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

Shruti Gulati,Anil Gulati,Shantel Jones,Shaifali Bhalla,Seema Briyal

doi:10.1016/j.heliyon.2017.e00317

Abstract

AimETA receptor antagonists reverse opioid tolerance but the involvement of ETB receptors is unknown. In morphine or oxycodone tolerant mice we investigated (1) the effect of ETB receptor agonist, IRL-1620, on analgesic tolerance; (2) changes in expression of the brain ETA and ETB receptors; and (3) alterations in the brain VEGF, NGF, PI3K and notch-1 expression.Main methodsBody 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 findingsTail 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 ETA or ETB receptor expression. IRL-1620 had no effect on ETA however it increased (61%) expression of ETB receptors. IRL-1620-induced increase in ETB 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.SignificanceETB 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.

Highlights

Opioids such as morphine and oxycodone are among the most potent analgesics used commonly for the management of moderate to severe pain
We have shown that ETA receptor antagonists potentiate morphine analgesia in mice and rats [21, 22] and reverse opioid tolerance via a G-protein mediated mechanism [22, 23, 24]
We determined possible mechanism and found that opioid tolerance decreased the expression of NGF and its signaling pathway phosphoinositide 3-kinase (PI3K), though, VEGF expression was not affected

Summary

Introduction

Opioids such as morphine and oxycodone are among the most potent analgesics used commonly for the management of moderate to severe pain. Due to their high analgesic efficacy, they are considered to be the drug of choice for numerous clinical situations such as managing acute pain following surgery or physical injury and chronic pain due to cancer or arthritis. One explanation is opioid receptor downregulation which reduces the number of receptors available for opioid actions [1] Another explanation is opioid receptor desensitization, where sustained exposure to opioids produces decoupling of the opioid receptors, which leads to signaling desensitization [1, 2]. Tolerance mechanisms are extremely complex and not very well understood

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