Inhibition of morphine tolerance by spinal melanocortin receptor blockade

Chronic use of morphine is accompanied by the development of morphine tolerance, which is one of the major problems associated with opiate treatment. Possible modulation of opioid effects by melanocortin receptor ligands has been recently demonstrated. Therefore, we investigated the influence of repeated intrathecal injection of a melanocortin receptor antagonist (SHU9119, JKC-363) on the development of morphine tolerance as measured by tail-flick test. It was also examined whether a single i.t. SHU9119 and JKC-363 administration could counteract the loss of analgesic potency of morphine in morphine tolerant rats. We examined also the influence of chronic morphine administration on μ-opioid receptor (MOR) and melanocortin 4 receptor (MC4-R) mRNAs in the rat spinal cord and dorsal root ganglia (DRG) during morphine tolerance. Morphine treatment (10 mg/kg, i.p. twice daily) over 8 days induced tolerance as reflected by a significant reduction of withdrawal latency from 181 to 25% above baseline in the tail-flick test. Repeated co-administration of morphine and SHU9119 or JKC-363, significantly prevented the development of morphine tolerance. A single administration of an MC4-R antagonist restored morphine analgesic potency in morphine tolerant rats. Using RT-PCR we demonstrated no changes in the spinal cord but there was a decrease in MOR and increase in MC4-R gene expression in the DRG of rats tolerant to morphine. These results suggest that MC4-R may be involved in the mechanisms of opioid tolerance and antagonists of this receptor may be a possible new target in the search for strategies preventing the development of opioid tolerance.