The Intrathecally Administered Kappa-2 Opioid Agonist GR89696 and Interleukin-10 Attenuate Bone Cancer–Induced Pain Through Synergistic Interaction

Abstract

Although bone cancer-related pain is one of the most disruptive symptoms in patients with advanced cancer, patients are often refractory to pharmacological treatments; thus, more effective treatments for bone cancer pain are needed. We evaluated the analgesic efficacy of and interaction between intrathecal GR89696, a κ(2)-opioid receptor agonist, and interleukin (IL)-10 in a rat model of bone cancer pain. The rat model of bone cancer pain was produced by right tibia intramedullary injection of rat breast cancer cells, and an intrathecal catheterization was performed. Ten days later, a paw-withdrawal threshold to mechanical stimulus by von Frey hairs was measured using the up-down method, after intrathecal administration of GR89696 and IL-10. The interaction between the 2 drugs was also evaluated using an isobolographic analysis. Intrathecal GR89696 and IL-10 significantly increased the paw withdrawal threshold of the cancer cell-implanted rat, in a dose-dependent manner, with 50% effective dose values (95% confidence interval) of 50.78 μg (31.80-80.07μg) and 0.83 μg (0.59-1.15 μg), respectively. Isobolographic analysis revealed a synergistic interaction between intrathecal GR89696 and IL-10. Intrathecally administered GR89696 and IL-10 attenuated bone cancer-induced pain, and the 2 drugs interacted synergistically in the spinal cord. These results raise the intriguing possibility of κ(2)-opioid receptor agonists and IL-10 as a new therapeutic approach for the management of bone cancer-associated pain.