title: Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.
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 β2-adrenergic receptor (β2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1β, tumor necrosis factor (TNF)-α, 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 β2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective β2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1β, TNF-α, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates β2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization.
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Li
authors.forename: Xiaoyou
authors.initials: X
authors.lastname: Shi
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Guo
authors.forename: Tzuping
authors.initials: T
authors.lastname: Wei
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D002018:Bufanolides / Q000494:pharmacology; D020918:Complex Regional Pain Syndromes / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D010146:Pain / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C466795:20,21-epoxyresibufogenin-3-formate; D018663:Adrenergic Agents; D002018:Bufanolides; D015850:Interleukin-6; D011941:Receptors, Adrenergic; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016627:Oxidopamine