Dataset Information

Attenuation of opioid tolerance by ET_B 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 < 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.

SUBMITTER: Gulati S

PROVIDER: S-EPMC5466593 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Attenuation of opioid tolerance by ET<sub>B</sub> receptor agonist, IRL-1620, is independent of an accompanied decrease in nerve growth factor in mice.

Gulati Shruti S Briyal Seema S Jones Shantel S Bhalla Shaifali S Gulati Anil A

Heliyon 20170607 6

<h4>Aim</h4>ET<sub>A</sub> receptor antagonists reverse opioid tolerance but the involvement of ET<sub>B</sub> receptors is unknown. In morphine or oxycodone tolerant mice we investigated (1) the effect of ET<sub>B</sub> receptor agonist, IRL-1620, on analgesic tolerance; (2) changes in expression of the brain ET<sub>A</sub> and ET<sub>B</sub> receptors; and (3) alterations in the brain VEGF, NGF, PI3K and notch-1 expression.<h4>Main methods</h4>Body weight, body temperature, and tail-flick late ...[more]

PMID: 28626808

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Project description:The pharmacological properties of endothelin receptors (ETR) were investigated in guinea-pig bronchus by comparing binding and functional results. In binding assays, both the ET(B) agonists, endothelin-3 (ET-3) and N-suc-[Glu9,Ala11,15]ET-1(8-21) (IRL 1620), and the antagonist, N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D- 1-methoxycarbonyltryptophanyl-D-norleucine (BQ 788), showed biphasic inhibition curves of [125I]-endothelin-1 (ET-1) binding to bronchus membranes prepared from intact or epithelium-deprived tissue. IRL 1620 did not completely displace specifically [125I]-ET-1 bound to these tissue preparations. In the presence of the ET(A)-selective antagonist, cyclo(-D-Trp-D-Asp-L-Pro-D-Val-L-Leu) (BQ 123, 1 microM), IRL 1620 displacement curves were shallow but a complete inhibition was reached at a concentration of 1 microM. Both curves were better represented by two-site models. In addition, BQ 788 competition curves became monophasic when binding experiments were performed in the presence of 1 microM BQ 123. The non-selective agonist, ET-1, and BQ 123 inhibited [125I]-ET binding to bronchus membranes in dose-dependent fashions with monophasic curves. The contracting activity of IRL 1620 (0.55 nM- 1.6 microM) was tested on multiple-ring bronchial preparations pretreated with peptidase and cyclo-oxygenase inhibitors. BQ 788 shifted IRL1620 concentration-response curves to the right while BQ 123 did not influence bronchial responsiveness. In addition, a potentiation of the maximal response to the agonist was observed in BQ 788 treated bronchial rings. This effect was abolished by tissue pretreatment with Nomega-nitro-L-argininemethylester (L-NAME) or epithelium removal but not by pretreatment with atropine or iberiotoxin. Our results demonstrate that guinea-pig bronchus contains two populations of ET(B) receptors with different affinities for the ET(B)-selective agonist, IRL 1620. One ET(B) receptor population appears to activate bronchial muscle contraction while another on epithelial cells causes muscle relaxation through the release of nitric oxide (NO).

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Dataset Information

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

Aim

Main methods

Key findings

Significance

Publications

Attenuation of opioid tolerance by ET<sub>B</sub> receptor agonist, IRL-1620, is independent of an accompanied decrease in nerve growth factor in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Aim

Main methods

Key findings

Significance

Publications

Attenuation of opioid tolerance by ET<sub>B</sub> receptor agonist, IRL-1620, is independent of an accompanied decrease in nerve growth factor in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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