Nerve Growth Factor Signaling and Its Contribution to Pain

Figures & data

Figure 1 X-ray crystallographic structure of human NGF homodimer. NGF is a homodimer consisting of 2 strands of 120 amino acids each, which non-covalently dimerize to form a 26-kDa protein. Note the N-terminus of the monomers is not apparent (unresolved). Copyright© 2006. Portland Press. Reproduced with permission from Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clin Sci (Lond). 2006;110(2):175–191.⁷

Abbreviation: NGF, nerve growth factor.

Table 1 Summary of Disease States or Conditions in Humans in Which Increased Levels of NGF Were Detected Compared with Controls

Study	Disease/Condition	Sample Size	Sample Matrix	NGF Form
Aloe et al^Citation61	Rheumatoid arthritis, osteoarthritis, or other chronic arthritis	n = 6 osteoarthritis patients; n = 8 rheumatoid arthritis patients; n = 8 patients with other chronic arthritis; n = 2 control patients who did not have rheumatic disease	Synovial fluid	Protein
Halliday et al^Citation62	Rheumatoid arthritis or other inflammatory arthropathy	n = 13 rheumatoid arthritis patients; n = 10 other inflammatory arthropathies; n = 3 normal volunteers	Synovial fluid	Protein
Walsh et al^Citation63	Rheumatoid arthritis or osteoarthritis	n = 10 rheumatoid arthritis patients; n= 11 osteoarthritis patients; n = 11 non-arthritic post-mortem controls	Vascular channels of osteochondral junction	Protein
Iannone et al^Citation13	Osteoarthritis	n = 12 osteoarthritis patients; n = 3 healthy controls	Knee chondrocytes	Protein
Jiang et al^Citation65	Interstitial cystitis/bladder pain syndrome	n = 30 interstitial cystitis/bladder pain syndrome patients; n = 26 controls	Blood serum	Protein
Okragly et al^Citation66	Interstitial cystitis or bladder cancer	n = 4 interstitial cystitis patients; n = 6 bladder transition cell cancer-carcinoma patients; n = 7 urinary tract infection patients; n = 7 healthy volunteers	Urine	Protein
Liu et al^Citation67	Interstitial cystitis/bladder pain syndrome	n = 58 interstitial cystitis/bladder pain syndrome patients; n = 28 healthy controls	Urine	Protein
Lowe et al^Citation68	Idiopathic sensory urgency, chronic cystitis, or interstitial cystitis	n = 4 patients with idiopathic sensory urgency; n = 4 chronic cystitis patients; n = 4 interstitial cystitis patients; n = 4 controls (genuine stress incontinence on cystometry but with no irritative symptoms)	Urothelium	Protein
Watanabe et al^Citation69	Chronic prostatitis (CP) or chronic pelvic pain syndrome (CPPS)	n = 20 CP or CPPS patients; n = 4 healthy male controls with no history of genitourinary symptoms, instrumentation, or surgery	Expressed prostatic secretions	Protein
Giovenga et al^Citation70	Primary fibromyalgia syndrome	n = 34 fibromyalgia syndrome patients; n = 15 patients diagnosed with fibromyalgia in addition to another painful or inflammatory condition; n = 10 other (patients diagnosed with another painful or inflammatory condition, but not fibromyalgia); n = 35 healthy controls	Cerebrospinal fluid	Protein
Sarchielli et al^Citation71	Chronic daily headache	n = 20 chronic daily headache patients; n = 20 age-matched controls who underwent lumbar puncture for diagnostic purposes	Cerebrospinal fluid	Protein
Sobue et al^Citation72	Various neuropathies^a	n = 54 neuropathy; n = 4 specimens with normal appearance of morphology and normal nerve conduction	Sural nerve segments	mRNA
Freemont et al^Citation73	Low back pain	n = 21 “pain level” (discography at these levels reproduced the patients’ symptoms of low back pain and/or sciatica) intervertebral disc (IVD) specimens; n = 20 “non-pain level” (discography was either painless or induced sensations that were not described by the patient as mimicking their symptoms) IVD specimens. A total of 41 specimens were taken from 36 patients	Intervertebral disc	mRNA
Richardson et al^Citation74	Low back pain	n = 5 samples from 4 non-degenerate post-mortem nucleus pulposus (NP) patients; n = 9 post-mortem degenerate NP samples from 4 patients; n = 13 surgical degenerate NP samples from 11 patients	Nucleus pulposus	mRNA
Aoki et al^Citation75	Lumbar degenerative disc disease	n = 29 patients with herniated discs; n = 26 patients with other degenerated disc diseases^b	Nucleus pulposus	Protein
Zhu et al^Citation76	Pancreatic cancer	n = 37 pancreatic cancer patients; n = 27 pancreatic samples from humans free of pancreatic disease through an organ donor program in which there were no candidates for transplantation	Pancreatic cancer tissue^c	mRNA

