Human Studies

Activation of transient receptor potential ankyrin 1 (TRPA1) channels by both environmental irritants and endogenous inflammatory mediators leads to excitation of the nerve endings, resulting in acute sensation of pain, itch, or chronic neurogenic inflammation. As such, TRPA1 channels are actively pursued as therapeutic targets for various pathological nociception and pain disorders. We uncovered that exon 27 of human TRPA1 (hTRPA1) could be alternatively spliced into hTRPA1_27A and hTRPA1_27B splice variants. The resulting channel variants displayed reduced expression, weakened affinity to interact with WT, and suffered from complete loss of function because of disruption of the C-terminal coiled-coil domain. Using a human minigene construct, we revealed that binding of splicing factor serine/arginine-rich splicing factor 1 (SRSF1) to the exonic splicing enhancer was critical for the inclusion of intact exon 27. Knockdown of SRSF1, mutation within exonic splicing enhancer, or masking SRSF1 binding with antisense oligonucleotides promoted alternative splicing within exon 27. Finally, antisense oligonucleotides-induced alternative splicing produced transcript and protein variants that could be functionally determined as diminished endogenous TRPA1 activity in human Schwann cell-line SNF96.2 and hiPSCs-derived sensory neurons. The outcome of the work could potentially offer a novel therapeutic strategy for treating pain by targeting alternative splicing of hTRPA1.

Primary dysmenorrhea (PDM) refers to menstrual pain of which the pathological cause(s) are unknown. This study examined the associations among BDNF Val66Met polymorphisms, menstrual pain severity, and hippocampal volume among young PDM subjects. We recruited 115 PDM subjects, including severe cases (n = 66) and moderate cases (n = 44), and 117 young females (aged 20-30 years) as a control group (CON) for BDNF Val66Met genotyping and MRI examination. The assessment of hippocampal volume involved analysis at various anatomical resolutions, i.e., whole hippocampal volume, hippocampal subfields, and voxel-based morphometry (VBM) volumetric analysis. Two-way ANOVA analyses with planned contrasts and Bonferroni correction were conducted for the assessment of hippocampal volume. Linear regression was used to test for BDNF Val66Met Val allele dosage-dependent effects. We observed no main effects of group, genotype, or group-genotype interactions on bilateral whole hippocampal volumes. Significant interactions between PDM severity and BDNF Val66Met genotype were observed in the right whole hippocampus, subiculum, and molecular layer. Post-hoc analysis revealed that the average hippocampal volume of Val/Val moderate PDM subjects was greater than that of Val/Val severe PDM subjects. Note that right hippocampal volume was greater in the Val/Val group than in the Met/Met group, particularly in the right posterior hippocampal region. Dosage effect analysis revealed a positive dosage-dependent relationship between the Val allele and volume of the right whole hippocampus, subiculum, molecular layer, and VBM-defined right posterior hippocampal region in the moderate PDM subgroup only. These findings indicate that Val/Val PDM subjects are resistant to intermittent moderate pain-related stress, whereas Met carrier PDM subjects are susceptible. When confronted with years of repeated PDM stress, the hippocampus can undergo differential structural changes in accordance with the BDNF genotype and pain severity. This triad study on PDM (i.e., combining genotype with endophenotype imaging results and clinical phenotypes), underscores the potential neurobiological consequences of PDM, which may prefigure in neuroimaging abnormalities associated with various chronic pain disorders. Our results provide evidence for Val allele dosage-dependent protective effects on the hippocampal structure; however, in cases of the Val variant, these effects were modulated in accordance with the severity of menstrual pain.

The majority of hospitalizations of patients with sickle cell disease (SCD) are related to painful vaso-occlusive crises (VOCs). Although the pain of VOC is classically nociceptive, neuropathic pain (NP) has also been demonstrated in SCD patients. The aim of our study is to specify the prevalence of NP during VOCs in SCD children using a dedicated scale and to measure its characteristics. We performed a prospective study that included SCD children hospitalized for an acute VOC. The presence of NP was sought with the DN4 scale on the second and fourth days of hospitalization. A total of 54 SCD children were included in the study. Overall, 41% of the patients ( = 22) experienced neuropathic pain during the VOC, mostly at an early stage (Day 2). The median age, the sex ratio, the location of the pain, and the morphine consumption were similar for patients with and without NP. Our study shows that neuropathic pain is very common during VOCs in SCD children. The absence of identified risk factors should prompt us to be vigilant regardless of the patient's age, sex, and clinical presentation.

Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates.