Nerve Growth Factor and the Relief of Pain

Antagonism of Nerve Growth Factor-TrkA Signaling and the Relief of Pain | Anesthesiology. 2011 Jul;  | Free Full Text PubMed PMC article

Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development.

However in the adult, NGF has been found to play an important role in nociceptor sensitization following tissue injury.

Here we outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain

Further, we document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function 

Understanding whether there are any unexpected adverse events as well as how humans may change their behavior and use of the injured/degenerating tissue following significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF

The Problem of Pain and Its Management

International guidelines recommend a multimodal combination of pharmacologic and non-pharmacologic modalities as the most effective strategy to manage the pain and disability associated with chronic pain, where the goal of treatment should be to effectively reduce pain while improving function and reducing suffering

Where more conservative methods have failed, opioids, appropriately dosed and monitored, are associated with a lower incidence of organ toxicity and fewer potentially life-threatening complications than non-steroidal anti-inflammatory drugs

Again, a warning about NSAIDs and reassurance that opioids are actuallt less toxic that these over-the-counter remedies.

The effective management of chronic pain can improve patients’ quality of life, functional status, and reduce health care costs.

In the present article we present evidence for a new approach to the management of chronic pain that targets the effects elicited by nerve growth factor (NGF).

NGF belongs to a family of neurotrophins

The neurotrophin family of target-derived proteins regulates the survival, development, and function of subsets of sensory and sympathetic neurons

NGF binds to TrkA, whereupon the NGF-TrkA complex is internalized and transported from peripheral terminals to sensory cell bodies in the dorsal root ganglion (DRG).

Evidence from several sources suggests that NGF itself cannot initiate signaling in the cell soma, and that instead the NGF-TrkA complex activates transcription factors that control downstream gene expression.

The NGF-TrkA Nociceptor Axis: From Development to Adulthood

The role of NGF in neuronal development has been known since its discovery nearly 60 years ago. NGF plays a critical role in the development of the peripheral nervous system by promoting growth and survival of some neural crest- derived cells in developing embryos, in particular sensory and sympathetic neurons.

Collectively, immunologic and genetic studies of NGF deprivation during development and maturation demonstrate that NGF has three separate roles:

  1. one for survival and development of sensory and sympathetic neurons,
  2. the second in maintaining the peptidergic phenotype of primary afferent neurons in the early post-natal period, and
  3. the third being a key upstream modulator of the expression and sensitization of a variety of neurotransmitter, receptor and ion channels expressed by adult nociceptors.

However, whether adult sensory neurons require NGF for maintenance of their phenotype, if so, how much NGF remains to be determined.

NGF-TrkA Signaling, Nociceptors, and Pain in the Adult

A role for NGF has been demonstrated in both acute, transient nociceptive responses, as well as in longer-term, chronic pain. As early as 1977, a report that NGF exerts effects on mast cells suggested that the physiologic effects of NGF were not limited to neuronal development and maturation

As we discuss below, the NGF-TrkA axis appears to play a pivotal role in the early, intermediate, and long-term generation and maintenance of several types of acute and chronic pain.

An important point in assessing the involvement of the NGF/TrkA pathway in driving a particular chronic pain state is the issue of the specific populations of primary afferent sensory nerve fibers that innervate the injured/diseased tissue.

Direct Actions of NGF

The pivotal role of NGF in inflammatory pain is exemplified by the expression and/or release of NGF by certain inflammatory cells, including eosinophils, lymphocytes, macrophages and mast cells, as a consequence of injury

Moreover, NGF is up-regulated in experimental models of inflammation, including those induced by carrageenan, formalin, and complete Freund’s adjuvant, as well as in models of autoimmune arthritis, and ultraviolet B radiation-induced acute inflammation

Cutaneous administration of NGF to rodents and to humans causes hyperalgesia within 1 or 3 hours, respectively, suggesting that NGF leads to a relatively rapid sensitization of cutaneous nociceptors. These rapid effects in the rat are thought to be mediated primarily through NGF binding with TrkA expressed on mast cells, causing degranulation and release of a variety of algogenic mediators, such as histamine, prostaglandin E2, serotonin, hydrogen ions, and bradykinin, as well as additional NGF

