title: The role of enhanced cutaneous IL-1beta signaling in a rat tibia fracture model of complex regional pain syndrome.
abstract: Tibia fracture in rats initiates a syndrome resembling the complex regional pain syndrome type I. Accumulating evidence indicates that IL-1beta is involved in the modulation of nociceptive information and it acts as an intermediate inflammatory mediator via up-regulation of NGF. We hypothesized that IL-1beta signaling might mediate the development of the CRPS-like changes after tibial fracture, either directly or by stimulating NGF expression. Rats underwent distal tibia fracture and casting for 4 weeks and were chronically treated with an IL-1 receptor antagonist (IL-1ra). Nociceptive testing and assessment of edema and hindpaw warmth were performed at baseline and after cast removal. Bone microarchitecture was evaluated by micro-computed tomography. Confocal immunofluorescence and in situ hybridization techniques were used to evaluate changes in the cutaneous expression of IL-1beta at 4 weeks post-fracture. The nociceptive and vascular effects of intraplantar IL-1beta injections were evaluated in intact rats at different time points after injection. We found that: (1) IL-1ra reduced fracture-induced nociceptive sensitization, but did not decrease hindpaw edema or warmth, (2) fracture chronically up-regulated IL-1beta mRNA and protein expression in hindpaw skin keratinocytes, (3) IL-1beta intraplantar injection induced mechanical allodynia in a dose-dependent manner and stimulated keratinocyte NGF expression in the hindpaw skin, and (4) intraplantar injection of NGF-induced nociceptive sensitization. Collectively, these results indicate that cutaneous IL-1beta signaling can contribute to chronic regional nociceptive sensitization after fracture, possibly by stimulating NGF over-expression in keratinocytes. Our data also highlight the importance of the keratinocyte as the primary source of post-traumatic IL-1beta over-expression.
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA Anesthesiology Service, Veterans Affairs Palo Alto Health Care System Palo Alto, CA, USA Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Wen-Wu
authors.initials: WW
authors.lastname: Li
authors.forename: Ilya
authors.initials: I
authors.lastname: Sabsovich
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Zhao
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: David J
authors.initials: DJ
authors.lastname: Clark
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology / Q000503:physiopathology; D005528:Foot / Q000294:innervation / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006940:Hyperemia / Q000209:etiology / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009619:Nociceptors / Q000378:metabolism*; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012019:Reflex Sympathetic Dystrophy; D011984:Sensory Receptor Cells / Q000378:metabolism*; D012867:Skin / Q000294:innervation* / Q000503:physiopathology; D013978:Tibial Fractures / Q000150:complications; D015854:Up-Regulation / Q000502:physiology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D012333:RNA, Messenger; D020932:Nerve Growth Factor