Embodied pain in fibromyalgia: Disturbed somatorepresentations and increased plasticity of the body schema.

Fibromyalgia syndrome (FMS) is a highly prevalent, chronic musculoskeletal condition characterized by widespread pain and evoked pain at tender points. This study evaluated various aspects of body awareness in a sample of 14 women with FMS and 13 healthy controls, such as plasticity of the body schema, body esteem, and interoceptive awareness. To this end, the Rubber Hand Illusion (RHI), the Body Esteem Scale (BES), and the Body Perception Questionnaire (BPQ) were used, respectively. Consistent with increased plasticity of the body schema, FMS patients scored higher, with large or very large effect sizes, across all three domains evaluated in the RHI paradigm, namely proprioceptive drift and perceived ownership and motor control over the rubber hand. Scores on all items addressed by the BES were consistently lower among FMS subjects (2.52, SEM .19 vs 3.89, SEM .16, respectively, p < .01, Cohen's d = .38-.66). In the FMS sample, BES scores assigned to most painful regions also were lower than those assigned to the remaining body sites (1.58, SEM .19 vs 2.87, SEM .18, respectively, p < .01). Significantly higher scores (p < .01, Cohen's d = .51-.87) were found in the FMS sample across awareness (3.57 SEM .15 vs 1.87 SEM .11), stress response (3.76 SEM .11 vs 1.78 SEM .11), autonomic nervous system reactivity (2.59 SEM .17 vs 1.35 SEM .07), and stress style 2 (2.73 SEM .27 vs 1.13 SEM .04) subscales of the BPQ. Intensity of ongoing clinical pain was found to be strongly correlated with interoceptive awareness (r = .75, p = .002). The results suggest a disturbed embodiment in FMS, characterized by instability of the body schema, negatively biased cognitions regarding one's own body, and increased vigilance to internal bodily cues. These manifestations may be interpreted as related with the inability of incoming sensory inputs to adequately update negatively biased off-line somatorepresentations stored as long-term memory.

Coupling of serotonergic input to NMDA receptor-phosphorylation following peripheral nerve injury via rapid, synaptic up-regulation of ND2.

Evidence implicates serotonergic input to spinal dorsal horn neurons in shifting the NMDA receptor (NMDAR) into a high functional output profile after spinal nerve ligation (SNL). We investigated the involvement of adaptor protein NADH dehydrogenase subunit 2 (ND2) in NMDAR-phosphorylation and spinal hyperexcitability secondary to peripheral nerve injury. Immunofluorescence for ND2 was found in dorsal horn neurons immunopositive for NMDAR subunit NR1. Co-localization of ND2 with postsynaptic marker PSD-95 was significantly increased 60min after SNL (Rr 0.77 vs Rr 0.06 in sham controls; z=-242.85; p<0.01 at Fisher's exact test). Western blot analyses confirmed ND2 up-regulation both in cytoplasmic (S2) and synaptic (P3) compartments (p<0.01 at the Student's t test). SNL was followed by increased co-localization of ND2 with the phosphorylated form (serine 896) of NR1 (pNMDA). Spinal superfusion with ND2 inhibitor rotenone prevented up-regulation of ND2 (Rr 0.06 after rotenone vs Rr 0.78 in vehicle-treated controls, z=-253.22, p<0.01) and pNR1 in P3. C fiber-evoked dorsal horn field potentials were increased 60min after SNL by superfusion with NMDA agonist cis-ACPD at 100nM (p<0.01 at the Bonferroni test), however cis-ACPD was effective only at 10µM following prior administration of rotenone. Rotenone also abolished enhancement of evoked potentials induced by simultaneous stimulation of NMDA and 5-HR2B receptors in uninjured rats. Increased postsynaptic up-regulation of ND2/pNMDAR 60min after SNL was prevented by prior administration of selective 5-HT2B antagonist SB204741. These results support a pivotal role for ND2 in coupling serotonergic input to NMDAR-activation during neuropathic pain.

