In the milestone paper ‘Update of the NGF saga’, Montalcini and colleagues reviewed the role of NGF in neurobiology (Journal of the Neurological Sciences 130, 1995: II9-127).
In this paper the further fundaments for the action of PEA were described, and we qoute:
As early as 1971 effects of NGF were being reported on mast celis (Aloe and Levi-Montalcini, 1971), a ceil type belonging to the immune lineage. NGF was later found to act also on other immunocompetent ceils, as well as on cells of the endocrine system. A hypothesis has now gained ground in which NGF is viewed as playing a key role not only within the nervous system but, more importantly, in coordinating cross-talk between systems involved in the controi of homeostatic functions…
In the paper some important aspects were also discussed related to the negative role of NGF in neuropathic pain:
1. small peptidergic sensory neurons retain functional high-affinity NGF
receptors in the adult;
2. NGF upregulates CGRP mRNA expressed in adult dorsal root ganglion neurons both in vitro and in vivo,
3. increases the density of sensory nociceptive endings in dermis and epidermis,
4. modulates distal collateral sprouting and
5. upregulates central connectivity of nociceptive afferents.
Administration of NGF to rodents also rapidly induces a decrease in the threshold of nociceptors to heat and mechanical stimuli, and Montalcini was much ahead of her time, as most probably many neurobiologists working in pain at that time did not realize the Janus face of the NGF molecule.
NGF can induced thermal hyperalgesia and this is peripherally mediated by mast cells and a NMDA receptor-dependent mechanism plays a role. She and her colleagues pointed out that Nerve growth factor-induced hyperalgesia is comparable to hyperalgesia occurring in tissue inflammation. Local pain is one of the hallmarks associated with inflammatory tissue injury. Induction of neuropeptide synthesis in sensory neurons occurs within hours of onset of inflammation, and can be blocked by anti-NGF antibodies.
Based on all this Montalcini already pointed out her own ideas from 1990, that NGF could represent a key player in coordinating the defensive responses of both the immune and nervous systems to external noxious stimuli.
She reminded the reader that mast cells were the first cells of immune lineage to
be shown responsive to NGF, both in vivo as she pointed out in 1977, as well as and in vitro. She pointed out the many data suggesting a specific and direct NGF effect on the differentiation and maturation, as well the behaviour of the mast cell. Mast cells express also the functional (high-affinity) NGF receptor Trk.
Mast cells on itself are also capable of secreting NGF. The release of stored NGF from mast cells may represent a local and readily available source of this trophic factor to rapidly induce nociceptive C fiber sensitization and to recruit and activate, together with other cytokines, cellular elements of the immune system.
She also referred indirectly to the mechanism to control mast cells she described some years earlier, vai the natural modulator palmitoylethanolamide: Controlling inflammation and NGF levels by pharmacologic regulation of excessive mast cell neurogenic or immunogenic activation may be one approach to locally limit the effects of tissue defense processes.
Palmitoylethanolamide proved to be such a endogenous molecule controlling inflammation and nociceptive processes. This would be the item Levi-Montalcini discussed in greater detail in het TINS paper of 1996: Nerve growth factor: from neurotrophin to neurokine (Trends Neurosci. (1996) 19, 514–520). That paper will also be discussed in detail at our site.