Melanocortins and Neuropathic Pain

Abstract

Neuropathic pain (pain initiated by a lesion or dysfunction of the nervous system) is characterised by symptoms such as allodynia (pain due to a stimulus that does not normally provoke pain) and hyperalgesia (an increased response to a stimulus that is normally painful). It constitutes a major clinical problem, since in many cases treatment is unsatisfactory. The main focus of this thesis is the role of the melanocortin system in neuropathic pain and its possible contribution to the treatment of this syndrome. The melanocortins comprise a group of peptides derived from the precursor molecule POMC (e.g. alpha-MSH and ACTH), and synthetically derived analogues. Melanocortins are known to antagonize opioid effects, such as analgesia and tolerance, and to have direct effects on nociception. So far, 5 melanocortin receptor (MC-R) subtypes are identified. The MC4-R subtype is the only one present in the spinal cord, located in nociception-associated areas (laminae II and X), which prompted us to investigate its role in neuropathic pain. Therefore we used the rat chronic constriction injury (CCI) model for neuropathic pain. By using a radioactively labelled alpha-MSH analogue, 125I-NDP-MSH, we demonstrated an increased binding in the outer layer of the dorsal horn, suggesting an upregulation of spinal MC4R in neuropathic pain. Both acute and chronic intrathecal administration of MC-R agonists to CCI rats increased cold allodynia (as measured by withdrawal latency to immersion in 4.5oC water bath) and mechanical allodynia (as measured by withdrawal threshold to von Frey filaments). Conversely, the MC4R antagonist SHU9119 decreased symptoms, suggesting that blockade of the spinal MC4R alleviates neuropathic pain. In the dorsal horn the MC-R agonist alpha-MSH as well as the endogenous opioid agonist beta-endorphin, both derived from POMC, are present. Also the mu- and delta-opioid receptors (for which beta-endorphin displays high affinity) are located in the same area, suggesting the presence of both a functional melanocortin and opioid system in the dorsal horn. We hypothesize that the anti-allodynic effects of SHU9119 are caused by blockade of a tonic influence of alpha-MSH on nociception, through the MC4R. This could reveal tonic anti-nociceptive effects of beta-endorphin (through the opioid receptors), coreleased with alpha-MSH. By administering naloxone (which increased pain symptoms) we furhter supported this hypothesis. In addition we investigated a possible interaction of the spinal melanocortin and opioid systems, and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity. A low dose of naloxone (which by itself had no effect on nociception) was able to block the anti-allodynic effect of SHU9119, confirming an interaction between the two systems. Combined treatment with SHU9119 and morphine resulted in additive anti-allodynic effects. Based upon these results we suggest that MC4R antagonists, possibly combined with opioids, might contribute to the treatment of human neuropathic pain. In addition to the investigation of the role of the melanocortins in neuropathic pain a novel animal model for neuropathic pain (the sciatic nerve crush) and an alternative method for quantifying mechanical allodynia (the "CatWalk") are also described in this thesis.