Impact of genetic and pharmacological modulation of CB2 receptors on morphine-induced analgesia, tolerance, and reward in C57BL/6J mice

The use of morphine for pain management often leads to the development of tolerance and addiction, posing significant challenges in clinical practice. This study aims to achieve sustained morphine-induced analgesia while mitigating tolerance and reward development by targeting CB2 receptors. In this investigation, male and female C57Bl/6 mice, both wild-type and CB2 knockout, received various doses of morphine or vehicle daily over 10 days. Wild-type mice were also administered a CB2 antagonist (SR144528) prior to morphine injection to assess CB2 receptor involvement. Analgesic effects were evaluated using tail flick tests, while conditioned place preference tests measured reward effects. Our results demonstrate that wild-type mice developed tolerance to morphine within 6 days, whereas CB2 knockout mice showed sustained analgesia throughout the study period. Combining SR144528 with morphine prevented tolerance development, maintaining efficacy even at higher doses. Additionally, CB2 knockout mice exhibited increased sensitivity to morphine reward. Overall, genetic and pharmacological manipulation of CB2 receptors reduced tolerance but exacerbated drug-seeking behavior.