Possible Therapeutic Options for Complex Regional Pain Syndrome

Abstract

Complex regional pain syndrome (CRPS) describes an array of painful conditions that are characterized by continuing regional pain. CRPS comprises severe and inappropriate pain in cases of complete recovery after trauma. Research on the pharmacological treatment of CRPS, however, has not been well investigated. In this study, we compared the pain relief effects of different drugs (URB597, pyrrolidine dithiocarbamate, and hydralazine) in a rat model of chronic post-ischemic pain-induced CRPS. After drug injection, CRPS-induced mechanical allodynia was significantly recovered. After three repetitive drug injections, mechanical sensitivity generally improved as hyper-nociception subsided. Reduced Nav1.7 expression at dorsal root ganglions (DRGs) was observed in the drug treatment groups. Neural imaging analysis revealed decreased neural activity for each drug treatment, compared to vehicle. In addition, treatments significantly reduced IL-1β, IL-6, and TNFα expression in DRGs. These results indicated that drugs could reduce the expression of inflammatory factors and alleviate the symptoms of chronic post-ischemic pain-induced CRPS.

Keywords: URB597; chronic post-ischemic pain; complex regional pain syndrome; hydralazine; pyrrolidine dithiocarbamate.

Figure 1

Rat model of chronic post-ischemia pain (CPIP) and nocifensive behavior changes. (A). Representative photographs of the rat hind paw taken during CPIP model establishment. The red arrow indicates the paw treated with an O-ring. (B). Hind-view of the paw with the O-ring. (C). Mechanical threshold changes pre- and post-CPIP. n = 6 rats/group; one-way ANOVA followed by Tukey post hoc test was used for statistical analysis; * p < 0.05.

Figure 2

Activation of Nav1.7 channels in DRGs of the CPIP model. In DRG sections, immunohistochemical evidence showed that the expression of Nav1.7 increased in CPIP-injured rats. (A) Comparison of Nav1.7 expression in vehicle, URB597, PTDC, and Hydralazine injection groups. (B) Pie charts showing the percentage of DRG neurons expressing Nav1.7 among all treated drugs. The upper number indicates the number of Nav1.7-expressing neuron cells, and the lower number indicates the non-expressing neuron cells.

Figure 3

Comparison of DRG responses with electric stimulation in each group. (A) Comparison of VSD signals in the vehicle, URB597, PTDC, and hydralazine injection groups. (B) The typical time course of optical signals from DRG neurons. Red arrow represents the stimulus onset. Fluorescence changes: upward deflections of the signal indicate depolarization after electrical stimulation. (C) The reduced signals were observed in DRGs of drug-treated rats. n = 5 rats/group; one-way ANOVA followed by Tukey post hoc test was used for statistical analysis; data represent mean ± SEM; * p < 0.05.

Figure 4

Changes in the relative density of IL-1β, IL-6 and TNFα protein in the ipsilateral DRGs (L3, L4 and L5). (A) Representative data indicate Western blotting for IL-1β, IL-6, and TNFα in DRGs. After repetitive injection of drugs, protein levels decreased. (B) Protein expression changes after drug application. n = 5 rats/group; one-way ANOVA followed by Tukey post hoc test was used for statistical analysis; data represent mean ± SEM; * p < 0.05.