Background & Aims
The transformation of acute pain into a chronic condition, such as following accidental trauma or invasive surgery, is a phenomenon significantly shaping the global prevalence of chronic pain. Despite its widespread impact, the precise mechanisms facilitating this transition remain largely unknown. While various psychosocial factors are presumed to influence this process, cohesive causative pathways, if they exist, have yet to be discerned. This study endeavors to probe the neural circuitry implicated in the shift towards chronic pain, with specific attention directed towards the midbrain ventrolateral periaqueductal gray (vlPAG), a pivotal center for pain regulation, and its role in chronic pain development.
Methods
Experiments were conducted using adult male C57BL/6 mice (6-8 weeks old), obtained from the National Laboratory Animal Center, Taipei, Taiwan. Approval for all animal procedures was obtained from the Institutional Animal Care and Use Committee of the College of Medicine, I-Shou University, following ARRIVE guidelines. The study employed a well-established model of neuropathic pain, the spinal nerve ligation (SNL) model, with L5 spinal nerve ligation. Mechanical hypersensitivity in mice was assessed using the von Frey filament test. Depression- and anxiety-like behaviors were tested using the forced swimming test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity test. Additionally, midbrain and spinal slices were dissected for ex vivo whole-cell patch-clamp electrophysiological recordings.
Results
Mice exhibited only mechanical hypersensitivity, but not depression- and anxiety-like behavior, one day after SNL surgery. The mechanical hypersensitivity was accompanied by an increased frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the dorsal horn neurons of the L5 spinal cord. Additionally, we observed increased frequency and amplitude of sEPSCs in the vlPAG one day after SNL surgery. However, three days after SNL, mechanical hypersensitivity reached a steady state of behavioral phenotype. At this time point, we found that there was a persistent increase in the frequency and amplitude of sEPSCs in the dorsal horn, but this transformed into diminished frequency and amplitude of sEPSCs in the vlPAG three days after SNL surgery.
Conclusions
The transfer of acute pain to chronic conditions is due to a decrement in neuronal activity in the vlPAG, resulting in the diminishing of descending pain inhibition, leading to persistent mechanical hypersensitivity.
References
1.Impairment of adenylyl cyclase-mediated glutamatergic synaptic plasticity in the periaqueductal grey in a rat model of neuropathic pain. Ho YC, Cheng JK, Chiou LC. The Journal of Physiology. 2015 Jul 1;593(13):2955-73.
2.Hypofunction of glutamatergic neurotransmission in the periaqueductal gray contributes to nerve-injury-induced neuropathic pain. Ho YC, Cheng JK, Chiou LC. Journal of Neuroscience. 2013 May 1;33(18):7825-36.
3.Periaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression. Ho YC, Lin TB, Hsieh MC, Lai CY, Chou D, Chau YP, Chen GD, Peng HY. Neuropsychopharmacology. 2018 Jan;43(2):302-312.
4.Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice. Lee MT, Peng WH, Wu CC, Kan HW, Wang DW, Teng YN, Ho YC. Molecular Neurobiology. 2023 Oct;60(10):5708-5724.
Presenting Author
Yu-Cheng Ho
Poster Authors
YU-CHENG HO
Lead Author
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)