Notes: ^aPatients included had vasculitic and ischemic neuropathy; inflammatory demyelinating neuropathy with Guillain–Barre syndrome or chronic inflammatory demyelinating neuropathy; alcoholic neuropathy; familial amyloid polyneuropathy type 1; toxic neuropathy with cisplatin; Charcot–-Marie–Tooth disease type 1; X-linked recessive bulbospinal neuronopathy; diabetes mellitus; hypothyroidism; or neuropathy with unknown origin. ^bOther degenerated disc diseases were spondylolisthesis, spinal canal stenosis, and lumbar degenerative scoliosis. ^cTaken from patients undergoing a partial duodenopancreatectomy for pancreatic cancer.

Figure 2 Nociceptive effects of NGF on inflammatory cells. NGF binds TrkA receptors on inflammatory cells. The resulting NGF/TrkA signaling increases the release of a variety of inflammatory mediators such as serotonin, histamine, and NGF itself, which are known to cause sensitization of nociceptors via modulation of receptor or ion channel activity at the peripheral terminal.

Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); NGF, nerve growth factor; TrkA, tropomyosin receptor kinase A.

Table 2 Summary of Short- and Intermediate/Long-Term Effects of NGF Signaling on Ion Channels, Receptors, and Peptides

Term	Effect	Downstream Signaling Pathways Possibly Involved
Short-term (typically within a few minutes)	Increased TRPV1 channel activity.^Citation131,Citation134	PLC/PKC, MAPK/ErK, Likely PI3K.^Citation131^–^Citation134
	Increased P2X3 channel activity.^Citation137	PLC/PKC.^Citation137
	Increased tetrodotoxin-resistant sodium channel activity.^Citation140	Not identified
	Decreased delayed rectifier potassium channel activity.^Citation140	Not identified
	Increased calcium channel activity.^Citation202	Not identified
	Increased NMDA receptor activity.^Citation203	Possible direct interaction.^Citation203
Longer-term (typically several hours to days)	Increased NaV1.8 synthesis.^Citation204	Not identified
	Increased NMDA receptor subtype 2B synthesis.^Citation148	Not identified
	Increased synthesis of TRPV1.^Citation149	Not identified
	Increased synthesis of voltage-gated calcium channels.^Citation205	Not identified
	Increased synthesis of P2X3.^Citation153	Not identified
	Increased BK2R synthesis.^Citation128,Citation154	Not identified
	Increased activity of ASIC channels.^Citation156	Not identified
	Increased ASIC1a synthesis.^Citation158	Not identified
	Increased ASIC3 synthesis.^Citation157	NGF/TrkA and downstream PLC/PKC. NGF/p75NTR and downstream JNK/p38 MAPK.^Citation157
	Increased substance P synthesis.^Citation159,Citation160,Citation174	Not identified
	Increased CGRP synthesis.^Citation47,Citation159,Citation174	Not identified
	Increased BDNF synthesis.^Citation179,Citation206	Not identified

Abbreviations: ASIC, acid-sensing ion channel; BDNF, brain-derived growth factor; BK2R, bradykinin receptor 2; CGRP, calcitonin gene-related peptide; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; P2X3, P2X purinoceptor 3; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC, phospholipase C; TrkA, tropomyosin receptor kinase A; TRPV1, transient receptor potential cation channel subfamily V member 1.

