Microarray Analysis of Rat Sensory Ganglia after Local Inflammation Implicates Novel Cytokines in Pain

Abstract

Inflammation plays a role in neuropathic pain conditions as well as in pain induced solely by an inflammatory stimulus. Robust mechanical hyperalgesia and allodynia can be induced by locally inflaming the L5 dorsal root ganglion (DRG) in rat. This model allows investigation of the contribution of inflammation per se to chronic pain conditions. Most previous microarray studies of DRG gene expression have investigated neuropathic pain models. To examine the role of inflammation, we used microarray methods to examine gene expression 3 days after local inflammation of the L5 DRG in rat. We observed significant regulation in a large number of genes (23% of observed transcripts), and examined 221 (3%) with a fold-change of 1.5-fold or more in more detail. Immune-related genes were the largest category in this group and included members of the complement system as well as several pro-inflammatory cytokines. However, these upregulated cytokines had no prior links to peripheral pain in the literature other than through microarray studies, though most had previously described roles in CNS (especially neuroinflammatory conditions) as well as in immune responses. To confirm an association to pain, qPCR studies examined these cytokines at a later time (day 14), as well as in two different versions of the spinal nerve ligation pain model including a version without any foreign immunogenic material (suture). Cxcl11, Cxcl13, and Cxcl14 were found to be significantly upregulated in all these conditions, while Cxcl9, Cxcl10, and Cxcl16 were upregulated in at least two of these conditions.

Blocking the Mineralocorticoid Receptor Improves Effectiveness of Steroid Treatment for Low Back Pain in Rats

“…The concentration of active endogenous glucocorticoids can be locally regulated by the two forms of 11β-hydroxysteroid dehydrogenase: type 1 that reversibly forms these active corticosteroids from their 11-dehydroxy forms, and type 2 that inactivates them 16,22 . Both type 1 and type 2 enzymes were present in the DRG, and the type 1 was significantly upregulated 3 days after local DRG inflammation by microarray 42 . The activity of these enzymes also depends on the redox state of the cell, which may change with inflammation.…”

CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis

“…Moreover, this Ca 2+ response was remarkably attenuated by a CXCR3 antagonist. The upregulated CXCL10/CXCR3 signaling within DRG was also observed in the context of inflammatory/neuropathic pain [1; 10; 43]. Two variants of CXCR3 (CXCR3-A and CXCR3-B) have been identified [40].…”

“…Increasing evidence indicates that both CXCL10 and CXCR3 are expressed in the nervous tissues [20; 31], including primary sensory neurons [1]. Moreover, CXCL10/CXCR3 signaling in sensory neurons was upregulated under inflammatory or neuropathic pain conditions and was implicated in the maintenance of a chronic pain state [1; 10; 43]. Our recent study showed that cutaneous primary sensory neurons innervating the CHS skin became more excitable [34].…”

Allergic Contact Dermatitis: A Model of Inflammatory Itch and Pain in Human and Mouse

“…In other studies, CXCL10 was upregulated in DRG neurons in rats after an experimentally induced inflammation of the ganglion (Strong et al 2012) or after a demyelination of the nerve (Bhangoo et al 2007) and was upregulated in DRG neurons from human after infection of the ganglion with varicellazoster virus (Steain et al 2011). It remains to be determined whether the activation of neurons expressing message or protein for CXC10 would release CXCL10 from DRG neurons.…”