Professor Rita Levi-Montalcini explains her 1994 hypothesis that mast cells play an important role in inflammation and tissue injury, that mast cells can produce NGF, and that NGF irritates the nerves and thus a escalation of inflammation takes place. Palmitoylethanolamide is the natural mast cell modulator bringing rest in the system. This hypothesis has since been proven many times and the mast cell and NGF play a key role in chronic pain and inflammatory processes.
The professoressa explains:
We now refer to paper were clearly some years later she already proved to be right, a paper published in “The Journal of Neuroscience, April 15, 1996, 16(8):2716-2723 ” under the title: “Peripheral Cell Types Contributing to the Hyperalgesic Action of
Nerve Growth Factor in Inflammation” the authors:
Clifford J. Woolf, Qing-Ping Ma, Andrew Allchorne, and Stephen Poole
from the ‘Department of Anatomy and Developmental Biology, University College London, summerized the relation between NGF, inflammation and pain hypersensitivity and we quote hereunder.
The autors of course also referred in their paper to Montalcini’s work, and mentioned:
Aloe L, Levi-Montalcini R (1977) Mast cell increase in tissue of neonatal
rats injected with nerve growth factor. Brain Res 133:358-366.
Aloe L, Tuveri MA, Levi-Montalcini R (1992) Studies on carrageenan-
induced arthritis in adult rats: presence of nerve growth factor and role
of sympathetic innervation. Rheumatol Int 12:213-216, as well as to the 1994 paper Montalcini explains above.
Their summary of the mast cell-NGF-pain relation:
“A cardinal feature of inflammation is pain and hypersensitivity.
This originates both in the periphery and in the CNS. In the
periphery, inflammatory mediators increase the sensitivity of high-
threshold nociceptors so that a lower stimulus intensity is required
to activate them, the phenomenon of peripheral sensitization
(Treede et al., 1992). In the CNS, sensory signals activated by
tissue damage initiate a prolonged use-dependent synaptic facili-
tation in the spinal cord, the phenomenon of central sensitization,
whereby sensory inputs are amplified and normally innocuous
inputs may begin to elicit pain (Woolf, 1983). A major contributor
to the production of inflammatory hyperalgesia has been shown
recently to be the neurotrophin nerve growth factor (NGF). The
level of NGF rises substantially in inflamed tissue (Weskamp and
Otten, 1987; Donnerer et al., 1992; Woolf et al., 1994) secondary
to an earlier rise in the cytokine interleukin-l/3, and the administration of anti-NGF
serum (Lewin et al., 1994; Woolf et al., 1994) or trk&IgG fusion
proteins (McMahon et al., 1995) substantially reduces inflamma-
tory hypersensitivity. What is not known is the mechanism or site
of NGF action during inflammation.
The contribution of NGF to inflammatory sensitivity changes
may be local to the site of the inflammation-directly or indirectly
sensitizing nociceptors (Lewin et al., 1994). A peripheral action of
NGF could be mediated by NGF stimulating inflammatory cells to
release neuroactive cytokines or inflammatory mediators (Otten
et al., 1987; Bischoff and Dahinden, 1992). Mast cells, for exam-
ple, degranulate on exposure to NGF (Mazurek et al., 1986;
Pearce and Thompson, 1986; Horigome et al., 1993), and the
consequent release of amines, cytokines, or enzymes (Harvima et
al., 1994; Marshall and Bienenstock, 1994) may cause acute sen-
sitivity increases by acting on nociceptor terminals (Lewin et al.,
1994). Alternatively, the NGF may bind directly to trhA receptors
on the peripheral terminals of primary sensory neurons (McMa-
hon et al., 1994; Smeyne et al., 1994; Averill et al., 1995) and, in
a tyrosine kinase-mediated manner (Kaplan et al., 1991b), phos-
phorylate key transduction-related proteins or ion channels, sen-
sitizing the peripheral terminal. Finally, NGF might produce its
local sensitizing actions via the sympathetic nervous system. Post-
ganglionic sympathetic neurons express trld (Smeyne et al., 1994)
and interact with primary sensory neurons to produce the neuro-
genie component of inflammation (Levine et al., 1985; Coderre et
al., 1991; Green et al., 1993). An involvement of the sympathetic
nervous system in the behavioral sensitivity induced by inflamma-
tion is, however, controversial and has been both proposed (Le-
vine et al., 1986; Nakamura and Ferreira, 1987) and refuted in
different studies (Lam and Ferrell, 1991; Perrot et al., 1994).
Sympathectomy does, however, substantially reduce the transient
hyperalgesia produced by intraplantar NGF administration in the
rat (Andreev et al., 199.5), which has been interpreted as indicat-
ing that activation of these neurons is necessary for the hyperal-
gesic effects of NGF to manifest.
