Tissue damage-induced axon injury-associated responses in sensory neurons: requirements, prevention, and potential role in persistent post-surgical pain

bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-12

Abstract Pain resulting from tissue damage, including surgical incision, is often only partially responsive to standard treatments focusing on inflammation, suggesting additional mechanisms are involved. Tissue damage leads to expression in dorsal root ganglion (DRG) sensory neurons of activating transcription factor 3 (ATF3), a known injury-induced transcription factor. ATF3 expression is associated with sensitization of cellular physiology and enhanced amplitude/duration of a nociceptive reflex. It is unclear how tissue damage leads to these changes in the sensory neurons, but it could include direct damage to the tissue-innervating axons and inflammation-associated retrograde biochemical signalling. We examined the necessity and sufficiency of incision, inflammation, and axonal conduction for induction of ATF3 in response to skin incision. Incision outside of a single dermatome, but close enough to induce inflammation inside the dermatome, was not sufficient to induce ATF3 expression in the corresponding DRG. Incision inside the dermatomeled to strong expression of ATF3. Anti-inflammatory treatments did not prevent this induction of ATF3. In rodent models of repeated injury - a major etiological factor for chronic pain - ATF3 expression was synergistically increased and the threshold for paw-withdrawal to mechanical stimulation was significantly decreased for an extended duration. Together, these results suggest that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3, expression of which appears additionally increased by repeated injury. Further, pre-treatment of the nerves innervating the incised skin with bupivacaine, a local anesthetic commonly used to reduce surgical pain, did not prevent induction of ATF3, indicating that conduction of action potentials is not necessary for induction of ATF3. We also determined that closure of incision with surgical glue significantly reduced incision-induced expression of ATF3 and GAP-43. Intriguingly, treatment with polyethylene glycol (PEG), known to enhance membrane integrity after injury among other effects, reduced incision-associated ATF3 expression and electrophysiological changes. These results suggest that pain resulting from tissue damage may arise from a mix of ATF3-independent inflammation-related mechanisms as well as ATF3-/axonal-damage-associated mechanism and therefore require a mix of approaches to achieve more complete control some of which we suggest here.. Funding JCP NIH R01NS109936, R21NS120498, KSCHIRT 10-10 BJH NIH R01NS121533 SCOPE statement Pain resulting from tissue damage, including surgical incision, is often only partially responsive to anti-inflammatory treatments, suggesting multiple mechanisms at work, including neuropathic. Cutaneous tissue damage leads to expression in DRG sensory neurons of the injury marker ATF3 - associated with physiological sensitization and enhancement of a nociceptive reflex. We examined some of the conditions for induction of ATF3 in response to incision of skin and the impact of interventions. Treatment with anti-inflammatory ketoprofen and/or local anesthetic did not prevent the induction of ATF3, together suggesting that actual damage to axons innervating the skin is both necessary and sufficient for induction of ATF3. Repeated incision induced unique changes in expression of ATF3- and pain-associated genes. Closure with surgical glue reduced incision-induced gene expression compared to closure with staples. Treatment with polyethylene glycol (PEG), known to enhance membrane integrity after axonal injury, reduced induction of ATF3 and electrophysiological changes. These experiments were designed to identify distinct pain-related mechanisms with pre-clinical animal models that reflect existing clinical practice and feasible future practice. These results suggest that pain resulting from tissue damage likely arises from mixed mechanisms – including neuropathic – and therefore require a mix of approaches to achieve more complete control.

Tissue damage-induced axon injury-associated responses in sensory neurons: requirements, prevention, and potential role in persistent post-surgical pain

