Welcome to the July 2014 CRPS Bugle, your research update for complex regional pain syndrome.
Immobilization contributes to exaggerated neuropeptide signaling, inflammatory changes, and nociceptive sensitization after fracture in rats — Guo TZ1, Wei T1, Li WW2, Li XQ3, Clark JD3, Kingery WS4.
J Pain. 2014 Jul 22. pii: S1526-5900(14)00817-7.
A tibia fracture cast immobilized for 4 weeks can induce exaggerated substance P (SP) and CGRP signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hindlimbs of rats similar to those seen in complex regional pain syndrome (CRPS). Four weeks of hindlimb cast immobilization can also induce nociceptive and vascular changes resembling CRPS. To test our hypothesis that immobilization alone could cause exaggerated neuropeptide signaling and inflammatory changes we tested 5 cohorts of rats; 1) controls, 2) tibia fracture and hindlimb casted, 3) hindlimb casted, no fracture, 4) tibia fracture with intrameduallary pinning, no cast, and 5) tibia fracture with intrameduallary pinning and hindlimb casting. After 4 weeks the casts were removed and hindlimb allodynia, unweighting, warmth, edema, sciatic nerve neuropeptide content, cutaneous and spinal cord inflammatory mediator levels, and spinal c-Fos activation were measured. After fracture with casting there was allodynia, unweighting, warmth, edema, increased sciatic nerve SP and CGRP, increased skin NK1 receptors and keratinocyte proliferation, increased in inflammatory mediator expression in the hindpaw skin (TNF-α, IL-1β, IL-6, NGF) and cord (IL-1β, NGF), and increased spinal c-Fos activation. These same changes were observed after cast immobilization alone, except spinal IL-1β levels were not increased. Treating cast only rats with an NK1 receptor antagonist inhibited development of nociceptive and inflammatory changes. Four weeks after fracture with pinning all nociceptive and vascular changes had resolved and there were no increases in neuropeptide signaling or inflammatory mediator expression.
Collectively, these data indicate that immobilization alone increased neuropeptide signaling and caused nociceptive and inflammatory changes similar to those observed after tibia fracture and casting, and that early mobilization after fracture with pinning inhibited these changes. Early limb mobilization after fracture may prevent the development of CRPS.
Heart Rate Autonomic Regulation System at Rest and During Paced Breathing among Patients with CRPS as Compared to Age-Matched Healthy Controls — Bartur G1, Vatine JJ, Raphaely-Beer N, Peleg S, Katz-Leurer M.
Pain Med. 2014 Jul 24. doi: 10.1111/pme.12449.
The objective of this study is to assess the autonomic nerve heart rate regulation system at rest and its immediate response to paced breathing among patients with complex regional pain syndrome (CRPS) as compared with age-matched healthy controls.
Ten patients with CRPS and 10 age- and sex-matched controls.
Participants underwent Holter ECG (NorthEast Monitoring, Inc., Maynard, MA, USA) recording during rest and biofeedback-paced breathing session. Heart rate variability (HRV), time, and frequency measures were assessed.
HRV and time domain values were significantly lower at rest among patients with CRPS as compared with controls. A significant association was noted between pain rank and HRV frequency measures at rest and during paced breathing; although both groups reduced breathing rate significantly during paced breathing, HRV time domain parameters increased only among the control group.
The increased heart rate and decreased HRV at rest in patients with CRPS suggest a general autonomic imbalance. The inability of the patients to increase HRV time domain values during paced breathing may suggest that these patients have sustained stress response with minimal changeability in response to slow-paced breathing stimuli.
Pathological mechanism of musculoskeletal manifestations associated with CRPS type II. An animal study — Ota H1, Arai T2, Iwatsuki K2, Urano H2, Kurahashi T2, Kato S2, Yamamoto M2, Hirata H2.
Pain. 2014 Jul 9. pii: S0304-3959(14)00305-4. doi: 10.1016/j.pain.2014.06.016.
Patients with complex regional pain syndrome (CRPS) often complain of abnormal sensations beyond the affected body part, but causes of this spread of musculoskeletal manifestations into contiguous areas remain unclear. In addition, immobilization can predispose to the development of CRPS. We examined functional, biochemical, and histological alterations in affected parts, including contiguous zones, using an animal model. Ten-week-old male Wistar rats were assigned to 5 groups: a normal group receiving no treatment; a sham operation group with surgical exploration; an immobilization group with surgical exploration plus internal knee joint immobilization; a surgical neuropathy group prepared by spinal nerve ligation (SNL) of the left L5 nerve root; and a surgical neuropathy + immobilization group with simultaneous SNL and knee joint immobilization. Mechanical allodynia and knee contracture were compared between groups, and tissues were harvested for histological assessments and gene and protein expression analyses. Neither surgical procedures nor immobilization induced detectable mechanical sensitivity. However, the addition of nerve injury resulted in detectable mechanical allodynia and immobilization not only accelerated hyperalgesia, but also resulted in muscle fibrosis. Nerve growth factor (NGF) and other mediators of neurogenic inflammation were highly expressed not only in denervated muscles, but also in innervated muscles in contiguous areas, suggesting the spread of NGF production beyond the myotome of the injured nerve. Transforming growth factor β was involved in the development of contracture in CRPS. These findings imply that neuroinflammatory components play major roles in the progression and dispersion of both sensory and pathologies and that are exacerbated by immobilization.
