Nerve Growth Factor (NGF)
Neurotrophins

NGF : What a painful, stressing love!!!

F.Scicchitano, E.Valente

INTRODUCTION:

“Love is a mistery”. This old adage has been challenged by modern science once that neurobiology has become able to investigate on the very nature of human bonding. Romantic relationships could be somewhat a double-edged sword in a person’s life. When reciprocated, intense romantic love is accompanied by feelings of overwhelming joy and has been compared to a hypomanic state. In contrast, unreciprocated love can result in a host of negative emotions and destructive behaviours including anger, low self-esteem, obsessionality, feelings of social isolations, depression, stalking, violence, and even suicides or homicides.
From these observations, it clearly emerges that Love could be seen as a neuro-hormonal variation, just like other neuro-cognitive pathologies.
It is already known that many molecular changes take part in the first phases of positive social relationships. Oxytocine , dopamine, serotonine and limbic system are surely “the pleasure” musicians in this orchestra (Ossitocina, l'ormone-neurotrasmettitore del cervello emotivo, 2011). But another molecule, originally described as key regulator of synaptic plasticity and neural survival, may be involved in newborn relationships and human bonds in general: NGF (Nerve Growth Factor).

NGF

NGF (The nerve growth factor: thirty-five years later, 1987) is a 241 aa dimeric protein codified by a gene located on the 1p13.1 chromosome. This gene is a member of the β-NGF family and encodes a secreted protein which homodimerizes and is incorporated into a larger complex. This protein has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and sensory neurons. Mutations in this gene have been associated with Hereditary Sensory and Autonomic Neuropathy, type 5 (HSAN5), and dysregulation of this gene's expression is associated with Allergic Rhinitis (NGF nerve growth factor (beta polypeptide) [ Homo sapiens ], 2013).

NGF works by binding to its high-affinity tyrosine kinase receptor, TrkA, found on the plasma membrane of these target cells. NGF binding causes TrkA receptors to dimerize and the intrinsic tyrosine kinase activity of each receptor then phosphorylates its partner receptor. These phosphorylated tyrosines bind various adapter proteins or phospholipases (PLC), which, in turn, activate three major signaling pathways: the PI3kinase pathway leading to activation of Akt kinase, the ras pathway leading to MAP kinases, and the PLC pathway leading to release of intracellular Ca²⁺ and activation of PKC. The ras and PLC pathways primarily stimulate processes responsible for neuronal differentiation, while the PI3kinase pathway is primarily involved in cell survival.

Main roles of NGF:

• Development, proliferation and differentiation (i.e. sympathetic progenitor into adrenergic neurons) in early formation of CNS;
• Neuronal survival in more physiological circumstances;
• Stimulation of ACTH (indirectly, maybe by stimulating AVP secretion) and glucocorticoids;
• Survival of nociceptive neurons and their sensitisation: pain modulator;
• Modulation of MHC molecules and brain inflammation.

NGF mechanism of action during brain inflammation

Table taken from Targeting NGF-pathway for developing neuroprotective therapies for multiple sclerosis and other neurological diseases, 2011

NGF in love

NGF increases in early-stage of intense romantic love (NGF and romantic love, 2011). Levels of neurotrophins observed in subjects in love were compared with those of two comparison groups, consisting of subjects who were either single or already engaged in a long-lasting relationship. On the basis of PLS (Passionate Love Scale), only subjects whose relationships have begun within the previous 6 months were considered eligible for inclusion in the “early-stage romantic love group”. Results showed that NGF levels were significantly increased in subjects in love [227 (±14) pg/ml] than in the other two groups [long-lasting relationship: 123 (±10) pg/ml and singles: 149 (±12) pg/ml, both with p< 0.001]. Besides, the concentrations of BDNF, NT-3 and NT-4 did not differ among the study groups. Furthermore, NGF levels, assessed 12-24 months later in the subjects who maintained the same relationship (who were no longer in an “altered mental state”), were comparable with those measured in the two comparison groups.
These findings indicate that raised NGF levels could be related to specific emotions typically associated with intense early-stage romantic love, such as emotional dependency and/or euphoria.

