Accepted

To explore the role of strong negative emotions in spinal nociception, we evaluated the effect of fear-relevant videos of small animals on the nociceptive withdrawal reflex (NWR) and reflex-related pain perception in healthy subjects with a specific phobia of small animals. Twenty healthy subjects with a specific phobia of small animals diagnosed according to DSM-V criteria were included in this study. The NWR was evoked in the lower limb by stimulating the sural nerve and recording EMG activity in the biceps femoris. NWR pain-related perception was quantified on an 11-point numerical rating scale (NRS). Subjects were examined during 4 recording sessions. In the baseline session, no images were projected. In the other sessions, the subjects were invited to watch a video containing either neutral or phobic content. To evaluate neurovegetative responses, we measured heart rate using a pulse oximeter during each recording session. A series of clinical rating scales were administered to subjects to evaluate disgust, fear, and anxiety. The NWR amplitude was significantly increased during the phobic video session and was associated with the fear inventory scale scores. Women showed higher NWR amplitude values during the phobic video session and a lower recovery rate during the after-effect video session than did men. The NWR amplitude and related pain perception were dissociated from each other during the phobic video session, as the NRS score remained unchanged while the NWR increased in amplitude. Emotions induced by the viewing of phobic videos seem to enhance the activation of the spinal circuitries involved in nociception and the withdrawal reaction without interfering with pain processing pathways or dissociating the reflex response from related pain perception. This effect appears to differ by sex, as it was more intense and longer lasting in women than in men. Emotions induced by phobic video viewing increase the alertness devoted to the defensive reaction by emphasizing nociceptive responses independently from pain perception. The NWR may represent an interesting tool for exploring the interaction between strong negative emotions and spinal nociception. A better understanding of this mechanism may be a theoretical prerequisite for the optimization of pain management in several chronic pain syndromes.

We have reported child anxiety sensitivity (CASI) predicts chronic post-surgical pain (CPSP). Here, we evaluated DNA methylation profiles to understand gene-environmental interactions underlying CPSP and CASI, in order to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI, and pain data over 12 months post-surgery were collected. DNA from peripheral blood of evaluable subjects with (n=16) and without CPSP (n=40) were analyzed using MethylationEPIC arrays. We identified 637 and 2,445 differentially methylated positions (DMPs) associated with CPSP and CASI respectively (p≤0.05). Ingenuity pathway analysis of 39 genes with DMPs for both CPSP and CASI revealed enrichment of several canonical pathways, including GABA receptor (p=0.00016 (CPSP); 0.0008 (CASI)) and Dopamine-DARPP32 Feedback in cAMP (p=0.004 (CPSP) and 0.00003 (CASI)) Signaling. Gene-gene interaction network enrichment analysis revealed participation of pathways in cell signaling, molecular transport, metabolism and neurological diseases (p-value <10-8). Bioinformatic approaches to identify histone marks and transcription factor (TF) binding events underlying DMPs, showed their location in active regulatory regions in pain pathway relevant brain cells. Using Enrichr/Pinet enrichment and Library of Integrated Network-Based Cellular Signatures (LINCS) knockdown signatures, we identified TFs regulating genes with DMPs in association with CPSP and CASI. In conclusion, we identified epigenetically enriched pathways associated with CPSP and anxiety sensitivity in children undergoing surgery. Our findings support GABA hypofunction and Dopamine-DARPP32 pathway's roles in emotion/reward and pain. This pilot study provides new epigenetic insights into the pathophysiology of CPSP, and a basis for future studies in biomarker development and targetable interventions. Perspective: Differential DNA methylation in regulatory genomic regions enriching shared neural pathways were associated with chronic post-surgical pain and anxiety sensitivity in adolescents undergoing spine surgery. Our findings support GABA hypofunction and Dopamine-DARPP32 pathway's roles in emotion/reward contributing to behavioral maintenance of pain 10-12 months after surgery.

School anxiety is a prevalent and debilitating mental health problem among youth with chronic pain. Despite evidence that anxiety in the context of school is associated with significant school-related disability, no studies have examined specific aspects of school anxiety in a pediatric chronic pain population.

To investigate whether physician-patient agreement of potential patient problem areas impacts subsequent patient enrollment in an interdisciplinary pain management program.