(258) Reversal of Mechanical Hyperalgesia by a Dual-Acting, Peripherally-Restricted Kappa/Delta Opioid Agonist (CA1001) in a Rat Model of Inflammatory Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory pain condition. In RA and other inflammatory states, normally sequestersed peripheral delta-opioid receptors may become active, allowing\xa0delta-opioid agonists to participate in the pain pathway directly and through allosteric modulation of peripheral\xa0kappa-opioid receptors. This study evaluated the efficacy of a single intraperitoneal injection of CA1001 (a novel dual-acting, peripherally restricted kappa/delta opioid\xa0agonist) on hyperalgesic nociceptive behaviors in the CFA (Complete Freund s Adjuvant) Model of Inflammatory Arthritis Pain in Rats. Following IACUC approval, inflammatory arthritis pain was induced with injection of 50 μL CFA into the tibio-tarsal joint. Mechanical hyperalgesia was assessed via joint compression thresholds (JCTs). 50 animals were randomly assigned to 5 groups (Power: 80%). Ipsilateral and contralateral joint compression thresholds (JCTs) were assessed prior to CFA injection, pre-dosing on Day 0, and 1, 2, and 4 hours post-dosing. Animals were administered a single dose of vehicle, CA1001 (1, 5, or 10 mg/kg IP), or celecoxib (30 mg/kg PO: active control; internal validity) on day 0 (14 days after CFA). All behavioral evaluations were performed by a blinded observer. Mechanical hyperalgesia was measured using a digital Randall-Selitto device. CA1001 (10 mg/kg) significantly increased paw compression thresholds compared to vehicle at all time points, (p