The conclusion from their experiments was:
NGF is an important mediator in the generation of inflammatory
hypersensitivity. In the earliest phase of inflammation, this is
attributable exclusively to a peripheral action that is substantially
attenuated by either depletion of mast cell granules or sympathec-
tomy. Later phases of inflammatory hypersensitivity are indepen-
dent of the sympathetic nervous system but are still NGF-
dependent and likely to reflect both a peripheral action and a
transcription-dependent change in the function of sensory
This clearly underscores the importance to downregulate mast cells and NGF in states of chronic pain and inflammation. With palmitoylethanolamide (Normast, PaePure) we have such possibility in hands.
Appendix: sources mentioning mast cells, pain and NGF, based on a PubMed search January 2013:
Neurotrophic factor changes in the rat thick skin following chronic constriction injury of the sciatic nerve.
Peleshok JC, Ribeiro-da-Silva A.
Mol Pain. 2012 Jan 10;8:1. doi: 10.1186/1744-8069-8-1.
PMID: 22233577 [PubMed – indexed for MEDLINE] Free PMC Article
Neurotrophic Factors and Nociceptor Sensitization.
Jankowski MP, Koerber HR.
In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press; 2010. Chapter 2.
PMID: 21882462 [PubMed] Books & Documents
Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats.
De Filippis D, Luongo L, Cipriano M, Palazzo E, Cinelli MP, de Novellis V, Maione S, Iuvone T.
Mol Pain. 2011 Jan 10;7:3. doi: 10.1186/1744-8069-7-3.
PMID: 21219627 [PubMed – indexed for MEDLINE] Free PMC Article
Adrenergic stimulation mediates visceral hypersensitivity to colorectal distension following heterotypic chronic stress.
Winston JH, Xu GY, Sarna SK.
Gastroenterology. 2010 Jan;138(1):294-304.e3. doi: 10.1053/j.gastro.2009.09.054. Epub 2009 Oct 1.
PMID: 19800336 [PubMed – indexed for MEDLINE] Free PMC Article
The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors.
Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G.
Pain. 2008 Oct 31;139(3):541-50. doi: 10.1016/j.pain.2008.06.003. Epub 2008 Jul 3.
PMID: 18602217 [PubMed – indexed for MEDLINE]
[Perception of chronic pelvic pain in women: predictors and clinical implications.]
Urologia. 2008 April-June;75(1):67-72. Italian.
PMID: 21086354 [PubMed – as supplied by publisher]
Enhanced expression of mast cell growth factor and mast cell activation in the bladder following the resolution of trinitrobenzenesulfonic acid (TNBS) colitis in female rats.
Liang R, Ustinova EE, Patnam R, Fraser MO, Gutkin DW, Pezzone MA.
Neurourol Urodyn. 2007;26(6):887-93.
PMID: 17385238 [PubMed – indexed for MEDLINE] Free PMC Article
The autotomy relief effect of a silicone tube covering the proximal nerve stump.
Okuda T, Ishida O, Fujimoto Y, Tanaka N, Inoue A, Nakata Y, Ochi M.
J Orthop Res. 2006 Jul;24(7):1427-37.
PMID: 16732614 [PubMed – indexed for MEDLINE]
Mechanisms involved in the nociception produced by peripheral protein kinase c activation in mice.
Ferreira J, Trichês KM, Medeiros R, Calixto JB.
Pain. 2005 Sep;117(1-2):171-81.
PMID: 16099101 [PubMed – indexed for MEDLINE]
Involvement of substance P, CGRP and histamine in the hyperalgesia and cytokine upregulation induced by intraplantar injection of capsaicin in rats.
Massaad CA, Safieh-Garabedian B, Poole S, Atweh SF, Jabbur SJ, Saadé NE.
J Neuroimmunol. 2004 Aug;153(1-2):171-82.
PMID: 15265675 [PubMed – indexed for MEDLINE]
Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy.
Rice AS, Farquhar-Smith WP, Nagy I.
Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):243-56. Review.
PMID: 12052040 [PubMed – indexed for MEDLINE]
Estrogen and neuroinflammation.
Bjorling DE, Wang ZY.
Urology. 2001 Jun;57(6 Suppl 1):40-6.
PMID: 11378049 [PubMed – indexed for MEDLINE]
Cannabimimetic fatty acid derivatives in cancer and inflammation.
Di Marzo V, Melck D, De Petrocellis L, Bisogno T.
Prostaglandins Other Lipid Mediat. 2000 Apr;61(1-2):43-61. Review.
PMID: 10785541 [PubMed – indexed for MEDLINE]
Hyperalgesia due to nerve damage: role of nerve growth factor.
Theodosiou M, Rush RA, Zhou XF, Hu D, Walker JS, Tracey DJ.
Pain. 1999 Jun;81(3):245-55.
PMID: 10431712 [PubMed – indexed for MEDLINE]
Neurotrophins, nociceptors, and pain.