-Love or stress?

The hypothesis is that, in subjects in love, NGF levels can be increased in a stress-dependent manner (following stressful events and anxiety-associated behaviour) or arousal, associated with the beginning of a social bond, maybe useful to overcome neophobia.
Namely, in addition to its neurotrophic activity, in vivo experiments have shown that NGF increase circulating levels of ACTH and corticosterone, thus inducing activation of the HPA axis. This effect may be mediated by increasing the release of hypothalamic vasopressin or ADH, a neuropeptide which plays a pivotal role in other well-known vegetative answers (Hypothalamic involvement in the activation of the pituitary-adrenocortical axis by nerve growth factor, 1993).
In humans, highly arousing situations also result in increased blood levels of NGF and its sensitivity to environmental variables endowed by a social nature. This neurotrophic factor, together with BDNF, could be involved in the neurobiological changes underlying physiological and pathological reactions to stress that can result in increased vulnerability to disease in humans, including risk for anxiety disorders, or in the complex pathophysiology associated with mood disorders.

This is a schematic representation of the possible role of NGF and BDNF in stress-induced psychopathology. A sequential activation of NGF (periphery) and BDNF (CNS) takes place following stressful stimuli. NGF, acting through GCs released by the adrenal gland, could lead to a reduction in BDNF levels in CNS limbic structures, leading to a reduced brain plasticity and greater vulnerability for stress-related disorders, including depression. The dotted line suggests the possibility of a direct action of circulating NGF on the pituitary (The NGF saga: From animal models of psychosocial stress to stress-related psychopathology, 2009).

-Love or pain?

Recently, it has become clear that NGF plays an important role in the function of nociceptive afferents. Specifically, TrkA receptors on nociceptive fibers and the up-regulation of NGF during inflammation indicate a potential role for NGF in pain. Its hyperalgesic action has been confirmed by demonstrating that administration of NGF produces thermal and mechanical allodynia.
Pharmacological studies indicate that the most centrally implicated cell in this action is a nonneural cell: the mast cell.

This diagram shows how a skin injury leads to release of cytokines, such as TNF-α and IL-1β, which stimulate keratinocytes and fibroblasts to release NGF. The NGF can cause mast cells to degranulate their products, including 5-HT, histamine, and NGF. This endogenous source of NGF seems to be more potent than exogenous NGF in sensitizing nociceptors. Moreover, a direct effect on nociceptors has been demonstrated: it sensitizes the nociceptors facilitating pain response. (Neurotrophins and hyperalgesia, 1999).
New studies have confirmed a putative sensitisation pathway, which may be the phosphorylation by PKC and CaMK-II of TRPV1 (transient receptor potential cation channel subfamily V member1). (Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor, 2013).

Conclusions

NGF closes the loop among the triad Love, Stress and Pain.
It is experience of everyone of us that love is a wonderful emotion, but we are confident to suppose it's also a combination of stress and pain. In fact, NGF could have an important role in stressing responses to the New or the Different, defining a wider neuroendocrine and cognitive conception of human relationships.

Accordingly to the correlation between NGF and pain, is it possible to say that Love is a distress?

Lots of poets and artists have spent most of their life to describe the "Love-ache" and everyday we experience psychological disorders caused by affections. But we have just underlined that Emotions and Relationships do not implicate only psychological alterations but also physiological changes.

All the intimate psyco-social experiences, like Love, play an important role in the biological and physical machinery of any individual. Anthropologists, psychologists and medical researchers seriously take in account the influence of emotional and social factors.

Unfortunately it's not always the same for clinicians...

(Just for fun a video by the anthropologist Helen Fisher in The Brain in love, 2008)