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  • The present study was therefore conducted with

    2022-01-15

    The present study was therefore conducted with three aims; (1) we tested the effect of IRL-1620, a selective ETB receptor agonist, on the analgesic tolerance to morphine and oxycodone in mice; (2) we determined the expression of ETA receptors and ETB receptors in the clobetasol price of morphine and oxycodone tolerant mice; and (3) we determined the expression of VEGF, NGF, phosphoinositide 3-kinase (PI3K) and notch-1 in the brain of morphine and oxycodone tolerant mice.
    Material and methods
    Results
    Discussion This study examined the role of ETB receptor stimulation by IRL-1620 in morphine and oxycodone tolerant mice. Results provide evidence for the first time that ETB receptor agonist, IRL-1620, attenuates the development of tolerance to morphine and oxycodone. We also determined possible mechanism and found that opioid tolerance decreased the expression of NGF and its signaling pathway PI3K, though, VEGF expression was not affected. However, IRL-1620 did not attenuate opioid induced decrease in NGF/PI3K pathway, suggesting that attenuation of opioid tolerance by IRL-1620 is not mediated through NGF/PI3K pathway. Morphine tolerance produced a significant decrease in body weight, while it was not affected by oxycodone tolerance. IRL-1620 did not produce any effect on morphine induced change in body weight. A challenge dose of morphine and oxycodone in tolerant mice produced a significant decrease in body temperature, which was not altered by IRL-1620. Tail-flick latencies in morphine and oxycodone tolerant mice were decreased in response to their challenge dose, however, IRL-1620 significantly increased tail-flick latencies in both morphine and oxycodone tolerant mice. These results provide clear evidence that the development of analgesic tolerance to morphine and oxycodone is attenuated by IRL-1620, because the antinociceptive effect of morphine and oxycodone in tolerant mice was similar to that observed in non-tolerant mice. It can be interpreted that ETB receptor agonists may be effectively used in combination with opioids to prevent the development of tolerance and possibly avoid long-term adverse effects associated with opioids such as tolerance and dependence. Previous studies have shown that ETA receptors are involved in opioid analgesia [21, 22, 23, 24]. Therefore, in the present study, we sought to determine changes in the expression of ETA receptors in opioid tolerance. No change was observed in the expression of ETA receptors in the brains of mice that underwent morphine or oxycodone tolerance, with or without IRL-1620 treatment. It can be interpreted that development of opioid tolerance does not affect the expression of brain ETA receptors. We subsequently determined changes in the expression of ETB receptors in opioid tolerance. Treatment with IRL-1620, produced a significant up-regulation of ETB receptors in vehicle treated mice but not in morphine and oxycodone tolerant mice. This finding indicates that the up-regulation of ETB receptors due to IRL-1620 was attenuated by morphine or oxycodone tolerance. It is possible that the challenge dose of morphine or oxycodone either alone or when administered to animals pretreated with ETB receptor agonist, IRL-1620, caused an increase in ETB receptor expression and because of opioid tolerance this increase was not observed in IRL-1620 treated mice. However, this explanation is less likely because a challenge dose of morphine or oxycodone was administered to each animal including those in the vehicle treated groups that were or were not tolerant to opioid and no change in the expression of ETB receptors was observed. Serum levels of NGF were increased in patients suffering from heroin withdrawal, while VEGF levels were not altered [34]. It was also demonstrated that endogenous opioids such as Met-enkephalin decrease angiogenesis and both the number of blood vessels and the total length of vessels are significantly decreased [35]. These findings prompted us to examine the expression of VEGF in the brains of mice following morphine or oxycodone tolerance. VEGF levels did not change following morphine or oxycodone tolerance, with or without treatment of IRL-1620.