Disrupting 5-HT2A Receptor/PDZ Protein Interactions Reduces Hyperalgesia and Enhances SSRI Efficacy in Neuropathic Pain

Antidepressants are one of the first-line treatments for neuropathic pain. Despite the influence of serotonin (5-hydroxytryptamine, 5-HT) in pain modulation, selective serotonin reuptake inhibitors (SSRIs) are less effective than tricyclic antidepressants. Here, we show, in diabetic neuropathic rats, an alteration of the antihyperalgesic effect induced by stimulation of 5-HT_2A receptors, which are known to mediate SSRI-induced analgesia. 5-HT_2A receptor density was not changed in the spinal cord of diabetic rats, whereas postsynaptic density protein-95 (PSD-95), one of the PSD-95/disc large suppressor/zonula occludens-1 (PDZ) domain containing proteins interacting with these receptors, was upregulated. Intrathecal injection of a cell-penetrating peptidyl mimetic of the 5-HT_2A receptor C-terminus, which disrupts 5-HT_2A receptor–PDZ protein interactions, induced an antihyperalgesic effect in diabetic rats, which results from activation of 5-HT_2A receptors by endogenous 5-HT. The peptide also enhanced antihyperalgesia induced by the SSRI fluoxetine. Its effects likely resulted from an increase in receptor responsiveness, because it revealed functional 5-HT_2A receptor-operated Ca²⁺ responses in neurons, an effect mimicked by knockdown of PSD-95. Hence, 5-HT_2A receptor/PDZ protein interactions might contribute to the resistance to SSRI-induced analgesia in painful diabetic neuropathy. Disruption of these interactions might be a valuable strategy to design novel treatments for neuropathic pain and to increase the effectiveness of SSRIs.     

Resting energy expenditure in patients with alcoholic chronic pancreatitis

The aim of this study was to assess resting energy expenditure in patients with chronic pancreatitis; 33 patients with alcohol-related chronic pancreatitis (group 1: 13 normal weight, group 2: 20 underweight) and 11 undernourished patients without identifiable disease (group 3) were studied. Body composition was determined by bioelectric impedance analysis and energy expenditure by indirect calorimetry. The percentage of body weight occupied by fat-free mass was similar among the three groups (76.4±1.5%, 78.6±1.3% and 76.8±2.1% for groups 1, 2, and 3, respectively). The measured resting energy expenditure (REE) was higher than the predicted EE (Harris and Benedict formula and Cunningham's equation) for the underweight patients with chronic pancreatitis (group 2) (P<0.05), but not for the two other groups. According to Cunningham's equation, 65% of the group 2 patients were hypermetabolic (REE>110% of predicted EE) versus 23.1% and 20% in groups 1 and 3. When adjusted for fat free mass, REE was significantly (P<0.01) higher in group 2 (35.0±0.9 kcal/kg/24 hr) than in the other two groups (30.1±0.7 kcal/kg/24 hr and 30.8±1.4 kcal/kg/24 hr in groups 1 and 3, respectively). During chronic pancreatitis, weight loss is accompanied by hypermetabolism, which should be taken into consideration during nutritional support.     

Evolution over thirty years of the profile of inpatients with reactive arthritis in a tertiary rheumatology unit

Reactive arthritis (ReA) is sterile arthritis occurring after extra articular bacterial infection. The aim of this study was to analyze, over 30 years, clinical, biological and imaging characteristics as well as therapeutic management of new cases of ReA, comparing two periods.

Increased risk of tuberculosis in patients with rheumatoid arthritis

OBJECTIVE: To quantify the risk of tuberculosis (TB) in an unselected sample of patients with rheumatoid arthritis (RA) compared to the risk in the general population. METHODS: The incidence of TB in the general population of Spain was obtained from the National Network of Epidemiological Surveillance reports. The incidence of TB was ascertained from a cohort of 788 patients with RA selected randomly from the registries of 34 participating centers throughout Spain. A patient was considered a TB case only if information about disease symptoms, microorganism identification, and TB treatment were confirmed in the clinical records. The relative risk of TB in RA was calculated by dividing the standardized mean incidence of TB from 1990 to 2000 in the RA cohort by the mean incidence of TB in Spain during the same years. RESULTS: The mean incidence of TB in the general population of Spain from 1990 to 2000 was 23 cases per 100,000. Seven cases of TB were identified in the RA cohort, yielding a mean annual incidence (1990-2000) of 134/100,000 patients. The incidence risk ratio of pulmonary TB in patients with RA compared to the general population is 3.68 (95% CI 2.36-5.92). CONCLUSION: We found a 4-fold increased risk of TB infection in patients diagnosed with RA. These results might help to interpret the magnitude of the problem attributable to the introduction of new therapies in RA.