Intravenous Administration of BQ123, an ETA Receptor Antagonist Reverses Morphine Tolerance in Male Swiss Webster Mice
Authors: Bhalla Shaifali , Lyne Jaimee , Andurkar Shridhar V , Gulati Anil 
Published: June 2021

We have demonstrated that intracerebroventricular injection of ETA receptor (ETAR) antagonists enhances opioid analgesia and reverses analgesic tolerance. The effect of clinically‐relevant intravenous (IV) administration of ETAR antagonists on opioid analgesia and tolerance is not known. In the present study, we investigated the effect of ETAR antagonist BQ123 (IV) on morphine tolerance.

Morphine tolerance was induced in male Swiss Webster mice using a three‐day (twice‐daily) or seven‐day (twice‐daily) escalating dosing (30–120 mg/kg, subcutaneous [SC]) regimen. BQ123 (single dose: 8 mg/kg, IV) was injected on days 1, 2, 3 or 4 in 3‐day studies, and on days 4, 6 or 8 in 7‐day studies. Tail‐flick and hot‐plate tests were used to assess antinociceptive tolerance to morphine. Morphine challenge dose (5 mg/kg, SC) was given on day 4 or day 8 (depending on the study) and antinociceptive effects were determined before and 30, 60, 90, 120, 180, 240, 300 and 360 mins after the challenge dose. Antinociceptive responses (presented as Mean±SEM) were analyzed using analysis of variance followed by post‐hoc Bonferroni test. In vitro experiments are ongoing in SH‐SY5Y neuroblastoma cells to determine intracellular calcium response to morphine treatment using Fluorescent Imaging Plate Reader (FLIPR).

BQ123 (8 mg/kg, IV) alone did not affect analgesic parameters in tail‐flick and hot‐plate tests. Maximal tail‐flick and hot‐plate latencies in morphine tolerant mice were 3.21s and 13.01s respectively, which were lower (p<0.05) than control mice, indicating development of tolerance. BQ123 (IV) on days 1 or 2 did not affect morphine antinociception in tolerant mice. However, BQ123 (IV) injection on day 3 in tolerant mice increased tail‐flick latency to 6.36s and hot‐plate latency to 19.14s, which were higher (p<0.05) compared to vehicle‐treated tolerant mice. BQ123 (IV) on day 4 increased tail‐flick and hot plate latencies to 6.24s (p<0.05) and 19.38s (p<0.05) respectively. In 7‐day studies, BQ123 given on day 4 did not affect antinociception in tolerant mice. However, BQ123 given on day 6 in tolerant mice increased tail‐flick latency to 7.66s (p<0.05) and hot‐plate latency to 18.28s (p<0.05) compared to vehicle‐treated tolerant mice. Further, BQ123 given on day 8 increased (p<0.05) tail‐flick and hot‐plate responses to ‐‐‐‐‐8.03s and 18.15s respectively. Thus, morphine tolerance was attenuated by BQ123 (IV), and this effect lasted for 48 h in 7‐day studies. In SH‐SY5Y cells, increase in intracellular calcium response is seen following acute morphine treatment. The effect of BQ123 on intracellular calcium in morphine tolerance in SH‐SY5Y cells is under investigation.

BQ123 (IV) significantly reversed the analgesic tolerance to morphine. Therefore, BQ123 (IV) has the potential to eliminate tolerance to opioids in patients on chronic opioid regimens. Especially given the grave public health concern about misuse of opioids and subsequent withdrawal, use of BQ123 will have a positive clinical impact by enabling pain control at lower doses of opioids, thus lowering the incidence of adverse effects of opioids.

Support or Funding Information

This project was funded by Midwestern University, Downers Grove, IL

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.