Assareh Neda, Sokolaj Eddy E, Sadia Saima, Anderson Kristen E, Frith Caitlin, Walls Olivia B, Mitchell Vanessa A, Vaughan Christopher W, Winters Bryony L
Pain Management Research Institute, Kolling Institute, University of Sydney at Royal North Shore Hospital, Sydney, NSW, Australia.
Charles Perkins Centre, Sydney Pharmacy School, University of Sydney, Sydney, NSW, Australia.
Front Pain Res (Lausanne). 2025 Aug 29;6:1648374. doi: 10.3389/fpain.2025.1648374. eCollection 2025.
While chronic neuropathic pain is characterised by abnormal pain signs, such as allodynia, highly disabling co-morbidities, such as anxiety and depression, have a major impact. It is thought that these co-morbidities arise from learning maladaptations related to inappropriate associations between pain and stimulus/environmental cues. However, the impact of animal neuropathic pain models on the interactions between fear-learning, pain and anxiety are poorly understood, particularly during early stages prior to establishment of anxiety.
We examined the impact of fear-conditioning on fear, anxiety-like behaviours and cold/mechanical allodynia in the mouse sciatic nerve chronic constriction injury (CCI) model of neuropathic pain, at an early post-injury time point.
At 2 weeks post-surgery, CCI and sham operated mice displayed similar acquisition of fear-like freezing responses to a paired audio-tone/footshock fear-conditioning paradigm. On the following day, CCI mice displayed greater freezing than sham mice in response to the same context and subsequent tone presentations. While CCI and sham mice display similar anxiety-like behaviour in the light-dark box and open field, these were increased by fear-conditioning in CCI but not mice. Finally, CCI but not sham surgery produced cold and mechanical allodynia, however, these were unaffected by fear-conditioning.
These findings indicate that a neuropathic pain model enhances learned context/cue evoked fear behaviours at an early stage following nerve-injury. Furthermore, fear-conditioning enhances anxiety-like behaviour, before such behaviour is normally developed. Thus, fear-conditioning induces exaggerated fear-learning which triggers enhanced fear and anxiety, even during early stages of chronic neuropathic pain.
慢性神经性疼痛的特征是存在异常疼痛体征，如痛觉过敏，而高度致残的共病，如焦虑和抑郁，也有重大影响。人们认为这些共病源于与疼痛和刺激/环境线索之间不适当关联相关的学习适应不良。然而，动物神经性疼痛模型对恐惧学习、疼痛和焦虑之间相互作用的影响了解甚少，尤其是在焦虑形成之前的早期阶段。
我们在小鼠坐骨神经慢性压迫损伤（CCI）神经性疼痛模型中，在损伤后的早期时间点，研究了恐惧条件反射对恐惧、焦虑样行为以及冷/机械性痛觉过敏的影响。
术后2周，CCI小鼠和假手术小鼠对配对的音频/足部电击恐惧条件反射范式表现出相似的恐惧样僵住反应习得。在接下来的一天，CCI小鼠在相同环境和随后的音频呈现时比假手术小鼠表现出更强的僵住反应。虽然CCI小鼠和假手术小鼠在明暗箱和旷场试验中表现出相似的焦虑样行为，但恐惧条件反射增加了CCI小鼠的焦虑样行为，而假手术小鼠则未增加。最后，CCI手术而非假手术导致了冷和机械性痛觉过敏，然而，这些不受恐惧条件反射的影响。
这些发现表明，神经性疼痛模型在神经损伤后的早期阶段增强了习得的情境/线索诱发的恐惧行为。此外，恐惧条件反射在正常情况下这种行为形成之前就增强了焦虑样行为。因此，恐惧条件反射诱导了过度的恐惧学习，即使在慢性神经性疼痛的早期阶段，也会引发增强的恐惧和焦虑。
