Neurotrophins and Neuropathic Pain: Role in Pathobiology

Abstract

Neurotrophins (NTs) belong to a family of trophic factors that regulate the survival, growth and programmed cell death of neurons. In mammals, there are four structurally and functionally related NT proteins, viz. nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 and neurotrophin 4. Most research on NTs to date has focussed on the effects of NGF and BDNF signalling via their respective cognate high affinity neurotrophic tyrosine kinase viz TrkA and TrkB receptors. Apart from the key physiologic roles of NGF and BDNF in peripheral and central nervous system function, NGF and BDNF signalling via TrkA and TrkB receptors respectively have been implicated in mechanisms underpinning neuropathic pain. Additionally, NGF and BDNF signalling via the low-affinity pan neurotrophin receptor at 75 kDa (p75NTR) may also contribute to the pathobiology of neuropathic pain. In this review, we critically assess the role of neurotrophins signalling via their cognate high affinity receptors as well as the low affinity p75NTR in the pathophysiology of peripheral neuropathic and central neuropathic pain. We also identify knowledge gaps to guide future research aimed at generating novel insight on how to optimally modulate NT signalling for discovery of novel therapeutics to improve neuropathic pain relief.

Keywords: BDNF; NGF; NT-3; NT-4; allodynia; central sensitisation; neuropathic pain; neurotrophic tyrosine kinase (Trk) receptor; neurotrophins; p75NTR.

Figure 1

Proteolytic cleavage of pro-neurotrophins to mature neurotrophins. Neurotrophins (NTs) are synthesised as glycosylated precursors of ~32 kDa, called pro-neurotrophins, pro-NTs. These precursor molecules are cleaved intracellularly by furin or proconvertase, and extracellularly by the action of plasmin to generate mature NTs. Plasmin is a serine protease enzyme that is formed from plasminogen by several enzymes including tissue plasminogen activator (tPA) and urokinase. Intact pro-NTs may also be released extracellularly and evoke direct biological activities that in general oppose that of the mature NT counterpart although there are exceptions. For example, pro-NTs may induce apoptosis whereas mature NTs are mainly associated with neuronal survival. However, both pro- and mature-NTs appear to mediate central sensitisation and neuropathic pain.

Figure 2

Downstream signalling of neurotrophins and their receptors. Akt, Akt kinase; Ca+2, calcium ions; CGRP, calcitonin gene related peptide; DAG, diacylglycerol; DRG, dorsal root ganglia; ERK, extracellular-signal-regulated kinase; GABA, γ-Aminobutyric acid; IP3, inositol tris-phosphate; KCC2, potassium chloride cotransporter 2; MAPK, mitogen-activated protein kinases; MEK, mitogen-activated protein kinase/ERK kinase; Nav, sodium-ion voltage-gated channel; NMDA, N-methyl-d-aspartate; NT, neurotrophin; p75NTR, pan neurotrophin receptor at 75kDa; PI3K, phosphatidylinositol 3-kinase; PLC-γ1, phospholipase C-gamma-1; Ras, small GTP-binding protein; Sub-P, substance-P; Trk, tyrosine kinase receptor; TRPV1, transient receptor potential cation channel subfamily V member 1.