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Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats

Cowen, Stephen L.a,*; Phelps, Caroline E.b; Navratilova, Editab; McKinzie, David L.c; Okun, Alecb,c; Husain, Omarc; Gleason, Scott D.c; Witkin, Jeffrey M.c; Porreca, Frankb

doi: 10.1097/j.pain.0000000000001226
Research Paper
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Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.

Rats with spinal nerve ligation were impaired relative to controls in flexibly adapting to changing environmental demands.

Departments of aPsychology and

bPharmacology, University of Arizona, Tucson, AZ, USA

cNeuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, USA

Corresponding author. Address: The University of Arizona Life Sciences North, Rm 347 1501 N. Campbell Ave., Tucson, AZ 85721, USA. Tel.: 520 626 2615. E-mail address: scowen@email.arizona.edu (S.L. Cowen).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received November 29, 2017

Received in revised form February 15, 2018

Accepted March 06, 2018

© 2018 International Association for the Study of Pain
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