Sanjana Mada1,2, Lisa R Gerak1,2, Amélie Soyer1,2, David R Maguire1,2, Zehua Hu1,2, Vanessa Minervini1,2, Christopher W Cunningham3, Charles P France4,5,6. 1. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. 2. Addiction Research, Treatment & Training Center of Excellence, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. 3. Department of Pharmaceutical Sciences, School of Pharmacy, Concordia University Wisconsin, 12800 N. Lake Shore Drive, PH 239, Mequon, WI, 53097, USA. 4. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. france@uthscsa.edu. 5. Addiction Research, Treatment & Training Center of Excellence, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. france@uthscsa.edu. 6. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX, 78229-3900, USA. france@uthscsa.edu.
Abstract
RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at μ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other μ opioid receptor agonists. OBJECTIVES: The current study compared the acute behavioral effects of BOM with the effects of other μ opioid receptor agonists. METHODS: Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration. RESULTS: BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration. CONCLUSIONS: Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by μ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.
RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at μ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other μ opioid receptor agonists. OBJECTIVES: The current study compared the acute behavioral effects of BOM with the effects of other μ opioid receptor agonists. METHODS: Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration. RESULTS:BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration. CONCLUSIONS: Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by μ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.
Entities:
Keywords:
Antinociception; BOM; Benzylideneoxymorphone; Drug discrimination; Rats; Self-administration
Authors: Maia Terashvili; Bhavana Talluri; Watchareepohn Palangmonthip; Kenneth A Iczkowski; Patrick Sanvanson; Bidyut K Medda; Banani Banerjee; Christopher W Cunningham; Jyoti N Sengupta Journal: Neuropharmacology Date: 2021-07-10 Impact factor: 5.273