Differential Regulation of Immune Responses and Macrophage/Neuron Interactions in the Dorsal Root Ganglion in Young and Adult Rats following Nerve Injury

Abstract

BackgroundNeuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period.ResultsWe have performed a microarray analysis of the rat L4/L5 dorsal root ganglia (DRG), 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour. The results show a set of genes, differentially regulated in the adult DRG, that are principally involved in immune system modulation. A functional consequence of this different immune response to injury is that resident macrophages cluster around the large A sensory neuron bodies in the adult DRG seven days post injury, whereas the macrophages in young DRG remain scattered evenly throughout the ganglion, as in controls.ConclusionsThe results show, for the first time, a major difference in the neuroimmune response to nerve injury in the dorsal root ganglion of young and adult rats. Differential analysis reveals a new set of immune related genes in the ganglia, that are differentially regulated in adult neuropathic pain, and that are consistent with the selective activation of macrophages around adult, but not young large A sensory neurons post injury. These differences may contribute to the reduced incidence of neuropathic pain in infants.

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

“…Interestingly, 5-HT 2B R-positive macrophages are predominantly localized around large cell bodies that are presumably responsible for mechanical transduction. This distribution of macrophages has already been described [60] and a clear relationship was observed between tactile allodynia and macrophage infiltration [16].…”

“…Intrathecal injections were performed under volatile anesthesia (see next paragraph). We injected 20 µl (30,60, 125 ng RS127445) of the antagonist or vehicle directly through the intact skin, between the L5 and L6 vertebrae, with a Hamilton syringe equipped with a 26-gauge needle. We applied 10 µl of solution (125 ng) to the sciatic nerve, as described below.…”

Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization

“…Indeed, a recent study showed that following nerve injury a very high level of transcriptional activity occurs in adult rat DRGs but not in younger ones. Our observations suggest that the different pattern of mRNAs in the axons of DRG neurons of adult and young rats might be instrumental in the postnatal developmental of neuropathic pain (Vega-Avelaira et al 2009). The DRGs in our experiments were grown in the presence of NGF to maintain neuronal viability.…”

Contribution of TRPV1 Receptor^|^ndash;Expressing Fibers to Spinal Ventral Root After-Discharges and Mechanical Hyperalgesia in a Spared Nerve Injury (SNI) Rat Model

“…In fact, the levels of the β-catenin and menin proteins, which are involved in the formation of new synapses (25), and the number of neurons reacting to the Aβ-fiber stimulation (26) are increased in lamina II of the spinal dorsal horn of SNI rats. In dorsal root ganglia (DRG), macrophages form clusters around the cell bodies of A-fibers, but not small C-fibers, in the SNI model (27). These changes in spinal cord neurotransmission after SNI surgery may contribute to mechanical allodynia.…”