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Complex regional pain syndrome (CRPS) is a disorder that involves abnormal inflammation and nerve dysfunction frequently resistant to a broad range of treatments. Peripheral nerve stimulation with electroacupuncture (EA) has been widely used in different clinical conditions to control pain and inflammation; however, the use of EA in the treatment of CRPS is under investigation. In this study, we explore the effects of EA on hyperalgesia and edema induced in an animal model of chronic post-ischemia pain (CPIP model) and the possible involvement of endothelin receptor type B (ET B ) in this effect. Female Swiss mice were subjected to 3 h hind paw ischemia/reperfusion CPIP model. EA treatment produced time-dependent inhibition of mechanical and cold hyperalgesia, as well as edema in CPIP mice. Peripheral administration (i.pl.) of BQ-788 (10 nmol), an ET B antagonist, prevented EA-induced antihyperalgesia while intrathecal administration prolonged EA's effect. Additionally, peripheral pre-treatment with sarafotoxin (SRTX S6c, 30 pmol, ET B agonist) increased EA anti-hyperalgesic effect. Furthermore, the expression of peripheral ET B receptors was increased after EA treatments, as measured by western blot. These results may suggest that EA's analgesic effect is synergic with ET B receptor activation in the periphery, as well as central (spinal cord) ET B receptor blockade. These data support the use of EA as a nonpharmacological approach for the management of CRPS-I, in an adjuvant manner to ET B receptor targeting drugs.

Background: The activation of spinal glial cells (astrocyte and microglia) is reported in patient with complex regional pain syndrome (CRPS). However, the roles of spinal glial activities in the pathophysiology of CRPS are unclear. Here, we explored the roles of spinal astrocyte and microglia and the molecular mechanisms underlying CRPS using a mouse model of chronic post-ischemia pain (CPIP)., Results: CPIP injury increased the level of glial fibrillary acidic protein (GFAP, reactive astrocyte biomarker), but had no significant impact on ionized calcium binding adaptor molecule 1 (IBA1, reactive microglia biomarker), in the ipsilateral dorsal horn on post-injury day (PID) 3 when the pain threshold started to reduce significantly. Astrocytic inhibition with fluorocitrate but not microglial inhibition with minocycline attenuated the development of allodynia in CPIP-injured mice, which was concomitant with increased spinal levels of phosphorylated c-jun N-terminal kinase 1/2 (pJNK1/2) on PID 3. Furthermore, the intrathecal administration of SP600125 (JNK inhibitor) prevented the development of allodynia in CPIP-injured mice. Double immunofluorescence staining showed that pJNK1/2 was mainly co-localized with GFAP. Subsequently, increased levels of pJNK1/2 were reversed by intrathecal fluorocitrate. Furthermore, the level of spinal matrix metalloproteinase-2 (MMP2) was increased and mainly expressed in NeuN (neuron biomarker) on PID 3 in the CPIP-injured mice, while intrathecal APR 100 (MMP2 inhibitor) delayed the development of allodynia and decreased spinal levels of GFAP and pJNK1/2 on PID 3., Conclusion: This study shows that activation of astrocyte MMP2/JNK1/2 signaling pathway contributes to the pathogenesis of pain hypersensitivity in the CPIP model., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS), a type of primary chronic pain, occurs following trauma or systemic disease and typically affects the limbs. CRPS-induced pain responses result in vascular, cutaneous, and autonomic nerve alterations, seriously impacting the quality of life of affected individuals. We previously identified the involvement of keratinocyte N-methyl-d-asparagic acid (NMDA) receptor subunit 2 B (NR2B) in both peripheral and central sensitizations in CRPS, although the mechanisms whereby NR2B functions following activation remain unclear. Using an in vivo male rat model of chronic post-ischemia pain (CPIP) and an in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) cell model, we discovered that oxidative injury occurs in rat keratinocytes and HaCaT cells, resulting in reduced cell viability, mitochondrial damage, oxidative damage of nucleotides, and increased apoptosis. In HaCaT cells, OGD/R induced increases in intracellular reactive oxygen species levels and disrupted the balance between oxidation and antioxidation by regulating a series of antioxidant genes. The activation of NMDA receptors via NMDA exacerbated these changes, whereas the inhibition of the NR2B subunit alleviated them. Co-administration of ifenprodil (an NR2B antagonist) and NMDA (an NMDA receptor agonist) during the reoxygenation stage did not result in any significant alterations. Furthermore, intraplantar injection of ifenprodil effectively reversed the altered gene expression that was observed in male CPIP rats, thereby revealing the potential mechanisms underlying the therapeutic effects of peripheral ifenprodil administration in CRPS. Collectively, our findings indicate that keratinocytes undergo oxidative injury in CRPS, with NMDA receptors playing regulatory roles. