Recent studies have suggested that
melanocortins contribute to the generation and/or maintenance of pathological
pain. Experimental evidence indicates a primary role for
melanocortin 4 (MC4) receptors in pathological
pain. In a previous study, we described the presence of
MC4 receptor transcripts in the dorsal root ganglia (DRG). This finding prompted us to investigate the peripheral antinociceptive effects of
MC4 receptor antagonists. In addition, we assess the expression of MC4 receptors in the spinal cord and the DRG of rats subjected to
neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Injection of the
MC4 receptor antagonists Asp3-Lys8- Ac-Nle-Asp-His-D-Nal(2')-Arg-Trp-Lys-NH(2) (
SHU9119) and Mpr1-Cys8-Mpr-Glu-His-(D-Nal)-Arg-Trp-Gly-Cys-Pro-Pro-Lys-Asp-NH(2) (JKC-363) into the ipsilateral paw resulted in a significant and dose-dependent alleviation of
mechanical allodynia (assayed by the von Frey test) and
thermal hyperalgesia (assayed by the Hargreaves test). Compared to naive control animals, immunohistochemistry revealed a 40% and 22% increase in
MC4 receptor-immunoreactivity (IR) in the dorsal horn of the spinal cord ipsilateral to the injury at 3 and 14 days after CCI, respectively. Similarly, in the ipsilateral L4-L5 DRG, a 21.1% enhancement in
MC4 receptor-IR was seen 3 days after CCI, as well as a 40.5% increase 14 days after CCI. Together,
painful neuropathy resulted in the up-regulation of MC4 receptors in the spinal and peripheral nociceptive pathways. This up-regulation of MC4 receptors promotes the pronociceptive action of their endogenous
ligands. Therefore, a block of the MC4 receptors results in the antagonism of
neuropathic pain and such treatment could be beneficial therapeutically for individuals with chronic
neuropathic pain.