title: Peripheral antinociceptive effects of MC4 receptor antagonists in a rat model of neuropathic pain - a biochemical and behavioral study.
abstract: 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.
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Starowicz
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Ilona
authors.initials: I
authors.lastname: Obara
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chocyk
authors.forename: Ryszard
authors.initials: R
authors.lastname: Przewłocki
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wedzony
authors.forename: Halina
authors.initials: H
authors.lastname: Machelska
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewłocka
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D019824:beta-MSH / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C471568:11-Mrp-14-Nal-18-Cys-22-Asp-beta-MSH(11-22)NH2; D000700:Analgesics; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones