Nerve Growth Factor Signaling and Its Contribution to Pain

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NGF Administration Induces Hyperalgesia

In addition to the observation of increased NGF levels in chronic pain conditions and animal models of pain/inflammation, it has been demonstrated that exogenous administration or overexpression of NGF results in hyperalgesia and/or allodynia. ³⁸ ^, ⁷⁹ ^- ⁸¹

Interestingly, striking hyperalgesic effects of NGF administration have also been observed in humans. In healthy adults, for example, a single subcutaneous injection of recombinant NGF has been shown to elicit local injection-site hyperalgesia that persists for up to 7 weeks, depending on the dosage. ⁸² Likewise, intradermal injection of NGF produces long-lasting local thermal (early onset) and mechanical (delayed) hyperalgesia. ⁸³ ^– ⁸⁷ Localized priming of nociceptors following intradermal injection of NGF has also been demonstrated through an enhancement of hyperalgesia in response to irradiation with ultraviolet-B. ⁸⁸ ^, ⁸⁹

Intramuscular injection of NGF has been shown to cause lasting mechanical hyperalgesia in a variety of muscles. ⁹⁰ ^– ¹⁰¹ Notably, injection of NGF into the tibialis anterior muscle induces local mechanical hyperalgesia within 3 hours of injection that spreads to distant areas on days 1 to 4, suggesting involvement of central pain mechanisms. ⁹³ Repeated injections result in both temporal summation and spreading of mechanical pain, again implicating both peripheral and central mechanisms. ¹⁰² Spreading of NGF-induced hyperalgesia has also been observed following injection into the supraspinatus muscles. ⁹⁴ A single injection of NGF into the facia of the musculus erector spinae muscle produces both mechanical and chemical (proton) hyperalgesia. ¹⁰³ Chemical hyperalgesia has also been demonstrated following the injection of NGF into the tibialis anterior. ¹⁰¹

NGF Treatment Lowers Nociceptor Activation Threshold

Intradermal injection of NGF increases the conduction velocity and decreases activity-dependent slowing of conduction velocity in unmyelinated porcine (pig) mechano-insensitive nociceptors. ¹⁰⁴ ^– ¹⁰⁶ The activation threshold of mechano-sensitive nociceptors at the injection site decreases following NGF treatment and the proportion of mechano-sensitive nociceptors increases. ¹⁰⁴ While the receptive field of these nociceptors increased, there was no increase in intraepidermal nerve fiber density, suggesting that previously silent nociceptors may be recruited in this circumstance. ¹⁰⁴ These changes were measured 3 weeks after NGF administration and, therefore, likely represent long-term effects of NGF signaling. Sensitization of skin nociceptors has been confirmed in humans using microneurography techniques which demonstrate that axonal branches exhibit reduced activation thresholds within the NGF injection zone but not outside of the injection zone. ¹⁰⁷

Nociceptive Actions of NGF Signaling

Effects of NGF on Inflammatory Cells and Mediators

There is evidence that NGF modulates nociception, in part, by influencing the actions of inflammatory cells and mediators. It has been shown that rodent mast cells produce and store NGF in granules until degranulation and NGF mRNA has been detected in a human mast cell line. ¹⁰⁸ ^, ¹⁰⁹ Moreover, cultured media from this mast cell line is able to induce neurite outgrowth in cultured chick embryonic sensory neurons, suggesting that NGF is secreted from these cells. ¹⁰⁹ NGF has also been found to be present in, and released from, human CD14+ T cell clones and human monocytes. ¹¹⁰ ^, ¹¹¹

