Attenuation of opioid tolerance by ETB receptor agonist, IRL-1620, is independent of an accompanied decrease in nerve growth factor in mice

Abstract Aim ET A receptor antagonists reverse opioid tolerance but the involvement of ET B receptors is unknown. In morphine or oxycodone tolerant mice we investigated (1) the effect of ET B receptor agonist, IRL-1620, on analgesic tolerance; (2) changes in expression of the brain ET A and ET B receptors; and (3) alterations in the brain VEGF, NGF, PI3K and notch-1 expression. Main methods Body weight, body temperature, and tail-flick latency were assessed before and after a challenge dose of morphine or oxycodone in vehicle or IRL-1620 treated mice. Expression studies were carried out using Western blots. Key findings Tail flick latency to a challenge dose of opioid was significantly increased by IRL-1620 from 39% to 100% in morphine tolerant and from 8% to 83% in oxycodone tolerant mice. Morphine or oxycodone did not alter ET A or ET B receptor expression. IRL-1620 had no effect on ET A however it increased (61%) expression of ET B receptors. IRL-1620-induced increase in ET B receptor expression was attenuated by morphine (39.8%) and oxycodone (51.8%). VEGF expression was not affected by morphine or oxycodone and was unaltered by IRL-1620. However, NGF and PI3K expression was decreased (P Significance ET B receptor agonist, IRL-1620, restored analgesic tolerance to morphine and oxycodone, but it did not affect morphine and oxycodone induced decrease in NGF/PI3K expression. It is concluded that IRL-1620 attenuates opioid tolerance without the involvement of NGF/PI3K pathway.