Frontiers in Pain Research · 2025-11-14

Pain resulting from tissue damage, including surgical incision, is often only partially responsive to anti-inflammatory drugs, suggesting the contribution of a neuropathic mechanism. Tissue damage leads to expression in dorsal root ganglion (DRG) sensory neurons of activating transcription factor 3 (Atf3), a known injury-induced transcription factor. Atf3 expression is associated with sensitization of cellular physiology and enhanced amplitude/duration of a nociceptive reflex. It is unclear how tissue damage leads to these changes in the sensory neurons, but it could include direct damage to the tissue-innervating axons and inflammation-associated retrograde biochemical signalling. We examined the necessity and sufficiency of incision, inflammation, and axonal conduction for induction of Atf3 in response to skin incision in rat. Incision outside of a single dermatome, but close enough to induce inflammation inside the dermatome, was not sufficient to induce Atf3 expression in the corresponding DRG. Incision inside the dermatome led to strong expression of Atf3. An anti-inflammatory drug did not prevent this induction of Atf3. In a mouse model of repeated injury – a major etiological factor for chronic pain – a second plantar incision induced a significant extension in the duration of mechanical hypersensitivity as compared to a single plantar incision. This corresponded with a remarkable increase in Atf3 expression in a rat model of repeated incision. Together, these results suggest that damage to axons innervating the skin is both necessary and sufficient for induction of Atf3 expression in sensory neurons. This is dramatically increased by repeated injury. Further, pre-treatment of the nerves innervating the incised skin with bupivacaine, a local anesthetic commonly used to reduce surgical pain, did not prevent induction of Atf3, indicating that conduction of action potentials is not necessary for induction of Atf3. Closure of incision with surgical glue or treatment with polyethylene glycol, known to enhance membrane integrity after injury, reduced incision-associated regulation of Atf3, Growth-Associated Protein-43 ( Gap43 ), and electrophysiological changes. We conclude that tissue damage-induced pain arises from a mix of Atf3-independent inflammation-related mechanisms and axonal damage-associated mechanisms and therefore requires a mix of approaches to prevent/treat persistent post-surgical pain.

Teaching science in outreach programs may enhance health science communication and engagement in medical students

Frontiers in Communication · 2025-07-23 · 2 citations

Medical education increasingly emphasizes the development of communication, empathy, and teaching skills alongside scientific knowledge. Community outreach programs offer a unique opportunity for medical students to cultivate these competencies in real-world settings. This pilot study investigates the impact of participation in science outreach programs on the engagement and perceived professional development of medical students. Thirty medical students from the Virginia Tech Carilion School of Medicine volunteered in two community-based outreach programs—Kids’ Tech University (KTU) and Medical Discovery of Careers (MedDOCs). These programs involved interactive, hands-on teaching of physiological concepts to middle and high school students. Engagement levels were assessed using a modified Utrecht Work Engagement Scale (UWES), comparing students’ self-reported experiences during teaching versus studying. Thematic analysis was applied to qualitative reflections. Students reported significantly higher engagement scores while teaching compared to studying (5.8 ± 0.1; 4.4 ± 0.1) on a 7-point Likert scale, p < 0.05. Thematic analysis revealed four key themes: community engagement and social responsibility, personal and professional growth, educational creativity and communication skills, and inspiration through role modeling. Participation in community outreach programs may enhance medical students’ engagement, communication skills, and sense of purpose. These findings support the integration of structured outreach opportunities into medical education to foster holistic professional development.

Bodies and Bites: a medical school program that teaches anatomy, physiology, and nutrition to elementary school kids

Frontiers in Public Health · 2024-07-09 · 3 citations

Undergraduate medical students who participate in community outreach programs gain a multitude of benefits that impact not only their professional development but also the well-being of the communities they serve. At the Virginia Tech Carilion School of Medicine (VTCSOM), students have the opportunity to volunteer in the "Bodies and Bites" program at the West End Center for Youth, an after-school educational center that serves K-12 children in Roanoke, Virginia. The purpose of Bodies and Bites is to teach elementary school children in 2nd to 5th grade how their bodies work and how to keep them healthy through good nutrition and exercise. All sessions are led by VTCSOM medical students and graduate students from our partnering academic institution, the Fralin Biomedical Research Institute (FBRI). Each week, the children and Health Professions students explore a different topic related to human anatomy and physiology using anatomical models, small group discussions, and hands-on activities. At the end of each session, the participants create a healthy snack related to the day's topic. The overall goal of the present study was to assess the perception of the Bodies and Bites program from the view of our student volunteers, and the 4th and 5th graders who attend the West End Center. Now in its 6th year, Bodies and Bites continues to be popular as a voluntary program among our Health Professions students, and is well received by the West End Center and the elementary school children they serve. Our students and community mutually benefit from this program, with the former having an opportunity to briefly disengage from the rigors of their studies while gaining valuable skills in science communication and inspiring children to pursue fields in Science, Technology, Engineering, Math, and Medicine (STEMM), and the latter having fun while learning about their bodies and discovering ways to improve their health.

