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

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 < 0.001) by morphine and oxycodone and was unaffected by IRL-1620. Notch-1 expression was not altered by morphine, oxycodone or IRL-1620. 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.