Pain following surgery reduces quality of life and produces both physical and cognitive disabilities that are difficult to treat and bear substantial costs to society. Cognitive dimensions of pain include decreased attention, increased impulsivity, and avoidance of physical activity that induces pain. We have developed a variant of the 5 choice serial reaction time task (5CSRT) in which attention threshold is assessed by titrating the duration of a light stimulus that the subject must detect in order to achieve a food reward based on the real time performance of the animal (5CSRTitration). This procedure is sensitive to pain after partial ligation of the L5 spinal nerve (pSNL). Pre-existing social stress induced by repeated social defeat (RSD) enhances disruption of performance in the 5CSRTitration procedure in rats after pSNL and prolongs recovery. We have developed a novel surface that induces increased noxious stimulation in rats after pSNL upon movement (NOX surface). This NOX surface induces avoidance following pSNL in open field exploration and significantly worsens attention performance after pSNL in the 5CSRTitration task. Three distinct cognitive dimensions of behavior are obtained in a single session for each animal: attention threshold, impulsive action, and avoidance of movement. While RSD and the NOX surface enhance impairment of attention by pSNL, these manipulations diminish impulsive action after pSNL, while avoidance of movement is specifically enhanced by the NOX surface after pSNL. The underlying circuitry that mediates attention, impulsivity, and avoidance of noxious stimuli has been studied. Attention is controlled by the prelimbic and infralimbic regions of the medial prefrontal cortex (mPFC), while impulsive action is controlled by the orbitofrontal cortex (OFC). Both of these regions receive rich noradrenergic (NErgic) innervation from the locus coeruleus (LC), and NErgic signaling in these regions is necessary for attention and impulse control. The mPFC also receives glutamatergic input from the basolateral amygdala (BLA), which responds to noxious stimulation by increasing GABAergic inhibition of the mPFC. The OFC receives dense serotonergic from the dorsal raphe nucleus (DRN) and disruption of 5HTergic signaling in the OFC is associated with increased impulsivity. The central part of the amygdala (CeA) receives input from both the BLA and from the parabrachial nucleus (PbN). Stimulation of the medial aspect of the CeA (CeM) by noxious input through the PbN increases avoidance behavior in rodents while having little effect on sensory/discriminative dimensions of pain. In this project we will explore mechanisms through which pSNL, RSD, and the NOX surface modulate attention, impulsive action, and avoidance of movement using the 5CSRTitration procedure with in vivo electrophysiology, pharmacology, and pharmacogenomics and manipulating systems involving the LC, DRN, CeA, mPFC and OFC. !
Pain after surgery induces both physical and cognitive dysfunction including decreased attention, impulsive behavior, and avoidance of movement or physical activity. In this project we will apply a model of surgical trauma to determine mechanisms by which pain induces similar deficits in rats using electrophysiology, pharmacology, and pharmacogenomics. Additionally, the mechanisms through which pre-existing affective distress alters these mechanisms will be explored using a model of chronic social stress. We have developed novel surfaces that induce avoidance behavior and reluctance towards movement and will utilize these surfaces to explore mechanisms of kinesiophobia.
