75: Persistent changes in spinal cord projection neuron activity after hindpaw incision

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic postsurgical pain, , , , , , , , Animal imaging (includes Ca2+ imaging, fluorescence microscopy), Behavioral studies,

Background and Aims: Although peripheral injury produces robust behavioral hypersensitivity that often resolves, clinical and preclinical evidence suggests that long-lasting changes in pain-generating circuits may persist, contribute to, and exacerbate future pain episodes[1–3]. Most interestingly, the behavioral manifestation of pain following injury recovery can be reestablished by injection of opioid antagonists[4,5], suggesting a latent sensitization process that may affect the long-term activity of dorsal horn pain processing circuits. Here, in awake behaving mice, we longitudinally track the activity of spinal cord projection neurons before, during, and after injury recovery, and test whether opioid receptor blockade unmasks persistent injury-induced neuronal hyperexcitability.

Methods: We took advantage of our recently developed calcium imaging method to monitor the activity of the same population of Phox-2A expressing lamina I projection neurons, long-term, in the awake, behaving mouse[6]. After spinal cord window implantation, animals are repeatedly imaged, before, during, and after behavioral recovery from unilateral hindpaw incision. After recovery, the mice are injected with naltrexone, which reinstates a latent sensitization-mediated behavioral hypersensitivity and we test whether comparable changes in neuronal activity can be uncovered.

Results: At baseline, animals exhibited limited neuronal responses to noxious and innocuous stimulation, with greater sensitivity to thermal rather than mechanical stimulation. Following unilateral hindpaw incision injury, we recorded a marked increase in neuronal activity in response to noxious cold, heat, and mild mechanical stimulation (0.07 g filament). Although the behavioral hypersensitivity resolved by 7 days, the increased neuronal responsiveness persisted, underscoring the long-term consequences of injury, in the absence of a behavioral correlate. Furthermore, following recovery, naltrexone significantly increased behavioral sensitivity and further increased stimulus-induced neuronal activity.

Conclusions: Our studies are the first to follow the activity of the same population of dorsal horn neurons before, during and after recovery from injury, and provide a key demonstration that injury-induced long-term changes persist in the nervous system beyond the recovery window. Importantly, we demonstrate that such changes can occur independently but also are exacerbated by an endorphin-mediated latent sensitization process.

References: 1. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain. 2011;152(3):S2–S15. PMCID: PMC3268359
2. Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE, Taylor BK. Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence. Science. 2013;341(6152):1394–1399. PMCID: PMC4440417
3. Walker SM, Beggs S, Baccei ML. Persistent changes in peripheral and spinal nociceptive processing after early tissue injury. Exp Neurol. 2016;275:253–260. PMCID: PMC4686380
4. Marvizon JC, Walwyn W, Minasyan A, Chen W, Taylor BK. Latent Sensitization: A Model for Stress‐Sensitive Chronic Pain. Curr Protoc Neurosci. 2015;71(1):9.50.1-9.50.14. PMCID: PMC4532319
5. Cooper AH, Hedden NS, Prasoon P, Qi Y, Taylor BK. Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla. J Neurosci. 2022;42(30):5870–5881. PMCID: PMC9337598
6. Ahanonu B, Crowther A, Kania A, Rosa-Casillas M, Basbaum AI. Long-term optical imaging of the spinal cord in awake behaving mice. Nat Methods. 2024;1–13. PMID: 39533007

Presenting Author: Tia A. Tummino
Submitting Author: Tia Tummino

Senior Author: Allan I. Basbaum

IASP 2026 Global Year theme of Neuropathic Pain: No

• Tia A. Tummino: PhD - UCSF
• Joao Braz: PhD - UCSF
• Mariela Rosa Casillas: NA - UCSF
• Allan I. Basbaum: PhD - UCSF