Neurocognitive Correlates of Clinical Decision Making: A Pilot Study Using Electroencephalography

Brain Sciences · 2023 · 4 citations

• Psychology
• Cognitive psychology
• Medicine

< 0.001). PSD showed no significant differences between the groups. Several coherence features showed significant differences between fellows and residents, mostly related to the channels within the frontal, between the frontal and parietal, and between the frontal and temporal areas. The functional connectivity patterns found in this study could provide some clues for future hypothesis-driven studies in examining the underlying cognitive processes that lead to better clinical reasoning.

Mrgprd Enhances Excitability in Specific Populations of Cutaneous Murine Polymodal Nociceptors

UNC Libraries · 2020-11-09 · 8 citations

The Mrgprd receptor is selectively expressed in nonpeptidergic nociceptors that innervate the outer layers of mammalian skin. The function of Mrgprd in nociceptive neurons and the physiologically-relevant somatosensory stimuli that activate Mrgprd-expressing (Mrgprd+) neurons are currently unknown. To address these issues, we studied three Mrgprd knockin mouse lines using an ex vivo somatosensory preparation to examine the role of the Mrgprd receptor and Mrgprd+ afferents in cutaneous somatosensation. In mouse hairy skin, Mrgprd, as marked by expression of GFP reporters, was expressed predominantly in the population of non-peptidergic, TRPV1-negative, C-polymodal nociceptors. In mice lacking Mrgprd, this population of nociceptors exhibited decreased sensitivity to cold, heat and mechanical stimuli. Additionally, in vitro patch clamp studies were performed on cultured DRG neurons from Mrgprd−/− and Mrgprd+/− mice. These studies revealed a higher rheobase in neurons from Mrgprd−/− mice than from Mrgprd+/− mice. Furthermore, in vitro the application of the Mrgprd ligand β-alanine significantly reduced the rheobase and increased the firing rate in neurons from Mrgprd+/− mice, but was without effect in neurons from Mrgprd−/− mice. Our results demonstrate that Mrgprd influences the excitability of polymodal nonpeptidergic nociceptors to mechanical and thermal stimuli.

Review for "Polyethylene glycol‐fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses"

2019-12-23

Review for "Polyethylene glycol‐fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses"

2019-10-19

T107. Membrane Potential of Differentiated Olfactory Neuroepithelial Progenitors Derived From Bipolar and Non-Bipolar Subjects

Biological Psychiatry · 2018-04-09

Cutaneous TRPM8-expressing sensory afferents are a small population of neurons with unique firing properties

Physiological Reports · 2017-04-01 · 34 citations

It has been well documented that the transient receptor potential melastatin 8 (TRPM8) receptor is involved in environmental cold detection. The role that this receptor plays in nociception however, has been somewhat controversial since conflicting reports have shown different neurochemical identities and responsiveness of TRPM8 neurons. In order to functionally characterize cutaneous TRMP8 fibers, we used two ex vivo somatosensory recording preparations to functionally characterize TRPM8 neurons that innervate the hairy skin in mice genetically engineered to express GFP from the TRPM8 locus. We found several types of cold-sensitive neurons that innervate the hairy skin of the mouse but the TRPM8-expressing neurons were found to be of two specific populations that responded with rapid firing to cool temperatures. The first group was mechanically insensitive but the other did respond to high threshold mechanical deformation of the skin. None of these fibers were found to contain calcitonin gene-related peptide, transient receptor potential vanilloid type 1 or bind isolectin B4. These results taken together with other reports suggest that TRPM8 containing sensory neurons are environmental cooling detectors that may be nociceptive or non-nociceptive depending on the sensitivity of individual fibers to different combinations of stimulus modalities.