The Effect of Pain on Cognitive Function: Preclinical and Clinical Investigations

Abstract

Chronic pain is associated with high social and economic costs due to its disabling physical and psychological effects. Despite some evidence that chronic pain negatively affects cognitive function, little is known about the mechanisms by which pain and cognition interact and influence one another. Theories based on the existing literature suggest that pain may alter the accessibility of cognitive resources or may be associated with changes in neuroplasticity and neurochemistry, which may in turn impact on cognition. A role for age in the interaction between pain and cognition has also been suggested. The aims of the work presented in this thesis were to investigate the relationship between pain and cognitive function, and to elucidate potential mechanisms underlying this relationship, using a translational approach involving preclinical and clinical models. The L5-L6 spinal nerve ligation (SNL) and complete Freund's adjuvant models of chronic neuropathic and inflammatory pain, respectively, were employed in young and mid-aged rats and cognitive performance was assessed using behavioural tests of spatial learning, spatial and recognition memory and cognitive flexibility. A novel behavioural paradigm, which used air-puff to induce passive avoidance, was also developed and used to test aversive learning and memory in rat models of chronic pain. HPLC, immunohistochemistry and western immunoblotting were used to investigate the neural mechanisms underlying the relationship between chronic pain and cognitive function, specifically the role of the monoaminergic system and that of the synaptic protein synaptophysin as a potential indicator of synaptic plasticity. Cognitive function was also examined in a clinical sample of chronic neuropathic or radicular pain patients, in the domains of verbal memory, spatial memory, attention and executive function. The studies provide some evidence for deficits in cognitive performance associated with the SNL model of neuropathic pain, which were dependent on age and on the cognitive task. Furthermore, the studies identify pain-related alterations in synaptophysin expression in regions such as the hippocampus and the prefrontal and amygdaloid cortices, which may contribute to the observed impairments in cognitive behaviour. Alterations in monoaminergic transmission were also identified in the SNL model in mid-aged rats. In the clinical study, chronic pain patients were found to perform poorly compared with controls on measures of intelligence and memory, and showed an altered pattern of responding in tests of attention. Significant interactions between these cognitive outcomes and age were also observed, highlighting the influence of age on the relationship between chronic pain and cognition. In conclusion, these results expand on the previous literature suggesting that chronic pain is associated with impaired cognitive function, and suggest the involvement of neurochemical and neuroplastic mechanisms.