Studies of efficacy of sustained-release buprenorphine in Sprague Dawley Rats

Abstract

Buprenorphine in a sustained-release formulation is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine persist in serum once sustained-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of sustained-release buprenorphine in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg sustained-release buprenorphine, analgesic efficacy did not persist to 24 hours. No changes in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally-mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to sustained-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or sustained-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1 – 3 mg/kg). Rats previously given sustained-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in rats after exposure to the sustained-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.