Association of Nerve Growth Factor and Vascular Endothelial Growth Factor A with Psychometric Measurements of Opiate Dependence: Results of a Pilot Study in Patients Participating in a Structured Diamorphine Maintenance Program

Abstract

Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate-dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application – t1) and in the afternoon (7 h after last application – t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF.

Epigenetic Regulation of the Promotor Region of Vascular Endothelial Growth Factor-A and Nerve Growth Factor in Opioid-Maintained Patients

“…2), but this difference did not reach significance. Here, it might be assumed that diamorphine maintenance treatment may be of such good clinical efficacy that there is not much difference to the healthy control group, and this finding matches our previous results [14]. Siddique et al[36] showed that targeted methylation led to a gene silencing of VEGF-A.…”

“…The aim of this study was to figure out if epigenetic mechanisms could account for altered VEGF- and NGF serum levels in opioid-dependent patients shown in an earlier study [14]. Therefore, we analyzed whether there is a difference in methylation rates of the NGF- and VEGF-promotor in controls compared to patients receiving different forms of opioid maintenance therapy, diamorphine and levomethadone.…”

“…Growing evidence proves a direct link between stress and central VEGF expression levels in rodent brains [41], which were shown to be reduced. In an earlier study, we could demonstrate an association of higher peripheral VEGF-A serum levels with alcohol intoxication and the severity of alcohol dependence in human, hypothetically indicating a counter-regulation mechanism that prevents (neuronal) cell damage due to alcohol intoxication and alcohol withdrawal [14]. Consistently, we found a negative association between VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire (HCQ) measuring the rewarding effects of diamorphine in a recent study [14].…”

“…Lack of NGF is associated with apoptosis of sensory and sympathetic neurons [15]. Clinical evidence shows protective effects of NGF in neurologic diseases like multiple sclerosis [16] as well as many psychiatric diseases like dementia [17], schizophrenia [18], eating disorders, depression [19] and substance use disorders, in particular alcohol [20] and opioid dependence [14]. For example, Wiener et al [21] identified NGF as a possible biomarker of major depressive disorder (MDD), as they found a significant reduction of NGF serum levels in patients affected by MDD compared to that in a healthy control group.…”

“…All in all, stress associated with opioid-dependence might explain significantly increased NGF serum levels in diamorphine-assisted patients compared to those in healthy controls [14]. …”