(257) The Efficacy of a Dual-Acting, Peripherally-Restricted Kappa/Delta Opioid Agonist (CA1001) in Neuropathic Pain in the Rat

Abstract

Nerve injury can precipitate a neuroimmune inflammatory response. This response might lead to the activation of peripheral delta-opioid receptors, allowing\xa0delta-opioid agonists in the periphery to become analgesic directly and through allosteric modulation of peripheral\xa0kappa-opioid receptors. This study evaluated the efficacy of a single intraperitoneal injection of CA1001 (a novel peripherally-restricted dual-acting\xa0kappa/delta-opioid\xa0agonist) and the comparator, gabapentin, in the spinal nerve ligation (SNL) model for neuropathic pain in the rat. Following IACUC approval, neuropathy was induced by surgically ligating the 5th and 6th lumbar spinal nerves (L5 and L6). Mechanical sensitivity was assessed via paw compression thresholds (PCTs) using a digital Randall-Selitto device. 50 animals that met the inclusion criteria were randomly assigned to 5 groups with 10 animals per group (Power: 80%). Animals were administered a single dose of vehicle, CA1001 (1 mg/kg, 5 mg/kg, or 10 mg/kg IP), or control compound (gabapentin 100 mg/kg PO; active control: internal validity) on day 0 (15 days after SNL) and PCTs were determined 1, 2, and 4 hours after compound administration. All behavioral evaluations were performed by a blinded observer. CA1001 at the 1 mg/kg dose did not significantly reverse mechanical hyperalgesia at any of the time points tested. The 5 mg/kg and 10 mg/kg doses of CA1001 did not significantly reverse mechanical hyperalgesia at the 1-hour post-dosing time point but did significantly reverse mechanical hyperalgesia at the 2-hour (p