Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats

The amygdala plays a key role in fear learning and extinction and has emerged as an important node of emotional-affective aspects of pain and pain modulation. Impaired fear extinction learning, which involves prefrontal cortical control of amygdala processing, has been linked to neuropsychiatric disorders. Here we tested the hypothesis that fear extinction learning ability can predict the magnitude of neuropathic pain. We correlated fear extinction (FE) learning in naive adult male rats with sensory and affective behavioral outcome measures (mechanical thresholds, vocalizations, anxiety- and depression-like behaviors) before and after induction of the spinal nerve ligation (SNL) model of neuropathic pain compared to sham controls. Auditory fear conditioning, extinction learning, and extinction retention tests were conducted after baseline testing. All rats showed increased freezing responses after fear conditioning. During extinction training the majority (75%) of rats showed a decline of freezing level to 50% in 5 min (FE+) whereas 25% of the rats maintained a high freezing level (>50%, FE-). FE- rats showed decreased open-arm preference in the elevated plus maze (EPM), reflecting anxiety-like behavior, but there were no significant differences in sensory thresholds, vocalizations, or depression-like behavior (forced swim test, FST) between FE+ and FE- types. In the neuropathic pain model (4 weeks after SNL), FE- rats showed a greater increase in vocalizations and anxiety-like behavior than FE+ rats. FE- rats, but not FE+ rats, also developed depression-like behavior. Extracellular single unit recordings of amygdala (central nucleus) neurons in behaviorally tested rats (anesthetized with isoflurane) found greater increases in background activity, bursting, and evoked activity in FE- rats than FE+ rats in the SNL model compared to sham controls.The data may suggest that fear extinction learning ability predicts the magnitude of neuropathic pain-related affective rather than sensory behaviors, which correlates with differences in amygdala activity changes.