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Inhibition of morphine tolerance by spinal melanocortin receptor blockade

Recent research suggests that the melanocortin system is an important component influencing the changes in the spinal neuronal plasticity observed after chronic morphine administration//.

The 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.

Researchers from Poland, writing in the October issue of the journal Pain, investigated the influence of repeated intrathecal injection of a melanocortin receptor antagonist on the development of morphine tolerance as measured by tail-flick test. It was also examined whether a single administration of the antagonist could counteract the loss of analgesic potency of morphine in morphine tolerant rats. The authors examined also the influence of chronic morphine administration on ì-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 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 melanocortin receptor antagonist, 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 they 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. The authors propose that besides other systems, the melanocortin s ystem may also be involved in the changes in spinal neuronal plasticity. The specific MC4-R antagonists would be promising compounds to alleviate the side effects of long-term morphine treatment. Their ability to restore morphine analgesia may have clinical benefits.

The melanocortin receptor antagonist tested may widen the options of the use of opioids for treatment of chronic pain by reducing the need for opioid dose escalation, which is often associated with unwanted side effects and by attenuating the development of analgesic tolerance and hyperalgesia following chronic use of morphine.

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