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome (CRPS) is a debilitating neurologic disorder with an interlinked and yet incompletely defined pathogenesis. Treatment options remain a therapeutic challenge. Linagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors which are used for the treatment of diabetes mellitus. Apart from the improvement of glycemic control, accumulating evidence points to the beneficial effects of DPP-4 inhibitors in a wide array of conditions. Herein, the present study was outlined to investigate the antinociceptive effect of linagliptin in acute pain conditions, and in an animal model of CRPS. A prolonged hind paw ischemia reperfusion (I/R) injury to the left hind paw was done to induce chronic post-ischemia pain (CPIP) in rats. Allodynia and hyperalgesia were assessed in both ipsilateral and contralateral hind paws at different time points. At the end of the experiment, markers of oxidative stress and inflammatory cytokines were assayed in paw skin samples. The results showed that linagliptin had no effect on acute nociception. On the other hand, linagliptin treatment, for seven days, ameliorated hyperalgesia, mechanical and cold allodynia, and attenuated oxidative and inflammatory markers in CPIP rats. In conclusion, linagliptin was able to ameliorate aberrant pain behavior induced by prolonged hind paw ischemia. These effects can be attributed, at least partially, to the reduction of inflammatory cytokine levels and restore oxidant/antioxidant balance in the CPIP model. Hence, linagliptin pleiotropic effects open a new horizon to further investigate its role in the treatment of inflammatory and chronic painful conditions, especially in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Sex differences have been increasingly highlighted in complex regional pain syndrome (CRPS) in clinical practice. In CRPS type I (CRPS-I), although inflammation and oxidative stress have been implicated in its pathogenesis, whether pain behavior and the underlying mechanism are sex-specific is unclear. In the present study, we sought to explore whether sex differences have an impact on inflammation, oxidative stress, and pain sensitivity in CRPS-I. Methods: Chronic post-ischemia pain (CPIP) was established in both male and female mice as an animal model of CRPS-I. Edema and mechanical allodynia of bilateral hind paws were assessed after reperfusion. Blood samples were analyzed for serum levels of oxidative stress markers and inflammatory cytokines. Results: Both male and female mice developed edema. Male mice developed CPIP at day 3 after reperfusion; female mice developed CPIP at day 2 after reperfusion. Female mice displayed significantly earlier and higher mechanical allodynia in the ischemic hind paw, which was associated with higher serum levels of IL-2, TNF-α, isoprostanes, 8 OhdG, and malondialdehyde at day 2 after reperfusion. Moreover, female mice showed significantly lower SOD and IL-4 compared to male mice at day 2 after reperfusion. Conclusion: Our results indicate that sex differences in inflammatory and oxidative stress states may play a central role in the sex-specific nociceptive hypersensitivity in CRPS-I, and offer a new insight into pharmacology treatments to improve pain management with CRPS. [ABSTRACT FROM AUTHOR]

Abstract: Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using a 3-h ischemia–reperfusion injury of the rodent hind paw. The contribution of local endothelin to nociception has been evaluated in CPIP mice by measuring sustained nociceptive behaviors (SNBs) following intraplantar injection of endothelin-1 or -2 (ET-1, ET-2). The effects of local BQ-123 (ETA-R antagonist), BQ-788 (ETB-R antagonist), IRL-1620 (ETB-R agonist) and naloxone (opioid antagonist) were assessed on ET-induced SNBs and/or mechanical and cold allodynia in CPIP mice. ETA-R and ETB-R expression was assessed using immunohistochemistry and Western blot analysis. Compared to shams, CPIP mice exhibited hypersensitivity to local ET-1 and ET-2. BQ-123 reduced ET-1- and ET-2-induced SNBs in both sham and CPIP animals, but not mechanical or cold allodynia. BQ-788 enhanced ET-1- and ET-2-induced SNBs in both sham and CPIP mice, and cold allodynia in CPIP mice. IRL-1620 displayed a non-opioid anti-nociceptive effect on ET-1- and ET-2-induced SNBs and mechanical allodynia in CPIP mice. The distribution of ETA-R and ETB-R was similar in plantar skin of sham and CPIP mice, but both receptors were over-expressed in plantar muscles of CPIP mice. This study shows that ETA-R and ETB-R have differing roles in nociception for sham and CPIP mice. CPIP mice exhibit more local endothelin-induced SNBs, develop a novel local ETB-R agonist-induced (non-opioid) analgesia, and exhibit over-expression of both receptors in plantar muscles, but not skin. The effectiveness of local ETB-R agonists as anti-allodynic treatments in CPIP mice holds promise for novel therapies in CRPS-I patients. [Copyright &y& Elsevier]