Figure 3 Effects of NGF on nociceptive ion channels, receptors, and peptides. (A) NGF signaling increases the activity of a variety of ion channels and receptors at the nociceptor peripheral terminal, which promotes depolarization and sensitization in a relatively short time frame. In a longer time frame, the NGF/TrkA complex is retrograde transported to the soma where NGF/TrkA signaling within the DRG promotes gene expression and leads to an upregulation of nociceptive ion channels, receptors, and peptides in the peripheral and central terminals. (B) NGF is released from a variety of cells following inflammatory injury. Reproduced with permission from Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology (Official Journal of the American Society of Anesthesiologists). 2011;115(1):189–20⁶; https://anesthesiology.pubs.asahq.org/article.aspx?articleid=1933906.

Abbreviations: ASIC3, acid-sensing ion channel 3; BDNF, brain-derived neurotrophic factor; BR, bradykinin receptor; Ca, calcium; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglion; K, potassium; Na, sodium; NGF, nerve growth factor; SP, substance P; TrkA, tropomyosin receptor kinase A; TRPV1, transient receptor potential cation channel subfamily V member 1.

Figure 4 Preventative administration of anti-NGF antibody reduces metastatic prostate cancer-induced CGRP+ and NF200+ sensory nerve sprouting. (A and D) CGRP+ and NF200+ innervation of the bone marrow in sham-operated mice (yellow). (B and E) 26 days post-injection. Proliferation of prostate cancer cells (transfected with green fluorescent protein; green) and increased sprouting of CGRP+ and NF200+ fibers (yellow). (C and F) Effects of anti-NGF antibody (mAb911) administered at 10, 15, 20, and 25 days after cell injection. CGRP+ and NF200+ nerve sprouting has significantly reduced. Republished with permission from Pathological Sprouting of Adult Nociceptors in Chronic Prostate Cancer-Induced Bone Pain. Juan M. Jimenez-Andrade, Aaron P. Bloom, James I. Stake, William G. Mantyh, Reid N. Taylor, Katie T. Freeman, Joseph R. Ghilardi, Michael A. Kuskowski and Patrick W. Mantyh. J Neurosci. 2010;30 (44) :14649-14656.¹⁶³ https://doi.org/10.1523/JNEUROSCI.3300-10.2010.

Abbreviations: CGRP, calcitonin gene-related peptide; GFP, green fluorescent protein; NF200, 200-kDa neurofilament; NGF, nerve growth factor.

Figure 5 Summary of NGF effects on nociception. NGF/TrkA signaling has relatively short-term actions at the peripheral nociceptor terminal and on inflammatory cells, followed by longer-term actions within the nociceptor soma in the DRG. The overall effect is neuronal sensitization in the periphery and in the dorsal horn, leading to increased nociceptive signaling to higher-order pathways. Reproduced with permission from Schmelz et al. Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety. Pain (Official Journal of the International Association for the Study of Pain). 2019 Oct;160(10):2210–2220; https://journals.lww.com/pain/Fulltext/2019/10000/Nerve_growth_factor_antibody_for_the_treatment_of.6.aspx.²⁰⁷

Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); ASIC, acid-sensing ion channels; BDNF, brain-derived neurotrophic factor; BK, bradykinin; Ca, calcium; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglion; K, potassium; Na, sodium; NGF, nerve growth factor; PGE₂, prostaglandin E₂; SubP, substance P; TrkA, tropomyosin receptor kinase A; TRPV1, transient receptor potential cation channel subfamily V member 1.

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