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Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.

ABSTRACT: In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. Our approach involved catecholamine depletion using 6-hydroxydopamine or, alternatively, guanethidine, to explore sympathetic contributions. Both agents substantially reduced nociceptive sensitization and selectively reduced the production of IL-6 in skin. Antagonism of IL-6 signaling using TB-2-081 also reduced sensitization in this model. Experiments using a rat keratinocyte cell line demonstrated relatively high levels of ?2-adrenergic receptor (?2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1?, tumor necrosis factor (TNF)-?, or nerve growth factor. Stimulation of the cells also promoted phosphorylation of the mitogen-activated protein kinases P38, extracellular signal-regulated kinase, and c-Jun amino-terminal kinase. Based on these in vitro results, we returned to animal testing and observed that the selective ?2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective ?2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1?, TNF-?, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates ?2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization.

SUBMITTER: Li W

PROVIDER: S-EPMC3713848 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.

Li Wenwu W Shi Xiaoyou X Wang Liping L Guo Tianzhi T Wei Tzuping T Cheng Kejun K Rice Kenner C KC Kingery Wade S WS Clark J David JD

Pain 20130412 8

In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of C ...[more]

PMID: 23718987

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Project description:Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenesis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that antiresorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously, we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS, and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, postfracture cutaneous cytokine upregulation, and adaptive immune responses in this CRPS model.Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by microcomputed tomography, and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed, and skin cytokine (tumor necrosis factor, interleukin [IL]-1, IL-6) and nerve growth factor (NGF) levels were determined by enzyme immunoassay. Skin and sciatic nerve immunoglobulin levels were determined by enzyme immunoassay.Rats with tibia fractures developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression and trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by microcomputed tomography, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression, and elevated immunocomplex deposition in skin and nerve. Alendronate (60 ?g/kg/d subcutaneously [s.c.]) or zoledronate (3 mg/kg/d orally) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44% ± 13% and 58% ± 5%, respectively. Orally administered zoledronate (3 mg/kg/d for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4 weeks postfracture. Histomorphometric and microcomputed tomography analysis demonstrated that both the 3 and 60 ?g/kg/d alendronate treatments reversed trabecular bone loss (an 88% ± 25% and 188% ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing postfracture levels of tumor necrosis factor by 43% ± 9%, IL-1 by 60% ± 9%, IL-6 by 56% ± 14%, and NGF by 37% ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition.Collectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS.

Project description:Complex Regional Pain Syndrome (CRPS) is a multifactorial and disabling disorder with complex etiology and pathogenesis. Goals of therapy in CRPS should be pain relief, functional restoration, and psychological stabilization, but early interventions are needed in order to achieve these objectives. Several drugs have been used to reduce pain and to improve functional status in CRPS, despite the lack of scientific evidence supporting their use in this scenario. They include anti-inflammatory drugs, analgesics, anesthetics, anticonvulsants, antidepressants, oral muscle relaxants, corticosteroids, calcitonin, bisphosphonates, calcium channel blockers and topical agents. NSAIDs showed no value in treating CRPS. Glucocorticoids are the only anti-inflammatory drugs for which there is direct clinical trial evidence in early stage of CRPS. Opioids are a reasonable second or third-line treatment option, but tolerance and long term toxicity are unresolved issues. The use of anticonvulsants and tricyclic antidepressants has not been well investigated for pain management in CRPS. During the last years, bisphosphonates have been the mostly studied pharmacologic agents in CRPS treatment and there are good evidence to support their use in this condition. Recently, the efficacy of intravenous (IV) administration of neridronate has been reported in a randomized controlled trial. Significant improvements in VAS score and other indices of pain and quality of life in patients who received four 100 mg IV doses of neridronate versus placebo were reported. These findings were confirmed in the open-extension phase of the study, when patients formerly enrolled in the placebo group received neridronate at the same dosage, and these results were maintained at 1 year follow-up. The current literature concerning sympathetic blocks and sympathectomy techniques lacks evidence of efficacy. Low evidence was recorded for a free radical scavenger, dimethylsulphoxide (DMSO) cream (50%). The same level of efficacy was noted for vitamin C (500 mg per day for 50 days) in prevention of CRPS in patients affected by wrist fracture. In conclusion, the best available therapeutic approach to CRPS is multimodal and is based on the use of several classes of drugs, associated to early physiotherapy. Neridronate at appropriate doses is associated with clinically relevant and persistent benefits in CRPS patients.

Project description:BACKGROUND: Aberrant expression of small noncoding RNAs called microRNAs (miRNAs) is a common feature of several human diseases. The objective of the study was to identify miRNA modulation in patients with complex regional pain syndrome (CRPS) a chronic pain condition resulting from dysfunction in the central and/or peripheral nervous systems. Due to a multitude of inciting pathologies, symptoms and treatment conditions, the CRPS patient population is very heterogeneous. Our goal was to identify differentially expressed miRNAs in blood and explore their utility in patient stratification. METHODS: We profiled miRNAs in whole blood from 41 patients with CRPS and 20 controls using TaqMan low density array cards. Since neurogenic inflammation is known to play a significant role in CRPS we measured inflammatory markers including chemokines, cytokines, and their soluble receptors in blood from the same individuals. Correlation analyses were performed for miRNAs, inflammatory markers and other parameters including disease symptoms, medication, and comorbid conditions. RESULTS: Three different groups emerged from miRNA profiling. One group was comprised of 60% of CRPS patients and contained no control subjects. miRNA profiles from the remaining patients were interspersed among control samples in the other two groups. We identified differential expression of 18 miRNAs in CRPS patients. Analysis of inflammatory markers showed that vascular endothelial growth factor (VEGF), interleukin1 receptor antagonist (IL1Ra) and monocyte chemotactic protein-1 (MCP1) were significantly elevated in CRPS patients. VEGF and IL1Ra showed significant correlation with the patients reported pain levels. Analysis of the patients who were clustered according to their miRNA profile revealed correlations that were not significant in the total patient population. Correlation analysis of miRNAs detected in blood with additional parameters identified miRNAs associated with comorbidities such as headache, thyroid disorder and use of narcotics and antiepileptic drugs. CONCLUSIONS: miRNA profiles can be useful in patient stratification and have utility as potential biomarkers for pain. Differentially expressed miRNAs can provide molecular insights into gene regulation and could lead to new therapeutic intervention strategies for CRPS.

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Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.

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Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome.

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