Caudal Granular Insular Cortex to Somatosensory Cortex I: A critical pathway for the transition of acute to chronic pain.
Journal Article
Overview
abstract
Allodynia (perceiving touch as painful) is an enduring symptom of neuropathic pain. While acute pain is initiated by afferent signaling from the periphery to spinal cord, pain chronification recruits ongoing activity in supraspinal sites. One such site that has been proposed to be important in pain chronification is the caudal granular insular cortex (CGIC). The present studies of allodynia in response to sciatic nerve injury in male and female rats focus on the role of CGIC in pain chronification by analyzing: circuit-specific mGreenLantern expression to define CGIC-to-somatosensory cortex I (SI) projections; behavioral and electrophysiological effects of chemogenetic (DREADD) excitation and inhibition of CGIC; behavioral and immediate-early gene effects of pathway-specific activation and inhibition of CGIC-to-SI projections; and mGreenLantern expression in dendritic arbors of CGIC-to-SI projection neurons to assess CGIC dendritic spine changes following neuropathic pain. These studies demonstrate that signals from CGIC-to-SI are necessary for neuropathic pain. Nerve injury induces plasticity in CGIC dendritic spine morphology, multi-week chemogenetic inhibition of CGIC or CGIC-to-SI projection neurons produces an enduring reversal of neuropathic pain, and DREADD-induced excitation of this pathway in non-neuropathic rats induces allodynia and increases c-Fos expression in CGIC, SI, and pain responsive laminae in spinal cord dorsal horn. Together with recent findings showing that SI modifies incoming nociceptive and touch information, these data demonstrate that input from CGIC-to-SI input shapes SI gating of nociceptive signals and promotes the transition to chronic pain following peripheral nerve injury.Significance Statement These studies demonstrate that signals from rat caudal granular insular cortex (CGIC) to primary somatosensory cortex (SI) are necessary for neuropathic pain. We show that nerve injury induces plasticity in CGIC dendritic spine morphology, multi-week chemogenetic inhibition of CGIC or CGIC-to-SI projection neurons reverses neuropathic pain after peripheral nerve injury. Also, excitation of this pathway in non-neuropathic rats induces allodynia and increases c-Fos expression in pain-responsive dorsal horn laminae, indicating that CGIC engages ascending pain pathways via SI. When considered along with recent publications showing that output from SI modifies incoming nociceptive and touch information, these data demonstrate that input from CGIC-to-SI impacts SI gating of incoming nociceptive signals and facilitates the transition to chronic pain after peripheral nerve injury.
