Pareen Patel
Research Mentor: Jessica Anand
Mentor Department: Pharmacology, Medicine
Author(s): Pareen Patel, John Traynor, Dawn Jessup
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type:
Abstract
OUD is a condition defined by the chronic use of opioids by patients causing significant and progressive impairment in the quality of their day-to-day life. When left untreated, OUD can lead to an increased chance of misuse which can result in overdose and death. In fact, according to the National Library of Medicine, around 2.1 million people in the US struggle with OUD (National Institute of Health 2024). Patients diagnosed with OUD often struggle with halting opioid use due to the severe withdrawal symptoms caused by the Mu and Kappa opioid receptor. Our previous studies have shown that an opioid positive allosteric modulator, BMS-986122 (BMS122) reduces withdrawal symptoms in mice models and in turn, could help prevent patients struggling with OUD from relapsing. However, since BMS122 is a modulator that broadly enhances opioid receptor mediated effects, it is unclear how this compound influences other chronic opioids effects such as tolerance. For example if BMS122 were to increase tolerance, patients would end up needing higher doses of opioids which in turn could introduce fatal opioid side effects such as Wooden Chest Syndrome. To test this, 20 C57 mice were split equally into groups each with two conditions. The first condition was morphine or saline control and the second condition was BMS122 or vehicle control. Mice were injected twice daily intraperitoneally with 10 mg/kg of morphine in the morning followed by 10 mg/kg BMS122 or vehicle. In the evening, mice were injected with increasing doses of morphine or saline followed by BMS122 or vehicle. This schedule was repeated for four days where evening doses would begin ramping from 20 mg/kg to 80 mg/kg for morphine or saline to induce tolerance. To test antinociceptive response, mice were given a Warm Water Tail Withdrawal assay (WWTW) at 50°C 20 minutes after morning injections. On day 5, mice were injected with a 10 mg/kg challenge dose of morphine followed by 10 mg/kg BMS or vehicle followed by the WWTW assay. On day 1, mice had a tail flick latency of around 15s. In the next few days, tail flick latency decreased indicating an increased degree of tolerance to the challenge dose of morphine (10 mg/kg i.p). By day 3, the Morphine and Vehicle group had a tail flick latency of 9.7±3.8 seconds whereas other groups had a tail flick latency of 18.5±2 seconds. On days 4 and 5, tail flick latency of all groups begin to overlap as animals cease responding to the challenge dose, commensurate with the development of tolerance. Taken together, this data shows that BMS122 does not exacerbate tolerance and instead, might be decreasing or delaying it, though this result remains under further investigation. This reinforces how BMS122 has potential in the clinical settings for treating patients with OUD. By not exacerbating tolerance, patients can continue taking lesser doses while also experiencing a decrease in side effects and withdrawal symptoms. This in turn will give patients better treatment management and allow them to stay in rehabilitation. We wish to further test this by examining the BMS122 effects on tolerance on a milder, more long term scale. In this proposed assay, 16 mice are split into two conditions once again with saline control and morphine being one condition and BMS122 and vehicle being the other condition. Mice were injected with the same doses in the morning followed by WWTW at 50°C 20 minutes after morning injections. In the evening, the dose ramping would range from 20 mg/kg to 80 mg/kg but at a slower, more spread out pace. As these studies remain ongoing, we look forward to presenting our findings. Taken together our data have so far shown the significant therapeutic potential of positive allosteric modulation to significantly reduce both opioid withdrawal and tolerance, two critical barriers to effective treatment and management of the ongoing opioid crisis.
