Insular Cortex is Critical for the Perception, Modulation, and Chronification of Pain

Abstract

An increasing body of neuroimaging and electrophysiological studies of the brain suggest that the insular cortex (IC) integrates multimodal salient information ranging from sensation to cognitive-affective events to create conscious interoception. Especially with regard to pain experience, the IC has been supposed to participate in both sensory-discriminative and affective-motivational aspects of pain. In this review, we discuss the latest data proposing that subregions of the IC are involved in isolated pain networks: the posterior sensory circuit and the anterior emotional network. Due to abundant connections with other brain areas, the IC is likely to serve as an interface where cross-modal shaping of pain occurs. In chronic pain, however, this mode of emotional awareness and the modulation of pain are disrupted. We highlight some of the molecular mechanisms underlying the changes of the pain modulation system that contribute to the transition from acute to chronic pain in the IC.

Keywords: Dopamine; Emotion; GABA; Insular cortex; Molecular mechanism; Neural network; Pain.

Fig. 1

The anterior insular cortex (AI) and the posterior insular cortex (PI) are involved in different pain circuits that mediate different aspects of pain. The AI serves as an interface where attention, anticipation, or belief shape pain perception by activating cognitive areas such as the prefrontal (PFC) and anterior cingulate (ACC) cortices and attention areas such as the frontal-parietal cortex and amygdala (AMY). Through the AI, the modulatory signal reaches the descending pain modulation system, whereas the PI plays a fundamental role in chronic pain maintenance through a spinal-CGIC-S1-spinal positive-feedback circuit. CGIC caudal granular insular cortex, LC locus coeruleus, Spinal spinal cord, PAG periaqueductal grey, PB parabrachial nucleus, RVM rostroventral medulla, S1 primary somatosensory cortex.

Fig. 2

Neural mechanisms underlying pain modulatory circuits involving the rostral agranular IC (RAIC). Neurons in the RAIC receive dopaminergic fibers from the VTA/SN. In the RAIC, there are close appositions between dopaminergic fibers and GABAergic interneurons. Then, GABAa neurons project to the locus coeruleus (LC), while GABAb neurons project to the amygdala (AMY). Altogether, by the activation of D1 and D2 receptors, dopaminergic modulation of the RAIC occurs through different types of GABAergic interneurons. The circuit provides potential access for reward-motivation information to pain modulation system. PAG periaqueductal gray, RVM rostroventral medulla, SN salience network, VTA ventral tegmental area.