Alleviating Bone Cancer–induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex. (October 2016)

• Record Type: Journal Article
• Authors: Chiou, Chiuan-Shiou; Chen, Chien-Chung; Tsai, Tsung-Chih; Huang, Chiung-Chun; Chou, Dylan; Hsu, Kuei-Sen
• Is Part Of: Anesthesiology. Volume 125:Number 4(2016)
• Publication Date: 2016-10
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000001237
• Languages: English
• ISSNs: 0003-3022

Abstract

Abstract : Background: The anterior cingulate cortex (ACC) is a brain region that has been critically implicated in the processing of pain perception and modulation. While much evidence has pointed to an increased activity of the ACC under chronic pain states, less is known about whether pain can be alleviated by inhibiting ACC neuronal activity. Methods: The authors used pharmacologic, chemogenetic, and optogenetic approaches in concert with viral tracing technique to address this issue in a mouse model of bone cancer–induced mechanical hypersensitivity by intratibia implantation of osteolytic fibrosarcoma cells. Results: Bilateral intra-ACC microinjections of γ-aminobutyric acid receptor type A receptor agonist muscimol decreased mechanical hypersensitivity in tumor-bearing mice (n =10). Using adenoviral-mediated expression of engineered Gi/o -coupled human M4 (hM4Di) receptors, we observed that activation of Gi/o -coupled human M4 receptors with clozapine- N -oxide reduced ACC neuronal activity and mechanical hypersensitivity in tumor-bearing mice (n = 11). In addition, unilateral optogenetic silencing of ACC excitatory neurons with halorhodopsin significantly decreased mechanical hypersensitivity in tumor-bearing mice (n = 4 to 9), and conversely, optogenetic activation of these neurons with channelrhodopsin-2 was sufficient to provoke mechanical hypersensitivity in sham-operated mice (n = 5 to 9). Furthermore, we found that excitatory neurons in the ACC send direct descending projections to the contralateral dorsal horn of the lumbar spinal cord via the dorsal corticospinal tract. Conclusions: The findings of this study indicate that enhanced neuronal activity in the ACC contributes to maintain bone cancer–induced mechanical hypersensitivity and suggest that the ACC may serve as a potential therapeutic target for treating bone cancer pain. Abstract : Using an animal model of bone cancer–induced pain, it was shown that the γ-aminobutyric acid receptor type A agonist muscimol when injected into the anterior cingulate cortex (ACC) could reduce nociceptive sensitization in tumor-bearing mice. Using optogenetic techniques and engineered receptors to reciprocally regulate the activity of ACC neurons, it was shown that the ACC may regulate nociceptive signaling at the level of the spinal cord.