One of the mechanisms contributing to morphine

One of the mechanisms contributing to morphine tolerance is uncoupling of G-protein occurs from opioid receptors, resulting in a lower analgesic response. Our previous findings in morphine tolerant neonatal rats indicate that G-protein stimulation in the brain was significantly attenuated during tolerance [31]. However, ETA receptor antagonists restored G-protein coupling thereby reversing morphine tolerance. It has been shown that in opiate-dependent and opiate-withdrawing animals, there is a significant increase in G-protein mediated adenylyl cyclase activity in the striatum and cortex of the brain [19]. This increase may represent a compensatory DZNep which is opposite to the responses observed in opiate tolerance. This is supported by our present findings that morphine-induced G-protein activation is enhanced in neonatal rats undergoing morphine withdrawal. ET-1 produces a concentration-dependent increase in G-protein activation which is not altered during morphine withdrawal. ETA receptor antagonists do not activate G-proteins in naïve animals; however they significantly activate G-protein coupling during morphine withdrawal. Therefore, the response of G-protein activation with ETA receptor antagonists is similar in morphine tolerance and morphine withdrawal. Therefore, ETA receptor antagonists have the similar effect on G-protein activation in the brain during morphine tolerance and morphine withdrawal. During withdrawal partial coupling and uncoupling may occur, or there may be rapid changes in the G-protein coupling mechanisms during withdrawal. Our results indicate that these changes taking place in G-protein coupling mechanisms are restored by ETA receptor antagonists. Although opioid receptor and ET receptor coupling to G-proteins is affected in a similar manner in morphine tolerance, the present findings suggest that opioid receptors and ET receptors are affected differently during withdrawal. The development of tolerance and dependence in vivo may involve complex interactions between several neurotransmitter systems having opposing actions on the G-protein system [7]. Neonates have been found to have significantly different characteristics of receptors and concentration of neurotransmitters compared to adults, and extensive postnatal developmental changes take place in the CNS. Based on the findings of the present study we speculate that ETA receptors may play a major role in morphine withdrawal in neonatal rats. Since ETA receptor antagonists restore coupling of G-proteins to opioid receptors, this may be clinically significant in the management of opiate tolerance and withdrawal syndrome.
Conclusion It is concluded that ET induced stimulation of G-protein is altered in the brain of neonatal rats undergoing morphine withdrawal. ETB receptor agonists are not involved in morphine withdrawal in neonatal rats. However, ETA receptor antagonists restore coupling of G-proteins to opioid receptors in neonatal rats undergoing morphine withdrawal. ETA receptor antagonists are likely to normalize opioid functions and may be useful in opiate withdrawal.