Evidence for the involvement of MC4 receptors in the central mechanisms of opioid antinociception

Abstract

The data described in this thesis extend general knowledge of the involvement of the MC4 receptor in mechanisms of analgesia. The following aspects outlined below constitute novel information. Firstly, the MC4R localization in the DRG is demonstrated. The MC4 receptor was assumed to exist exclusively in the CNS, but our recent data and reports of other authors proved that this assumption needs to be revised. The novel information on the MC4R localization in the peripheral ganglia may facilitate understanding of the role of melanocortins in pain transmission and may open new avenues for future clinical applications. Secondly, the present studies revealed that the modulation of the activity of the spinal and supraspinal melanocortin system delayed the development of morphine tolerance. Thirdly, morphine analgesia was shown to be subject of modulation by melanocortin receptor ligands. The observed effects were very much dependent on the sequence of intercellular events, of the potential value is the interaction observed after the spinal MC4R blockade followed by administration of morphine. Combining the data of our study on the effectiveness of an MC4R antagonist in alleviating neuropathic pain symptoms and in preventing morphine tolerance may prompt preclinical study and future clinical trials on chronic neuropathic pain, where opioid dosing is needed. This may eliminate the need to increase the opioid dose necessary for maintaning a satisfactory pain relief, thus minimizing unwanted side effects of the treatment. Despite increasing knowledge of the function of the melanocortins, the mode of the function of regulation of the µ-opioid and MC4 receptor remains elusive. Anatomical basis of their interaction needs to be established; therefore co-localization of µ-opioid and MC4Rs both in the lumbar spinal cord and in corresponding DRG would be an interesting issue to address in subsequent studies. Furthermore, it would also be of great interest to localize the MC4R in a subpopulation of primary afferent neurons under neuropathic pain conditions, using specific marker for subpopulations of A- and/or C-fibers. Last but not least, based on the demonstration of the MC4R-IR in the DRG, it would be interesting to investigate MC4R at primary afferents in the dorsal horn of the spinal cord after peripheral injury to the sciatic nerve.