependent patients with positive family histories showed a greater decrease in their NGF levels than those subjects with negative family histories (64.7 vs 83.3 pg/mL, respectively). Our study suggests that the NGF levels may be a trait marker for the development of alcohol dependence.

Adrenergic innervation of rat sensory ganglia following proximal or distal painful sciatic neuropathy: distinct mechanisms revealed by anti-NGF treatment.

Sympathetic axons invade dorsal root ganglia (DRG) following nerve injury, and activity in the resulting pericellular axonal 'baskets' may underlie painful sympathetic-sensory coupling. Sympathetic sprouting into the DRG may be stimulated by nerve growth factor (NGF). To test this hypothesis, we investigated the effect of daily anti-NGF administration on pain and on sprouting in the DRG induced by chronic sciatic constriction injury (CCI) or L5 spinal nerve ligation (SNL). These models have been shown to differ subtly in the onset of pain behaviours and adrenergic sprouting, and we now demonstrate a fundamental difference in the way sympathetic axons invade the DRG: after CCI, perivascular noradrenergic collaterals sprouted into the DRG in a manner dependent upon peripherally derived NGF. In contrast, after SNL, regenerating sympathetic axons were diverted towards the DRG from the spinal nerve by the obstructing ligature, and this effect was only moderately impeded by anti-NGF. The differential dependence on anti-NGF suggests that adrenergic innervation of the DRG after SNL and CCI may reflect regenerative and collateral sprouting, respectively. Pain behaviour was similarly affected: anti-NGF completely prevented CCI-induced thermal hyperalgesia and mechanoallodynia, but the same treatment only partly relieved these symptoms following SNL. These differences emphasize that although CCI and SNL may result in similar behavioural abnormalities, the underlying mechanisms may be governed by distinct processes, differentially dependent on peripheral NGF. These mechanistic differences will have to be considered in the development of appropriate treatment strategies for neuropathic pain produced by different types of pathology.

Axonal Transport of Endogenous Nerve Growth Factor (NGF) and NGF Receptor in Experimental Diabetic Neuropathy

There is increasing evidence that deprivation of the retrogradely transported neurotrophic protein nerve growth factor (NGF) accounts for some functional deficits known to occur in experimental diabetic neuropathy. Here we have studied changes in the axonal transport of endogenous NGF, NGF receptor (NGFR), and NGFR saturation (NGF/NGFR ratio) in the rat sciatic nerve after 2 months of streptozotocin (STZ)-induced diabetes mellitus. Compared with vehicle-treated control rats (blood glucose: 6-12 mM), there was a very clear reduction in the retrograde transport of NGF by 50% (P < 0.001) in STZ-treated, diabetic animals (blood glucose: 33-62 mM). No significant reduction in NGF axonal transport was observed in a subpopulation of STZ-treated rats (poor responders) with nearly normal glucose levels (range: 9-12 mM). No change was observed in any group in the retrograde transport of NGFR. Compared with control rats, however, the apparent NGFR saturation was reduced by 45% (P < 0.002) in STZ diabetics, whereas no change in NGFR saturation was observed in the STZ-poor responders. Moreover, the NGFR saturation and amount of retrogradely transported NGF were negatively correlated to the individual glucose concentration in diabetics (r2 = 0.47 and 0.55, respectively; P < 0.0001). These findings indicate that, while NGFR expression is normal in the STZ-diabetic neuropathy model, the marked decrease in receptor saturation observed in diabetics may reflect low peripheral NGF levels, which in consequence leads to the apparent deprivation of neuronal NGF in diabetic rats.