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  • Review Article
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Neurotrophic factors as novel therapeutics for neuropathic pain

Nature Reviews Drug Discovery volume 2, pages 460–472 (2003)Cite this article

Key Points

  • Neuropathic pain can be defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system.

  • Neuropathic pain has many causes, including physical injury of the nerve, diabetes, herpes zoster and cytotoxic cancer drugs. The relationship between the cause, neuropathic syndrome and efficacy of treatment is complex.

  • As neuropathic pain has a variety of causes and presents with differing symptoms, multiple underlying mechanisms have been proposed as being crucial for its manifestation, including afferent discharge, spinal sensitization, activation of descending facilitiation, upregulation of spinal dynorphin, redistribution of the Nav1.8 sodium channel, and anatomical reorganization.

  • Present therapies are of modest efficacy, and are palliative rather than curative. There is a high unmet need for drugs that can address neuropathic pain by normalizing the underlying neuropathophysiology.

  • Evidence indicates that neurotrophic factors — natural proteins that promote the growth and survival of particular populations of neurons — might represent such drug candidates.

  • The potential of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the glial cell line-derived neurotrophic factor family are discussed.

Abstract

Neuropathic pain is a chronic condition that is caused by injury to the nervous system. Unlike acute pain, which is protective, neuropathic pain persists and serves no useful purpose, and severely affects quality of life. However, present therapies have modest efficacy in most patients, are palliative rather than curative, and their side effects represent significant limitations. Tremendous progress has been made over the past decade in our understanding of the biology of pain sensory neurons. The recent discovery that neurotrophic factors play an important role in neuropathic pain indicates that these pathways could serve as novel intervention points for therapy. Moreover, neurotrophic factors have the potential to address the underlying pathophysiology of neuropathic pain, thereby halting or reversing the disease process.

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Figure 1: Cellular mechanisms of neuropathic pain.
Figure 2: Subclasses of dorsal root ganglia neurons and sensory input to the spinal cord.

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Author information

Authors and Affiliations

  1. Biogen, 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Dinah W.Y. Sah

  2. Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, 85724, Arizona, USA

    Michael H. Ossipo & Frank Porreca

Authors
  1. Dinah W.Y. Sah
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  2. Michael H. Ossipo
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  3. Frank Porreca
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Correspondence to Frank Porreca.

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DATABASES

LocusLink

Artemin

ATF3

BAX

BDNF

galanin

GDNF

GFRα1

GFRα2

GFRα3

GFRα4

neurturin

NGF

NTF3

NTF5

NTRK2

p75

persephin

RET

somatostatin

substance P

TrkA

Online Mendelian Inheritance in Man

Amyotrophic laeral sclerosis

Huntington's disease

Parkinson's disease

stroke

FURTHER INFORMATION

Encyclopedia of Life Sciences

Pain and analgesia

Pain: control

Glossary

ALLODYNIA

Pain resulting from a stimulus that does not normally provoke pain. The stimulus can be mechanical/tactile or thermal (cold or warm).

HYPERALGESIA

An increased response to a stimulus that is normally perceived as painful. The stimulus can be mechanical/tactile or thermal (cold or warm).

DORSAL ROOT GANGLIA

Groups of sensory neuron cell bodies that correspond to a particular level of the spinal cord.

RHIZOTOMY

Experimental surgery in which the dorsal roots are transected.

LIGATION

Tying a suture (or similar material) around a nerve, in order to experimentally induce nerve injury.

WALLERIAN DEGENERATION

Slow loss of the axon segment distal to damage.

C-FIBRES

Thin, unmyelinated sensory nerve fibres that transduce pain information from peripheral tissues.

DEAFFERENTATION

The loss of sensory nerve fibres that normally convey sensory information from peripheral tissues to the spinal cord.

NMDA RECEPTORS

N-methyl-D-aspartate receptors are a sub-type of glutamate receptors that are activated by NMDA.

AMPA RECEPTORS

AMPA receptors are a sub-type of glutamate receptors that are activated by AMPA as well as other glutamate agonists.

DESCENDING FACILITATION

The potentiation of neurotransmission in the spinal cord by neurons that originate in higher centres in the brain and send axons into the spinal cord to form facilitatory synaptic connections.

CALCITONIN GENE-RELATED PEPTIDE

A peptide neurotransmitter that often co-localizes with substance P in a subset of small sensory neurons that transduce pain information.

ECTOPIC DISCHARGES

Bursts of action potentials that are generated at sites that do not normally initiate firing of nerve impulses.

TETRODOTOXIN

(TTX). A potent sodium channel blocker present in puffer fish, that defines TTX-sensitive versus TTX-resistant sodium current.

Aβ-FIBRES

Large, myelinated sensory nerve fibres that normally transmit tactile and proprioceptive information from peripheral tissues to the spinal cord.

TAILFLICK

The tailflick test assesses the animal's ability to perceive acute pain by measuring the time required to lift the tail out of hot water.

SUBSTANCE P

A peptide neurotransmitter that is used by a subset of small sensory neurons that transduce pain information.

MYALGIA

Generalized muscle pain, a side effect of the administration of nerve growth factor in humans.

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Sah, D., Ossipo, M. & Porreca, F. Neurotrophic factors as novel therapeutics for neuropathic pain. Nat Rev Drug Discov 2, 460–472 (2003). https://doi.org/10.1038/nrd1107

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