Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy.

BACKGROUND: Recently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat's emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task. RESULTS: SNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area. CONCLUSIONS: Our results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning.

Differential effects of left/right neuropathy on rats' anxiety and cognitive behavior.

Chronic pain is frequently accompanied by a deterioration of emotional behavior and cognitive function. A small number of studies in humans concluded that pain-associated negative affect is more pronounced when pain is localized in the left side of the body. It has been suggested that such side bias results from cortical function lateralization. It is not known, however, if other pain-associated behavioral changes are differentially affected by left- and right-sided pain. To test this hypothesis, the performance of rats with a unilateral spared nerve injury neuropathy installed in the left (SNI-L) or in the right (SNI-R) side was compared in anxiety (elevated-plus maze) and cognitive (spatial working and reference memory, attentional set-shifting task, and delay-to-signal impulsivity task) behavioral paradigms. Results show that SNI-L animals presented an increased anxiety-like profile while maintaining preserved cognitive function. On the contrary, SNI-R animals presented cognitive deficits in all tasks except in the reference memory, but displayed a normal anxiety-like profile. Our results show that left- and right-sided neuropathic pain differentially affects emotional behavior, which is in accordance with previous observations in human subjects, both in experimentally induced pain and in chronic pain conditions. Additionally, our results demonstrate that the cognitive function deterioration associated with unilateral neuropathic chronic pain conditions is also differentially affected.