The NGF-induced release of inflammatory mediators from mast cells contributes to the sensitization of polymodal nociceptors

An important mechanism seen within minutes to hours of NGF-TrkA binding is the sensitization of the heat-sensitive ion channel, TRPV1

Acute sensitization of TRPV1 by NGF may involve direct phosphorylation

Ultimately, sensitization of TRPV1 lowers the temperature threshold of sensory neurons to noxious heat

Thus any change in temperature threshold of a thermal nociceptor due to NGF-induced sensitization of TRPV1 receptors results from a greater depolarization causing the fiber to reach firing threshold at a lower temperature

Retrograde Transport of NGF-TrkA Drives Transcriptional Changes in Nociceptors

Following the period of immediate hypersensitivity with NGF release after tissue injury, early transcriptional changes occur in the sensory signaling pathway.

As NGF principally signals via retrograde transport of the internalized NGF-TrkA complex, there is a delay (from hours to days) before some of NGF’s contribution to hypersensitivity is seen. After retrograde transport to the DRG, the signal from the NGF-TrkA complex can produce changes in sensory phenotype through the switching on (and off) of gene promoters (fig. 2), which leads to increased synthesis of peptides (e.g., SP, calcitonin gene-related peptide [CGRP], and BDNF), and of nociceptor-specific ion channels (NaV1.8, CaV 3.2, 3.3) at the DRG

NGF, BDNF, and Central Sensitization

A delayed phase of the inflammatory response to NGF (7 hours to 4 days after NGF-TrkA binding in rodents), involves an indirect effect of NGF on synaptic transmission between nociceptors and second-order cells in laminae I and II of the spinal cord via its effect on the release of peptides such as BDNF

These preclinical data point to a fundamental difference between the role of NGF as a factor during growth and differentiation, and its role in the adult sensory system, when NGF-TrkA becomes a major player in the modulation and sensitization of a significant population of nociceptors which are involved in driving chronic pain.

As NGF plays a prominent role not only in acute nociception, but in mechanisms behind chronic hypersensitivity, there is a clear scientific rationale for interrupting NGF-TrkA signaling as a target for pain relief therapeutics.

NGF/TrkA induced sprouting and neuroma formation

One intriguing but largely unexplored mechanism by which NGF may also generate and maintain hypersensitivity is by inducing aberrant sprouting and/or neuroma formation in response to tissue and/or nerve injury

NGF activation of TrkA+ has also been demonstrated to induce a remarkable reorganization of sensory and sympathetic nerve fibers.

A major issue in interpreting this remarkable and pathological nerve sprouting is the source of the NGF driving this growth

Sprouting of presumptive TrkA+ nerve fibers has also been observed in non-malignant skeletal pain states in both human and animals. For example, prior studies have reported that in humans with chronic discogenic pain there is growth of CGRP+ nerve fibers into normally aneural and avascular areas of the intervertebral disc

These data on the ectopic sprouting of TrkA+ sensory and sympathetic nerve fibers are interesting as they indicate how pre-emptive treatment with therapies that block NGF activation of TrkA may reduce the attendant pain, but also may block the pathologic remodeling of sensory and sympathetic nerve fibers that are themselves a major driver of chronic hypersensitivity

NGF-TrkA Interactions and Chronic Pain—Preclinical Evidence

A number of strategies have been developed to investigate the role of endogenous NGF in chronic pain. Most commonly, anti-NGF antibodies or a TrkA-IgG fusion protein to sequester NGF have been developed to block the biological activity of NGF. Alternatively, it is possible to prevent NGF binding and activation of TrkA, for example with anti-TrkA antibody or a small molecular inhibitor of TrkA, although NGF activity via p75 will remain intact. These approaches have provided further evidence for the role of NGF in acute and chronic hypersensitivity in adult animals after inflammatory injury.

it is important to point out that in models of visceral inflammatory pain, hyperalgesia is markedly reduced by pre-treatment with an NGF-neutralizing antibody or TrkA-IgG fusion molecule, for example in acetic acid-induced gastric inflammation,114 trinitrobenzene sulfonic acid-induced colonic hypersensitivity,115 and turpentine or acrolein-induced cystitis

