Assessing Conotoxin Contulakin-G as a Novel Non-Opioid Analgesic for Pain Management in Rodent Models of Cancer-Induced Bone Pain

Abstract

As cancer incidence and survival rates continue to grow, we find rising trends in associated conditions like pain. Cancer-related pain usually develops from metastatic bone lesions, which can cause relentless aching that disrupts patients’ quality of life. Compared to inflammatory and neuropathic pain, cancer-induced bone pain (CIBP) is exaggerated by tumor expansion leading to tissue destruction and compression. Studying novel non-opioid therapies is important to develop new strategies to treat challenging pain conditions. Particularly, current options used to manage cancer pain are limited in their efficacy and safety. Here, we present the snail venom peptide Contulakin-G as a novel compound targeting a unique analgesic pathway that successfully alleviates cancer-induced bone pain. Contulakin-G (CGX) is a novel conotoxin that showed treatment benefits in postsurgical and neuropathic pain models. Thus, we sought to investigate CGX antinociceptive potential in rodent models of CIBP. We demonstrated that single intrathecal CGX injections in mice with CIBP could alleviate ongoing pain behaviors and mechanical hypersensitivity. Furthermore, to validate previously identified targets underlying CGX antinociception, we used gene-editing to limit the expression of neurotensin receptor 2 (ntsr2) and R-type voltage-gated calcium channel (Cav2.3) in CIBP mice. We found that depleting ntsr2 or Cav2.3 at the spinal level did not influence the CIBP model development, and that both proteins were required individually to mediate CGX antinociceptive effects. We then showed that chronic spinal CGX infusions maintain analgesia without tolerance in rats with CIBP, and that acute analgesic dose preserves typical locomotor activity in this CIBP model. Together, these findings provide supporting preclinical evidence to consider CGX as a promising therapeutic for cancer pain.