Time-dependent cross talk between spinal serotonin 5-HT2A receptor and mGluR1 subserves spinal hyperexcitability and neuropathic pain after nerve injury.

Emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. Upregulation of the serotonin receptor 2A (5-HT(2A)R) in dorsal horn neurons promotes spinal hyperexcitation and impairs spinal µ-opioid mechanisms during neuropathic pain. We investigated the involvement of spinal glutamate receptors, including metabotropic receptors (mGluRs) and NMDA, in 5-HT(2A)R-induced hyperexcitability after spinal nerve ligation (SNL) in rat. High-affinity 5-HT(2A)R agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2) enhanced C-fiber-evoked dorsal horn potentials after SNL, which was prevented by mGluR1 antagonist AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid] but not by group II mGluR antagonist LY 341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid] or NMDA antagonist d-AP5 [D-(-)-2-amino-5-phosphonopentanoic acid]. 5-HT(2A)R and mGluR1 were found to be coexpressed in postsynaptic densities in dorsal horn neurons. In the absence of SNL, pharmacological stimulation of 5-HT(2A)R with TCB-2 both induced rapid bilateral upregulation of mGluR1 expression in cytoplasmic and synaptic fractions of spinal cord homogenates, which was attenuated by PKC inhibitor chelerythrine, and enhanced evoked potentials during costimulation of mGluR1 with 3,5-DHPG [(RS)-3,5-dihydroxyphenylglycine]. SNL was followed by bilateral upregulation of mGluR1 in 5-HT(2A)R-containing postsynaptic densities. Upregulation of mGluR1 in synaptic compartments was partially prevented by chronic administration of selective 5-HT(2A)R antagonist M100907 [(R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol], confirming 5-HT(2A)R-mediated control of mGluR1 upregulation triggered by SNL. Changes in thermal and mechanical pain thresholds following SNL were increasingly reversed over the days after injury by chronic 5-HT(2A)R blockade. These results emphasize a role for 5-HT(2A)R in hyperexcitation and pain after nerve injury and support mGluR1 upregulation as a novel feedforward activation mechanism contributing to 5-HT(2A)R-mediated facilitation.

Reporting of methodologic information on trial registries for quality assessment: a study of trial records retrieved from the WHO search portal.

BACKGROUND: Although randomized clinical trials (RCTs) are considered the gold standard of evidence, their reporting is often suboptimal. Trial registries have the potential to contribute important methodologic information for critical appraisal of study results. METHODS AND FINDINGS: The objective of the study was to evaluate the reporting of key methodologic study characteristics in trial registries. We identified a random sample (n = 265) of actively recruiting RCTs using the World Health Organization International Clinical Trials Registry Platform (ICTRP) search portal in 2008. We assessed the reporting of relevant domains from the Cochrane Collaboration's 'Risk of bias' tool and other key methodological aspects. Our primary outcomes were the proportion of registry records with adequate reporting of random sequence generation, allocation concealment, blinding, and trial outcomes. Two reviewers independently assessed each record. Weighted overall proportions in the ICTRP search portal for adequate reporting of sequence generation, allocation concealment, blinding (including and excluding open label RCT) and primary outcomes were 5.7% (95% CI 3.0-8.4%), 1.4% (0-2.8%), 41% (35-47%), 8.4% (4.1-13%), and 66% (60-72%), respectively. The proportion of adequately reported RCTs was higher for registries that used specific methodological fields for describing methods of randomization and allocation concealment compared to registries that did not. Concerning other key methodological aspects, weighted overall proportions of RCTs with adequately reported items were as follows: eligibility criteria (81%), secondary outcomes (46%), harm (5%) follow-up duration (62%), description of the interventions (53%) and sample size calculation (1%). CONCLUSIONS: Trial registries currently contain limited methodologic information about registered RCTs. In order to permit adequate critical appraisal of trial results reported in journals and registries, trial registries should consider requesting details on key RCT methods to complement journal publications. Full protocols remain the most comprehensive source of methodologic information and should be made publicly available.