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

TY - JOUR

T1 - Carbenoxolone as a novel therapy for attenuation of cancer-induced bone pain

AU - Falk, Sarah

PY - 2018

Y1 - 2018

N2 - 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 ongoing 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.

AB - 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 ongoing 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.

U2 - 10.1097/j.pain.0000000000001197

DO - 10.1097/j.pain.0000000000001197

M3 - Journal article

C2 - 29521811

SN - 0304-3959

VL - 159

SP - 1127

EP - 1136

JO - Pain

JF - Pain

IS - 6

ER -