The effect of morphine on MC4 and CRF receptor mRNAs in the rat amygdala and attenuation of tolerance after their blockade.

The relationships between the CRF, which enhances the proopiomelanocortin (POMC) biosynthesis, and POMC-derived peptides (opioids and melanocortins) might be a new target for rational treatment of morphine tolerance. In the present study, we investigated the effect of acute and chronic morphine administration on the level of CRF1 and melanocortin 4 receptor (MC4-R) mRNAs in the rat amygdala by quantitative real-time PCR method. Moreover, we investigated the effect of antagonists of melanocortin and CRF receptors, SHU9119 and alpha-helical CRF (alphah-CRF), respectively, administered bilaterally into the central nucleus of the amygdala, on morphine tolerance using tail-flick and paw withdrawal tests. Our study demonstrated that acute morphine administration decreased the level of MC4-R mRNA in the rat amygdala. This decrease was attenuated following chronic morphine administration, and mRNA level of MC4 receptors was gradually increased and, on 9th day of morphine administration, i.e. in the period when morphine tolerance already developed, the level was significantly increased in comparison with control and with the effect after single morphine dose. In contrast, morphine did not affect the CRF receptor. In behavioral study, we demonstrated that SHU9119 and alphah-CRF significantly increased the antinociceptive effect of morphine, when they were injected into the amygdala prior to morphine administration in tolerant rats. We have shown for the first time the contribution of amygdalar melanocortin receptors to morphine tolerance, and we conclude that the altered melanocortin receptor function may play an important role in the development of morphine-induced tolerance. CRF and melanocortin peptides can modulate the phenomena in the same direction, in opposition to opioids. Therefore, antagonists of melanocortin receptors may be regarded as possible therapeutic modulators of morphine tolerance.