We examined the expression of notch in the brains of

We examined the expression of notch-1 in the brains of mice following morphine or oxycodone tolerance. The results showed that notch-1 levels did not change following morphine or oxycodone tolerance, with or without the treatment of IRL-1620. This indicates the possibility that morphine or oxycodone tolerance did not produce any Clindamycin HCl damage to induce neurogenesis. We did experiments in the rat brains with right sided cerebral ischemia, where IRL-1620 has been shown to induce neurogenesis and angiogenesis [19], and found a massive decrease in the expression of notch-1 in the right cerebral hemisphere compared to non-ischemic left cerebral hemisphere (data not shown). This suggests that morphine and oxycodone tolerance produces adaptive changes in the brain that are different from those produced by neurodegenerative diseases. In summary, to our knowledge, this the first study indicating that ETB receptor agonist, IRL-1620 attenuated the development of analgesic tolerance to morphine and oxycodone. We investigated the possibility of the involvement of VEGF and NGF in morphine or oxycodone tolerance and found that there was a significant decrease in the expression of NGF in the brains of the mice following morphine or oxycodone tolerance. However, whether these changes mediate opioid tolerance is not clear. Similar findings were obtained in the expression of PI3K which has been implicated in the signaling pathway of NGF. Additionally, it was found that the expression of notch-1 did not change following morphine or oxycodone tolerance, with or without the treatment of IRL-1620, indicating to the possibility that morphine or oxycodone tolerance did not produce enough damage to the brain to induce the neurorestorative and neuroprotective processes.
Conclusion IRL-1620, an ETB receptor agonist, attenuated tolerance to morphine and oxycodone induced analgesia. A significant decrease in the expression of NGF/PI3K in the brain was observed following opioid tolerance which was not affected by ETB receptor agonist, IRL-1620. It is concluded that ETB receptor agonist, IRL-1620 attenuates tolerance to opioids without the involvement of NGF/PI3K pathway.
Declarations
Introduction The endothelin family of vasoactive peptides consists of endothelin-1 (ET-1), -2 (ET-2), and -3 (ET-3). The endothelins mediate their effects through two distinct G-protein coupled receptor subtypes, ETA and ETB (Arai et al., 1990a, Sakurai et al., 1990, Yanagisawa et al., 1988). Under normal physiological conditions ETA is the dominant endothelin receptor subtype expressed in vascular smooth muscle cells (VSMC), where it mediates strong vasoconstriction (Adner et al., 1998b, Wang et al., 1998). ETB receptors are under normal conditions mainly expressed on endothelial cells where they mediate vasodilatation via production and release of nitric oxide (Hirata et al. 1993) and prostacyclin (Filep et al. 1991). However, in several pathophysiological conditions ETB receptors are upregulated in VSMC where they mediate vasoconstriction. Upregulation of ETB receptors in VSMC of coronary arteries has been demonstrated in experimental congestive heart failure (Cannan et al. 1996) and in patients with ischemic heart disease (Wackenfors et al., 2004, Dagassan et al., 1996a). In addition, forearm blood flow studies have revealed increased ETB receptor-dependent vasoconstriction in patients with atherosclerosis as compared to controls (Pernow et al. 2000). Upregulation of contractile ETB receptors in VSMC has also been demonstrated to take place in a variety of arteries during in vitro organ culture in serum-free culture medium. In left coronary arteries (LAD), it has been demonstrated that the stimulation of fresh human, rat and porcine arteries with the ETB-specific agonist S6c gives no or only a weak vasocontractile response, whereas a strong contractile ETB receptor-mediated response appears after 1–2day of organ culture in serum-free Dulbecco's Modified Eagles Medium (DMEM) (Johnsson et al., 2008, Nilsson et al., 2008). Information about ETB receptor plasticity in other parts of the coronary arterial tree is lacking.