Acute and chronic phases of complex regional pain syndrome in mice are accompanied by distinct transcriptional changes in the spinal cord.
Gallagher JJ, Tajerian M, Guo T, Shi X, Li W, Zheng M, Peltz G, Kingery W, Clark JD.
CRPS is a painful, debilitating, and often-chronic condition characterized by various sensory, motor, and vascular disturbances. Despite many years of study, current treatments are limited by our understanding of the underlying mechanisms. Little is known on the molecular level concerning changes in gene expression supporting the nociceptive sensitization commonly observed in CRPS limbs, or how those changes might evolve over time.
We used a well-characterized mouse tibial fracture/cast immobilization model of CRPS to study molecular, vascular and nociceptive changes. We observed that the acute (3 weeks after fracture) and chronic (7 weeks after fracture) phases of CRPS-like changes in our model were accompanied by unique alterations in spinal gene expression corresponding to distinct canonical pathways. For the acute phase, top regulated pathways were: chemokine signaling, glycogen degradation, and cAMP-mediated signaling; while for the chronic phase, the associated pathways were: coagulation system, granzyme A signaling, and aryl hydrocarbon receptor signaling. We then focused on the role of CcL2, a chemokine that we showed to be upregulated at the mRNA and protein levels in spinal cord tissue in our model. We confirmed its association with the nociceptive sensitization displayed in this model by demonstrating that the spinal but not peripheral administration of a CCR2 antagonist (RS504393) in CRPS animals could decrease mechanical allodynia. The spinal administration of CcL2 itself resulted in mechanical allodynia in control mice.
Our data provide a global look at the transcriptional changes in the spinal cord that accompany the acute and chronic phases of CRPS as modeled in mice. Furthermore, it follows up on one of the top-regulated genes coding for CcL2 and validates its role in regulating nociception in the fracture/cast model of CRPS.
An older paper identifying the effects of immobilisation that are similar to CRPS and the role of substance P in the vascular changes.
Substance P signalling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I.
Guo TZ, Offley SC, Boyd EA, Jacobs CR, Kingery WS.
Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Wrist and ankle fractures are the most frequent causes of complex regional pain syndrome (CRPS type I). The current study examined the temporal development of vascular, nociceptive and bony changes after distal tibial fracture in rats and compared these changes to those observed after cast immobilization in intact normal rats. After baseline testing the right distal tibial was fractured and the hindlimb casted. A control group was simply casted without fracturing the tibia. After 4 weeks the casts were removed and the rats retested. Subsequent testing was performed at 6, 8, 10, 16, and 20 weeks after onset of treatment. Distal tibial fracture or cast immobilization alone generated chronic hindlimb warmth, edema, spontaneous protein extravasation, allodynia, and periarticular osteoporosis, changes resembling those observed in CRPS. Hindlimb warmth and allodynia resolved much more quickly after cast immobilization than after fracture. Previously we observed that the substance P receptor (NK(1)) antagonist LY303870 reversed vascular and nociceptive changes in a sciatic section rat model of CRPS type II. Postulating that facilitated substance P signaling may also contribute to the vascular and nociceptive abnormalities observed after tibial fracture or cast immobilization, we attempted to reverse these changes with LY303870. Hindpaw warmth, spontaneous extravasation, edema, and allodynia were inhibited by LY303870. Collectively, these data support the hypotheses that the distal tibial fracture model simulates CRPS, immobilization alone can generate a syndrome resembling CRPS, and substance P signaling contributes to the vascular and nociceptive changes observed in these models.
Pain-related fear, perceived harmfulness of activities, and functional limitations in complex regional pain syndrome type I.
de Jong JR, Vlaeyen JW, de Gelder JM, Patijn J.
Department of Rehabilitation, University Hospital Maastricht, Maastricht, The Netherlands. firstname.lastname@example.org
Numerous studies have shown that pain-related fear is one of the strongest predictors of pain disability in patients with chronic musculoskeletal pain, and there is evidence that the reduction of pain-related fear through an exposure treatment can be associated with restoration of functional abilities in patients with complex regional pain syndrome type I (CRPS-I). These findings suggest that pain-related fear may be associated with functional limitations in neuropathic pain as well. The aim of the current study was to test whether the debilitating role of pain-related fear generalizes to patients with CRPS-I. The results of 2 studies are presented. Study I includes a sample of patients with early CRPS-I referred to an outpatient pain clinic. In Study II, patients with chronic CRPS who are members of a patients’ association were invited to participate. The results show that in early CRPS-I, pain severity but not fear of movement/(re)injury as measured with the Tampa Scale for Kinesiophobia was related to functional limitations. In patients with chronic CRPS-I, however, perceived harmfulness of activities as measured with the pictorial assessment method significantly predicted functional limitations beyond and above the contribution of pain severity. Not fear of movement/(re)injury in general, but the perceived harmfulness of activities appears a key factor that might be addressed more systematically in the clinical assessment of patients with CRPS-I. These results support the idea that pain-related fear might be a promising concept in the understanding of pain disability in patients with neuropathic pain.
This is the first study showing that perceived harmfulness of activities contribute to the functional limitations in CRPS-I. The current findings may help clinicians customizing cognitive-behavioral treatments for patients with chronic neuropathic pain.