Mendell LM, Albers KM, Davis BM.
Microsc Res Tech. 1999 May 15-Jun 1;45(4-5):252-61. Review.
PMID: 10383118 [PubMed – indexed for MEDLINE]
Nerve growth factor induced hyperalgesia in the rat hind paw is dependent on circulating neutrophils.
Bennett G, al-Rashed S, Hoult JR, Brain SD.
Pain. 1998 Sep;77(3):315-22.
PMID: 9808357 [PubMed – indexed for MEDLINE]
Effect of colchicine on nerve growth factor-induced leukocyte accumulation and thermal hyperalgesia in the rat.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Aug;358(2):264-9.
PMID: 9750013 [PubMed – indexed for MEDLINE]
Role of TNF-alpha but not NGF in murine hyperalgesia induced by parasitic infection.
Aloe L, Moroni R, Angelucci F, Fiore M.
Psychopharmacology (Berl). 1997 Dec;134(3):287-92.
PMID: 9438678 [PubMed – indexed for MEDLINE]
Mast cell interactions with the nervous system: relationship to mechanisms of disease.
Dines KC, Powell HC.
J Neuropathol Exp Neurol. 1997 Jun;56(6):627-40. Review.
PMID: 9184654 [PubMed – indexed for MEDLINE]
Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis.
Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL.
Br J Urol. 1997 Apr;79(4):572-7.
PMID: 9126085 [PubMed – indexed for MEDLINE]
Appendix: Rita Levi-Montalcini on “The scientific challenge of the 21st century: from a reductionist to a holistic approach via systems biology” explained via her work on NGF:
In the fifties and subsequent few decades, the discovery by one of us (RLM) of this growth factor [1,2], followed by the characterization of its functional properties [3-6] was a typical fruit of a reductionistic success: identifying a single substance, demonstrating its diffusible nature and showing its specific function of inducing the differentiation of two types of neurons constitutive of sympathetic and sensory ganglia. The subsequent experimental attempt was again a typical case of a reductionistic success: devising an in vitro culture system, to replace the complex and time consuming in vivo experiments carried out in chick embryo, in order to assess the presence of this “nerve growth promoting activity” – subsequently identified as nerve growth factor (NGF) – primarily in sarcoma and subsequently in tissues and biological fluids. This attempt ended with an in vitro bioassay which, within 18–24 hours, allowed to detect NGF activity evidenced by an impressive halo of nerve fibers. This was an even more stringent case of a successful reductionistic approach.
In the last decade of the past century the studies on NGF took a route which presently induces a growing number of laboratories to carry out systemic, “holistic” strategies. Thus, for instance, the properties of NGF receptors, endowed with completely different structure, functional properties and mechanism of action – to the extent, for instance, that they may exert both pro and anti-apoptotic actions via activation of a plethora of intracellular pathways – [7,8] need today a novel approach to answer questions such as: how many different genes are involved in such a complex pattern of activities, considering, for instance, that an anti-apoptotic pathway generally involves hundreds of different genes and proteins? In order to put together in a unique, comprehensible picture, all the data that are emerging in this field of investigations, a “global” approach with highly sophisticated techniques is mandatory.
On the other side, the broadening of studies on NGF target cells, which in the first 2–3 decades after its discovery were confined to sensory and sympathetic neurons, to cholinergic and possibly other neurons of the central nervous system, followed by the demonstration that several other cell types belonging to the endocrine and immune systems are target of NGF action, also requires a systemic strategy, to frame the whole populations of target cells into an “organismic” view of NGF functions and mechanism of action .
As mentioned above, in the 21st century, also due to the realization of extremely sophisticated and powerful techniques, such as the possibility of cloning any gene, analysing the expression of thousands of genes and of the corresponding coded proteins within the context of a specific cellular function, investigating the whole complex machinery linking energy metabolism to modulation of gene expression, neurobiologists must adopt novel strategies and technical procedures. The term that summarizes such an approach is “systems neurobiology” and the metaphor that better fits with such systemic strategy is that a single protein is to a neuron as a neuron is to whole brain. Accordingly, both for analyzing a neuron – which is constituted by thousands of proteins – and for studying the function of brain – composed of billions of neurons -, it is mandatory to resort to proper techniques such as genomics, proteomics or transcriptomics, which, by definition, involve the contemporaneous analysis of hundreds or thousands of genes and/or of the corresponding coded proteins or metabolic products.
Thus, considering the wholeness of cellular systems, adopting proteomics or functional genomics attacks might be as important for our understanding of brain functions as, for example, the wholeness of economical markets is to the study of macroeconomics.
BMC Neurosci. 2006; 7(Suppl 1): S1: The scientific challenge of the 21st century: from a reductionist to a holistic approach via systems biology. by Rita Levi-Montalcini1 and Pietro Calissano.