{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:11:46Z","timestamp":1789747906286,"version":"4.0.1"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2013induced mechanical hypersensitivity by intratibia implantation of osteolytic fibrosarcoma cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bilateral intra-ACC microinjections of \u03b3-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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The findings of this study indicate that enhanced neuronal activity in the ACC contributes to maintain bone cancer\u2013induced mechanical hypersensitivity and suggest that the ACC may serve as a potential therapeutic target for treating bone cancer pain.<\/jats:p><\/jats:sec>","DOI":"10.1097\/aln.0000000000001237","type":"journal-article","created":{"date-parts":[[2016,7,14]],"date-time":"2016-07-14T15:21:00Z","timestamp":1468509660000},"page":"779-792","source":"Crossref","is-referenced-by-count":39,"title":["Alleviating Bone Cancer\u2013induced Mechanical Hypersensitivity by Inhibiting Neuronal Activity in the Anterior Cingulate Cortex"],"prefix":"10.1097","volume":"125","author":[{"given":"Chiuan-Shiou","family":"Chiou","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Chung","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Chih","family":"Tsai","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiung-Chun","family":"Huang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"Chou","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuei-Sen","family":"Hsu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"2021031919393472700_R1","doi-asserted-by":"crossref","first-page":"8077","DOI":"10.1073\/pnas.141218998","article-title":"The affective component of pain in rodents: Direct evidence for a contribution of the anterior cingulate cortex.","volume":"98","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021031919393472700_R2","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1185\/03007995.2010.545813","article-title":"Epidemiology of chronic non-cancer pain in Europe: Narrative review of prevalence, pain treatments and pain impact.","volume":"27","year":"2011","journal-title":"Curr Med Res Opin"},{"key":"2021031919393472700_R3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.tins.2015.02.001","article-title":"Epigenetic mechanisms of chronic pain.","volume":"38","year":"2015","journal-title":"Trends Neurosci"},{"key":"2021031919393472700_R4","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/nn.3811","article-title":"Reward and motivation in pain and pain relief.","volume":"17","year":"2014","journal-title":"Nat Neurosci"},{"key":"2021031919393472700_R5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tins.2008.01.003","article-title":"Cortical excitation and chronic pain.","volume":"31","year":"2008","journal-title":"Trends Neurosci"},{"key":"2021031919393472700_R6","first-page":"35","article-title":"The anterior cingulate cortex and pain processing.","volume":"8","year":"2014","journal-title":"Front Integr Neurosci"},{"key":"2021031919393472700_R7","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1126\/science.288.5472.1769","article-title":"Psychological and neural mechanisms of the affective dimension of pain.","volume":"288","year":"2000","journal-title":"Science"},{"key":"2021031919393472700_R8","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/PSY.0b013e3182408f04","article-title":"Disrupted functional connectivity of the pain network in fibromyalgia.","volume":"74","year":"2012","journal-title":"Psychosom Med"},{"key":"2021031919393472700_R9","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0304-3959(99)00190-6","article-title":"Parietal and cingulate processes in central pain. 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