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Carbenoxolone as a novel therapy for attenuation of cancer-induced bone pain

Falk, Sarah

doi: 10.1097/j.pain.0000000000001197
Research Paper

Pain is a major complication for patients with cancer significantly compromising their quality of life. Current treatment is far from optimal and particularly bone-related cancer pain poses an increasing clinical and socioeconomical problem. Connexins, key proteins in cell–cell communication, have the potential to affect cancer-induced bone pain at multiple levels, including nociceptive signaling and bone degradation. This study tested the analgesic potential of carbenoxolone, a broad-acting connexin blocker, in a mouse model of cancer-induced bone pain. In addition, a pharmacological approach was used to elucidate the underlying mechanisms using the 2 specific blockers 37,43Gap27 and 43Gap26. Compared with vehicle treatment, chronic systemic administration of 20 or 40 mg/kg carbenoxolone caused a significantly later onset and attenuation of movement-evoked and on-going pain, assessed with limb use and weight bearing, respectively. In addition, the carbenoxolone-treated groups demonstrated a significant delay in time to reach the humane endpoint. Acute intrathecal administration of 37,43Gap27 significantly attenuated both limb use and weight bearing, whereas 43Gap26 had a less pronounced effect. Carbenoxolone treatment had a minor effect on the bone degradation in the early phase of disease progression, whereas no effect was observed in the late phase. Surprisingly, connexin43 was downregulated in the cancer-bearing animals compared with shams. The results suggest that connexins are involved in cancer-induced bone pain, and that carbenoxolone could be a novel analgesic treatment for the pain state.

Carbenoxolone is a novel therapy for treatment of cancer-induced bone pain, mediated partly by spinal inhibition of connexin43 and connexin37.

Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

Corresponding author. Address: Department of Neuroscience, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Tel.: +4551902256. E-mail address: falk@sund.ku.dk (S. Falk).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received November 24, 2017

Received in revised form February 14, 2018

Accepted February 20, 2018

© 2018 International Association for the Study of Pain
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