Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. METHODS: In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II - BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS: Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. CONCLUSIONS: The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.

Brain-Derived Neurotrophic Factor Modulates the Effect of Sex on the Descending Pain Modulatory System in Healthy Volunteers.

OBJECTIVES: We investigated sex differences and the influence of brain-derived neurotrophic factor (BDNF) in the descending pain modulatory system (DPMS), as measured by change on the numerical pain scale (NPS; 0-10) during conditioned pain modulation (CPM task; primary outcome) and by function of the corticospinal motor pathway and heat pain thresholds (HPTs; secondary outcomes). METHODS: This cross-sectional study included healthy volunteers ranging in age from 18 to 45 years (32 male and 24 female). Assessment included serum BDNF, HPT, change on the NPS (0-10) during the CPM task, and motor-evoked potential (MEP) using transcranial magnetic stimulation (TMS). RESULTS: The MEP (Mv) amplitude was larger in male participants compared with female participants (mean [SE] = 1.55 [0.34] vs mean [SE] = 1.27 [0.27], respectively, P = 0.001). The mean NPS (0-10) during CPM task changed more substantially for female compared with male participants (mean [SE] = -3.25 [2.01] vs mean [SE] = -2.29 [1.34], respectively, P = 0.040). In addition, a higher serum BDNF (adjusted index for age) was associated with a larger decrease of the NPS during CPM task (P = 0.003), although further regression analyses by sex showed that this was only significant for females (P = 0.010). CONCLUSIONS: Significant sex differences were identified in DPMS function and corticospinal motor pathway integrity. Nevertheless, BDNF was associated with the function of the DPMS in female but not male participants, indicating that sex and neuroplasticity state are crucial factors for pain perception in healthy subjects.

The Effects of Melatonin on the Descending Pain Inhibitory System and Neural Plasticity Markers in Breast Cancer Patients Receiving Chemotherapy: Randomized, Double-Blinded, Placebo-Controlled Trial.

Background: Adjuvant chemotherapy for breast cancer (ACBC) has been associated with fatigue, pain, depressive symptoms, and disturbed sleep. And, previous studies in non-cancer patients showed that melatonin could improve the descending pain modulatory system (DPMS). We tested the hypothesis that melatonin use before and during the first cycle of ACBC is better than placebo at improving the DPMS function assessed by changes in the 0-10 Numerical Pain Scale (NPS) during the conditioned pain modulating task (CPM-task) (primary outcome). The effects of melatonin were evaluated in the following secondary endpoints: heat pain threshold (HPT), heat pain tolerance (HPTo), and neuroplasticity state assessed by serum brain-derived neurotrophic factor (BDNF), tropomyosin kinase receptor B, and S100B-protein and whether melatonin's effects on pain and neuroplasticity state are due more so to its impact on sleep quality. Methods: Thirty-six women, ages 18 to 75 years old, scheduled for their first cycle of ACBC were randomized to receive 20mg of oral melatonin (n = 18) or placebo (n = 18). The effect of treatment on the outcomes was analyzed by delta (Δ)-values (from pre to treatment end). Results: Multivariate analyses of covariance revealed that melatonin improved the function of the DPMS. The Δ-mean (SD) on the NPS (0-10) during the CPM-task in the placebo group was -1.91 [-1.81 (1.67) vs. -0.1 (1.61)], and in the melatonin group was -3.5 [-0.94 (1.61) vs. -2.29 (1.61)], and the mean difference (md) between treatment groups was 1.59 [(95% CI, 0.50 to 2.68). Melatonin's effect increased the HPTo and HPT while reducing the (Δ)-means of the serum neuroplasticity marker in placebo vs. melatonin. The Δ-BDNF is 1.87 (7.17) vs. -20.44 (17.17), respectively, and the md = 22.31 [(95% CI = 13.40 to 31.22)]; TrKB md = 0.61 [0.46 (0.17) vs. -0.15 (0.18); 95% CI = 0.49 to 0.73)] and S00B-protein md = -8.27[(2.89 (11.18) vs. -11.16 (9.75); 95% CI = -15.38 to -1.16)]. However, melatonin's effect on pain and the neuroplastic state are not due to its effect on sleep quality. Conclusions: These results suggest that oral melatonin, together with the first ACBC counteracts the dysfunction in the inhibitory DPMS and improves pain perception measures. Also, it shows that changes in the neuroplasticity state mediate the impact of melatonin on pain. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03205033.

Morphine treatment alters nucleotidase activities in rat blood serum.

Morphine has been widely used in neonatal pain management. However, this treatment may produce adaptive changes in several physiologic systems. Our laboratory has demonstrated that morphine treatment in neonate rats alters nucleoside triphosphate diphosphohydrolase (NTPDase) activity and gene expression in central nervous system structures. Considering the relationship between the opioid and purinergic systems, our aim was to verify whether treatment with morphine from postnatal days 8 (P8) through 14 (P14) at a dose of 5 µg per day alters NTPDase and 5'-nucleotidase activities in rat serum over the short, medium, and long terms. After the in vivo assay, the morphine group showed increased hydrolysis of all nucleotides at P30, and a decrease in adenosine 5'-diphosphate hydrolysis at P60. Moreover, we found that nucleotidase activities change with age; adenosine 5'-triphosphate hydrolysis activity was lower at P16, and adenosine 5'-monophosphate hydrolysis activity was higher at P60. These changes are very important because these enzymes are the main regulators of blood nucleotide levels and, consequently, nucleotide signaling. Our findings showed that in vivo morphine treatment alters nucleotide hydrolysis in rat blood serum, suggesting that purine homeostasis can be influenced by opioid treatment during the neonatal period.