NGF has been shown to increase the release of mediators from inflammatory cells ( Figure 2 ). These mediators, such as bradykinin, histamine, ATP, serotonin, and protons, are released during inflammation or injury from ruptured cells or from infiltrating inflammatory cells and are capable of activating receptors and ion channels found on the peripheral nociceptor terminal, leading to neuronal depolarization and sensitization that manifests as pain hypersensitivity. ¹¹² For example, exogenous IL-1β causes mechanical and thermal hyperalgesia (measured as an increased nociceptive reflex) in rodents, and histamine has been shown to mediate pain-related behaviors in a rodent model of interstitial cystitis. ¹¹³ ^, ¹¹⁴ Further, serotonin administered to healthy human volunteers causes mechanical hyperalgesia and stimulates calcium influx into cultured rat sensory neurons, an indication of cell excitability. ¹¹⁵ ^, ¹¹⁶ Finally, bradykinin treatment causes mechanical hyperalgesia in rats and Protein Kinase C (PKC) signaling-dependent sensitization of the transient receptor potential cation channel subfamily V member 1 (TRPV1), when isolated via patch-clamp, which has a known role in nociception and noxious heat sensation. ¹¹⁷ ^, ¹¹⁸

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 ...

NGF can trigger the release of histamine and leukotriene from human basophils, serotonin and histamine from rodent mast cells, and histamine and tryptase from a human mast cell line. ¹¹⁹ ^– ¹²³ However, NGF administration did not activate mast cells in a separate rodent study, and there is some evidence that rodent mast cells do not express NGF receptors. ¹⁰⁹ ^, ¹²⁴ Though the contribution of mast cells to NGF signaling in humans is not clear, human mast cells express TrkA receptors and, thus, species differences must be considered when discussing the influence of NGF on inflammatory cells. ¹⁰⁹ Similar to effects seen in mast cells, isolated murine peritoneal macrophages exposed to NGF increase the production of interleukin 1β (IL-1β). ¹²⁵ This may occur through TrkA activation as TrkA expression, but not p75NTR expression, was observed in these cells. ¹²⁵ The effects that NGF-mediated release of inflammatory mediators have will depend on the tissue. For example, histamine evokes the sensation of itch when released in isolation in superficial skin and mucous membranes, but causes burning pain when applied to deep somatic tissues. ¹²⁶ ^, ¹²⁷

In addition to affecting cytokine release, NGF can also affect the actions of inflammatory mediators. For example, NGF can potentiate the sensitivity of rat DRG neurons to bradykinin. ¹²⁸ On the other hand, inflammatory mediators can influence the levels and effects of NGF. Evidence suggests that IL-1β contributes to increased NGF levels in cultured sciatic nerve explants, and inhibiting bradykinin-1 receptor activity blocks NGF-induced thermal hyperalgesia in rodents. ¹¹⁴ ^, ¹²⁹ ^, ¹³⁰ Thus, there may be instances of positive feedback loops in vivo in which NGF stimulates the release and actions of inflammatory mediators that in turn stimulate increased synthesis and/or release of NGF. However, the role, if any, such a feedback loop plays in the generation or maintenance of chronic pain is not known.

NGF Effects on Nociceptive Ion Channels, Receptors, and Peptides

In addition to enhancing the release of inflammatory mediators that alter sensory neuron excitability, NGF signaling itself also has effects on the activity of nociceptive ion channels and receptors that contribute to nociceptor sensitization ( Table 2 ). The changes may be due either to direct, immediate effects on ion channel/receptor activity at the cell membrane and/or through longer-term effects such as enhanced gene transcription that leads to increased numbers of ion channels/receptors at the cell surface ( Figure 3 ). Philos Trans R Soc Lond B Biol Sci . 1996; 351 ( 1338 ):389–394. [ PubMed ] [ Google Scholar ]

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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 ⁶¹	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 ⁶²	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 ⁶³	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 ¹³	Osteoarthritis	n = 12 osteoarthritis patients; n = 3 healthy controls	Knee chondrocytes	Protein
Jiang et al ⁶⁵	Interstitial cystitis/bladder pain syndrome	n = 30 interstitial cystitis/bladder pain syndrome patients; n = 26 controls	Blood serum	Protein
Okragly et al ⁶⁶	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 ⁶⁷	Interstitial cystitis/bladder pain syndrome	n = 58 interstitial cystitis/bladder pain syndrome patients; n = 28 healthy controls	Urine	Protein
Lowe et al ⁶⁸	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 ⁶⁹	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 ⁷⁰	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 ⁷¹	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 ⁷²	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 ⁷³	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 ⁷⁴	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 ⁷⁵	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 ⁷⁶	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:

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