Med Sci Monit. 2014 Jun 25;20:1067-77. doi: 10.12659/MSM.890702.
Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: etiological contribution to complex regional pain syndromes (Part I) — Wang F1, Stefano GB2, Kream RM2.
DRG is of importance in relaying painful stimulation to the higher pain centers and therefore could be a crucial target for early intervention aimed at suppressing primary afferent stimulation. Complex regional pain syndrome (CRPS) is a common pain condition with an unknown etiology. Recently added new information enriches our understanding of CRPS pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, and mechanisms of pain modulation, central sensitization, and autonomic functions in CRPS revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of CRPS. Epigenetics refers to mitotically and meiotically heritable changes in gene expression that do not affect the DNA sequence. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, neurotransmitter responsiveness, and analgesic sensitivity, they are likely key factors in the development of chronic pain. In this dyad review series, we systematically examine the nerve injury-related changes in the neurological system and their contribution to CRPS. In this part, we first reviewed and summarized the role of neural sensitization in DRG neurons in performing function in the context of pain processing. Particular emphasis is placed on the cellular and molecular changes after nerve injury as well as different models of inflammatory and neuropathic pain. These were considered as the potential molecular bases that underlie nerve injury-associated pathogenesis of CRPS.
Cyberpsychol Behav Soc Netw. 2014 Jun;17(6):366-70. doi: 10.1089/cyber.2014.0046.
Application of virtual body swapping to patients with complex regional pain syndrome: a pilot study — Jeon B1, Cho S, Lee JH.
This study aimed to apply virtual body swapping through mental rehearsal for patients with complex regional pain syndrome (CRPS) and to investigate whether it is applicable to them. Ten patients who met the diagnostic criterion for CRPS type 1 were randomly assigned to either the treatment or control group. All participants were asked to watch the virtual body swapping training video clip with a head mounted display. The treatment group was additionally asked to assume a posture similar to the body on the screen and rehearse the movements mentally, as if the body presented on the screen was their body. No difference between the groups was found for pain intensity, however, the treatment group showed significantly more improvement in body perception disturbance (BPD) after the treatment than the control group. Even if the presented study is a preliminary one, the above results suggest that virtual body swapping through mental rehearsal is applicable for patients with CRPS and may be useful for improving BPD. The limitations of the study and the future investigations needed to provide clearer clinical suggestions are presented and discussed.
Pain. 2014 Aug;155(8):1527-39. doi: 10.1016/j.pain.2014.04.029. Epub 2014 Apr 30.
Functional significance of macrophage-derived exosomes in inflammation and pain — McDonald MK1, Tian Y1, Qureshi RA2, Gormley M3, Ertel A4, Gao R1, Aradillas Lopez E5, Alexander GM5, Sacan A2, Fortina P6, Ajit SK7.
Exosomes, secreted microvesicles transporting microRNAs (miRNAs), mRNAs, and proteins through bodily fluids, facilitate intercellular communication and elicit immune responses. Exosomal contents vary, depending on the source and the physiological conditions of cells, and can provide insights into how cells and systems cope with physiological perturbations. Previous analysis of circulating miRNAs in patients with complex regional pain syndrome (CRPS), a debilitating chronic pain disorder, revealed a subset of miRNAs in whole blood that are altered in the disease. To determine functional consequences of alterations in exosomal biomolecules in inflammation and pain, we investigated exosome-mediated information transfer in vitro, in a rodent model of inflammatory pain, and in exosomes from patients with CRPS. Mouse macrophage cells stimulated with lipopolysaccharides secrete exosomes containing elevated levels of cytokines and miRNAs that mediate inflammation. Transcriptome sequencing of exosomal RNA revealed global alterations in both innate and adaptive immune pathways. Exosomes from lipopolysaccharide-stimulated cells were sufficient to cause nuclear factor-κB activation in naive cells, indicating functionality in recipient cells. A single injection of exosomes attenuated thermal hyperalgesia in a murine model of inflammatory pain, suggesting an immunoprotective role for macrophage-derived exosomes. Macrophage-derived exosomes carry a protective signature that is altered when secreting cells are exposed to an inflammatory stimulus. We also show that circulating miRNAs altered in patients with complex regional pain syndrome are trafficked by exosomes. With their systemic signaling capabilities, exosomes can induce pleiotropic effects potentially mediating the multifactorial pathology underlying chronic pain, and should be explored for their therapeutic utility.
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