Pain Medicine  |   October 2016
Alleviating Bone Cancer–induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex
Author Notes
  • From the Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (C.-S.C., T.-C.T., D.C., K.-S.H.); Department of Anesthesiology, China Medical University Hospital, China Medical University, Taichung, Taiwan (C.-S.C.); and Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (C.-C.C., T.-C.T., C.-C.H., D.C., K.-S.H.).
  • Submitted for publication November 5, 2015. Accepted for publication June 15, 2016.
    Submitted for publication November 5, 2015. Accepted for publication June 15, 2016.×
  • Address correspondence to Dr. Hsu: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan City 701, Taiwan. richard@mail.ncku.edu.tw. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Basic Science / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   October 2016
Alleviating Bone Cancer–induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex
Anesthesiology 10 2016, Vol.125, 779-792. doi:10.1097/ALN.0000000000001237
Anesthesiology 10 2016, Vol.125, 779-792. doi:10.1097/ALN.0000000000001237
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.