Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.
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ABSTRACT: In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. Our approach involved catecholamine depletion using 6-hydroxydopamine or, alternatively, guanethidine, to explore sympathetic contributions. Both agents substantially reduced nociceptive sensitization and selectively reduced the production of IL-6 in skin. Antagonism of IL-6 signaling using TB-2-081 also reduced sensitization in this model. Experiments using a rat keratinocyte cell line demonstrated relatively high levels of ?2-adrenergic receptor (?2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1?, tumor necrosis factor (TNF)-?, or nerve growth factor. Stimulation of the cells also promoted phosphorylation of the mitogen-activated protein kinases P38, extracellular signal-regulated kinase, and c-Jun amino-terminal kinase. Based on these in vitro results, we returned to animal testing and observed that the selective ?2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective ?2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1?, TNF-?, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates ?2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization.
SUBMITTER: Li W
PROVIDER: S-EPMC3713848 | biostudies-literature | 2013 Aug
REPOSITORIES: biostudies-literature
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