Reactive oxygen species mediate visceral pain-related amygdala plasticity and behaviors.

Clinical and pre-clinical evidence has established the amygdala as an important player in the emotional-affective dimension of pain [3;56;58;69]. In humans, increased amygdala activity is seen in experimental and clinical pain conditions, including visceral pain [4;39;40;45;69;72]. The amygdala is a limbic brain area in the medial temporal lobe and consists of several subnuclei. The amygdala circuitry that contributes to the emotional-affective component of pain is centered on the lateral-basolateral (LA-BLA) and central (CeA) nuclei [56;58]. The CeA serves output functions and receives nociceptive-specific input from the parabrachial area whereas the LA-BLA network provides highly processed nociceptive and affect-related information to the CeA. Neuroplasticity in the LA-BLA-CeA network correlates positively with pain behaviors in animals, and interventions that deactivate the amygdala have inhibitory effects in different pain models (for recent reviews see [3;56]), including visceral pain [13;24;31;71]. Still, little is known about synaptic and cellular mechanisms of viscero-nociceptive processing in the amygdala. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, play an important role in physiological plasticity critical for cognitive processes such as memory, but abnormally increased ROS levels have detrimental effects [49;51;61] and are involved in pain pathophysiology [11]. Inhibition of ROS production with ROS scavengers administered peripherally [33;74] or spinally [18;35;36;67;68;75] has antinociceptive effects in models of inflammatory and neuropathic pain. While evidence for an important role of peripheral and spinal ROS in pain mechanisms is accumulating, pain-related functions of ROS in the brain remain to be determined. Recent work from our laboratory showed that under normal conditions ROS scavengers in the amygdala inhibit visceral and somatosensory nociceptive responses [29] and excitability [44] of CeA neurons induced by the activation of metabotropic glutamate receptors. However, the role of endogenous ROS in pain-related changes in the amygdala is not yet known. Here we tested the effect of a membrane-permeable ROS scavenger, the superoxide dismutase mimetic tempol [34;43], to examine the contribution of ROS to pain behaviors, nociceptive processing and synaptic transmission in a rat model of visceral pain induced by intracolonic zymosan. The behavioral and electrophysiological analysis of the effects of a ROS scavenger in the amygdala in a pain model is a key novelty of this study.