Antibodies to NGF reversed the established hyperalgesia in a rodent model of autoimmune arthritis

Early preclinical experiments modeling long-term NGF deprivation by active immunization of adult animals to auto-produce antibodies against NGF demonstrated a reduction in the number of peripheral DRG fibers compared with untreated controls

One rather unique aspect of the sensory innervation of bone and joint, which may partially explain why anti-NGF therapy is effective in relieving both malignant and non-malignant skeletal pain, is that more than 50% of nerve fibers innervating bone are CGRP+ fibers52, nearly all of which co-express TrkA

Importantly, preventing NGF-TrkA signaling does not appear to compromise normal physiologic responses to injury, which are critical for effective healing. For example, NGF blockade does not affect the normal inflammatory response (erythema, heat, and swelling)

Furthermore, at least cursory examination of anti-NGF therapy reveals no modification of the biomechanical properties of the femur or histomorphometric indices of bone healing120 and load bearing remains intact

Collectively, the preclinical data suggest that reducing or preventing the NGF production that is associated with some types of injury, through the sequestering of NGF or the inhibition of NGF-TrkA signaling, is effective for reducing hypersensitivity in animal models

this approach does not obviously compromise normal nociceptor function or cause the loss of sympathetic or sensory nerve fiber innervation of the skin or bone.

NGF-TrkA Interactions and Pain—Human Studies

In humans, as in animal models, subcutaneous NGF evokes long-lasting mechanical hyperalgesia

Furthermore, NGF is locally upregulated in humans presenting with chronic pain, such as arthritis, migraine/headache, fibromyalgia, or peripheral nerve injury

These observations suggest that in humans, as in preclinical animal models, the ongoing production of NGF may be involved in chronic pain and changes in sensitization.

Indeed, there are at least three major pharmacologic strategies under development that target NGF-TrkA signaling for the treatment of chronic pain and that have produced effective reduction in hypersensitivity in preclinical models.

These are:

  1. sequestration of NGF or inhibiting its binding to TrkA;
  2. antagonizing TrkA so as to block NGF from binding to TrkA; and
  3. blocking TrkA kinase activity

Importantly, in studies published to date, and in line with preclinical studies, anti-NGF therapy appears to be anti-hyperalgesic (i.e. normalizing a decreased nociceptive threshold) as opposed to analgesic (i.e. increasing normal and sensitized nociceptive threshold)

The Potential for NGF-TrkA Therapeutics

Ultimately, the utility of NGF antagonism for pain relief in humans will depend on the contribution of the various NGF signaling pathways to the specific chronic pain condition. It is likely that not all types of pain are effectively reversed by antagonizing NGF-TrkA signaling. This therapeutic approach clearly relies on NGF being an important driver of the increased pain sensitivity; if other factors are responsible for driving the hyperalgesic state, inhibition of NGF may not be effective.

NGF may be primarily involved in the initiation of changes that lead to chronic pain, and may not itself have a prominent role in maintenance of hypersensitivity. Therefore, the stage at which NGF is important in the development of ongoing hypersensitivity needs to be defined.

In addition to defining the analgesic efficacy of blocking the NGF-TrkA axis, key safety issues which need to be addressed with any therapy targeting NGF or TrkA include effects on normal autonomic and sensory neuron structure and function; physiological responses to injury, wound healing and endocrine function; ability to cross placental or blood–brain-barrier in the normal or injured state, and thus any influence on central nervous system neurons such as the basal forebrain cholinergic neurons that are sensitive to NGF

Conclusion

This review provides an overview of the mechanisms by which NGF drives acute and chronic pain in the adult, and outlines how NGF has a distinct role in the adult as compared with the developing nervous system

To date, therapies that target NGF-TrkA-signaling have shown significant analgesic efficacy in both animals and humans in several difficult-to-treat chronic pain states

If successful, therapies that target NGF-TrkA signaling represent a new class of analgesic therapy that have the potential to profoundly change the therapeutic landscape of how we treat several types of chronic pain.  

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