Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome.
BACKGROUND
Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia, a syndrome resembling complex regional pain syndrome (CRPS). Previous studies suggest that the pathogenesis of some of these changes involves an exaggerated regional inflammatory response to injury and we postulated that inflammatory cytokines contribute to the development of CRPS-like changes after fracture.


METHODS
The distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were given drinking water with or without the cytokine inhibitor pentoxifylline (PTX) starting the day before fracture and continuing for 4 weeks, after which time the cast was removed and multiple assays were performed in the hindpaw. PCR and immunoassays were used to evaluate changes in cytokine expression. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured by microcomputed tomography (microCT).


RESULTS
Tibia fracture chronically up-regulated TNFalpha, IL-1beta and IL-6 mRNA and protein levels in hindpaw skin and PTX treatment significantly reduced the mRNA expression and cytokine protein levels for all these cytokines. PTX inhibited the nociceptive sensitization and some vascular changes, but had insignificant effects on most of the bone-related parameters measured in these studies. Immunostaining of hindpaw skin was negative for immunocyte infiltration at 4 weeks post-fracture.


CONCLUSIONS
These results suggest that pro-inflammatory cytokines contribute to the nociceptive and vascular sequelae of fracture and that PTX treatment can reverse these CRPS-like changes.
Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Tzuping
T
Wei
Ilya
I
Sabsovich
Tian-Zhi
TZ
Guo
Xiaoyou
X
Shi
Rong
R
Zhao
Wenwu
W
Li
Christian
C
Geis
Claudia
C
Sommer
Wade S
WS
Kingery
David J
DJ
Clark
D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000293:injuries / Q000473:pathology; D020918:Complex Regional Pain Syndromes / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005528:Foot / Q000294:innervation / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007378:Interleukins / Q000378:metabolism; D008297:Male; D009619:Nociceptors / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012881:Skin Temperature / Q000187:drug effects / Q000502:physiology; D013978:Tibial Fractures / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D016166:Free Radical Scavengers; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline