Abstract
The present study reproduces chronic post-ischemia pain (CPIP), a model of complex regional pain syndrome type I (CRPS-I), in rats to examine the possible transient and long-term anti-allodynic effect of mangiferin (MG); as well as its potential beneficial interactions with some standard analgesic drugs and sympathetic-mediated vasoconstriction and vasodilator agents during the earlier stage of the pathology. A single dose of MG (50 and 100 mg/kg, p.o.) decreased mechanical allodynia 72 h post-ischemia-reperfusion (I/R). MG 100 mg/kg, i.p. (pre- vs. post-drug) increased von Frey thresholds in a yohimbine and naloxone-sensitive manner. Sub-effective doses of morphine, amitriptyline, prazosin, clonidine and a NO donor, SIN-1, in the presence of MG were found to be significantly anti-allodynic. A long-term anti-allodynic effect at 7 and 13 days post-I/R after repeated oral doses of MG (50 and 100 mg/kg) was also observed. Further, MG decreased spinal and muscle interleukin-1β concentration and restored muscle redox status. These results indicate that MG has a transient and long-term anti-allodynic effect in CPIP rats that appears to be at least partially attributable to the opioid and α2 adrenergic receptors. Additionally, its anti-inflammatory and antioxidant mechanisms could also be implicated in this effect. The association of MG with sub-effective doses of these drugs enhances the anti-allodynic effect; however, an isobolographic analysis should be performed to define a functional interaction between them. These findings suggest the possible clinical use of MG in the treatment of CRPS-I in both early sympathetically maintained pain and long-term sympathetically independent pain.
Highlights
Complex regional pain syndrome (CRPS) is a disabling condition most often presenting after trauma affecting the distal part of an extremity
At 72 h after I/R injury, Chronic post-ischemia pain (CPIP) rats developed a reduction in paw-withdrawal threshold compared to sham (P < 0.001) (Figure 1)
Within the CPIP group, 33 rats (82.5%) displayed a 50% von Frey threshold
Summary
Complex regional pain syndrome (CRPS) is a disabling condition most often presenting after trauma affecting the distal part of an extremity. It is characterized by a continuing pain, which is disproportionate to the inciting event, in addition to sensory, autonomic, motor, and trophic disturbances (Bruehl et al, 2002; Beerthuizen et al, 2012). Hypothetical interactions between sympathetic noradrenergic nerve fibers, peptidergic afferent nerve fibers, blood vessels, and immune cells leading to vasoconstriction, further release of cytokines and sensitization, have been suggested. It has been suggested that the traditionally used sympathetic blocks should be an exception, rather than a rule for CRPS treatment (Birklein and Schlereth, 2015). In view of the positive results in clinical trials for both the ROS scavengers and corticosteroids, studies combining them are recommended (Zollinger et al, 1999; Pérez et al, 2003; Bianchi et al, 2006)
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