Abstract
In pathological states, repetitive inputs from the ascending pathways involved in the genesis and integration of nociception, leads to molecular, anatomical and electrophysiological adaptive changes of these pathways, contributing to the development of pain chronicity. In the past, neurotrophic factors have been implicated in neuronal plasticity in adult central nervous system. We have previously described plastic changes associated with the up-regulation of NGF's high affinity receptor, TrkA, in the spinoreticular pathway in a chronic inflammatory pain model of arthritis induced by complete Freund's adjuvant. The present study investigated the role of central NGF in the maintenance of inflammatory pain. Analysis of TrkA and NGF expression revealed that they are expressed in the medial thalamus and several reticular nuclei of the brain stem such as the lateral reticular nucleus (LRt) and not in pathways classically described to be involved in the sensory-discriminative aspect of pain such as the lateral thalamus. In addition NGF was over-expressed in the LRt, lateral thalamus and cortex of polyarthritic rats. Using micro-injection of an adenoviral vector synthesizing NGF (or green fluorescent protein) in the LRt of normal animals, we showed that increased NGF levels in the LRt leads to the development of mechanical hypersensitivity and increased nocifensive behavior following an inflammatory stimulus. These results suggest that, NGF acts centrally as a possible molecular inducer of synaptic plasticity in the LRt in conditions of chronic inflammatory pain.
Highlights
Nerve Growth Factor (NGF) is a neurotrophic factor involved in the survival and differentiation of neuronal populations such as the cholinergic neurons of the basal forebrain, sympathetic neurons and small sensory nociceptive neurons in the dorsal root ganglia (DRG) during development [1]
Our study first compared the densities of NGF and TrkA immunoreactivity as well as NGF mRNA expression in thalamic and brainstem structures, the main targets of ascending spinal nociceptive pathways, in a model of inflammatory pain compared with naïve animal
We observed that the lateral reticular nucleus (LRt), a brain stem nucleus involved in the integration of non sensorydiscriminative information and the affective-motivational aspect of pain, is a major site of NGF synthesis
Summary
Nerve Growth Factor (NGF) is a neurotrophic factor involved in the survival and differentiation of neuronal populations such as the cholinergic neurons of the basal forebrain, sympathetic neurons and small sensory nociceptive neurons in the dorsal root ganglia (DRG) during development [1]. Major advances in the understanding of the central processing of pain have been achieved in the last few decades using brain imaging techniques [11] From these studies, it has become evident that there is not one common structure or master switch for the generation of pain but a complex pattern and parallel network activation which can probably be triggered by different afferent inputs via distinct anatomical pathways [12]. The spinal neurons of the ‘medial system’ project to : i) the lateral reticular nucleus (LRt), subnucleus reticularis dorsalis (SRD) or the parabrachial internal lateral subnucleus (PBil) [13] These different nuclei send nociceptive information to various parts of the medial thalamus and are involved in the affective-motivational and cognitiveevaluative aspects of pain. Enhanced synthesis of NGF using an adenoviral vector in this nucleus increased noxious mechanical sensitivity and exacerbated nocifensive responses to a noxious inflammatory stimulus in naïve animals, suggesting that NGF is a crucial mediator of the neuronal plasticity of the spinoreticular pathway
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