Chronic Neuropathic Pain is Accompanied by Global Changes in Gene Expression and Shares Pathobiology with Neurodegenerative Diseases

Abstract

Neuropathic pain is induced by injury or disease of the nervous system. Studies aimed at understanding tile molecular pathophysiology of neuropathic pain have so far focused on a few known molecules and signaling pathways in neurons. However, the pathophysiology of neuropathic pain appears to be very complex and remains poorly understood. A global understanding of the molecular mechanisms involved in neuropathic pain is needed for a better understanding of the pathophysiology and treatment of neuropathic pain. Towards this end, we examined global gene expression changes as well as the pathobiology at the cellular level in a spinal nerve ligation neuropathic pain model using DNA microarray, quantitative real‐time PCR and immunohistochemistry. We found that the behavioral hypersensitivity that is manifested in the persistent pain state is accompanied by previously undescribed changes in gene expression. In the DRG, we found regulation of: (1) immediate early genes; (2) genes such as ion channels and signaling molecules that contribute to the excitability of neurons; and (3) genes that are indicative of secondary events such as neuroinflammation. In addition, we studied gene regulation in both injured and uninjured DRG by quantitative PCR, and observed differential gene regulation in these two populations of DRGs. Furthermore, we demonstrated unexpected co‐regulation of many genes, especially the activation of neuroinflammation markers in both the PINS and CNS. The results of our study provide a new picture of the molecular mechanisms that underlie the complexity of neuropathic pain and suggest that chronic pain shares common pathobiology with progressive neurodegenerative disease.

α2δ-1 Gene Deletion Affects Somatosensory Neuron Function and Delays Mechanical Hypersensitivity in Response to Peripheral Nerve Damage

“…The ␣ 2 ␦-1 ligands gabapentin and pregabalin are effective in the treatment of a range of chronic neuropathic conditions (Moore et al, 2009(Moore et al, , 2011. In several different animal models of neuropathic pain caused by peripheral nerve damage, there are many genes, including ion channels, whose expression is altered in injured dorsal root ganglion (DRG) neurons (Wang et al, 2002;Ji and Strichartz, 2004). In particular, there is an upregulation of the calcium channel auxiliary subunit ␣ 2 ␦-1 (Newton et al, 2001;Wang et al, 2002).…”

The α2δ Ligand Gabapentin Inhibits the Rab11-Dependent Recycling of the Calcium Channel Subunit α2δ-2

“…According to this study, GBP prevented the interaction of ␣ 2 ␦-1 with TSPs, thus reducing the TSP-mediated synaptogenesis. It is possible that GBP also prevents the interaction between ␣ 2 ␦ and TSP at an intracellular location, especially since TSP1 is known to be rapidly internalized (Godyna et al, 1995), and TSP4 is upregulated together with ␣ 2 ␦-1 in DRGs in experimental neuropathic pain (Wang et al, 2002). Furthermore, it is of interest that GBP was only found to prevent synapse formation when applied during synaptogenesis but did not disrupt established synapses (Eroglu et al, 2009).…”

Identification of genes regulating sensory neuron genesis and differentiation in the avian dorsal root ganglia

“…The identification of differentially expressed genes during development begins by either comparing the ensemble of transcripts or the ensemble of proteins from a particular immature tissue to those from the mature tissue. Previous DRG transcriptome analyses have been conducted (Akopian and Wood, 1995;Friedel et al, 1997;Dong et al, 2001;Costigan et al, 2002;Wang et al, 2003;Shin et al, 2003); however, none of these screens were designed to specifically identify molecules regulating early events in the immature DRG, i.e., during sensory neurogenesis and differentiation.…”