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Hyperalgesic activity of kisspeptin in mice

DOI: 10.1186/1744-8069-7-90

Keywords: Kisspeptin, GPR54, inflammatory pain, nociceptive sensitization

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Abstract:

Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl) induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl) injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol), caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone.These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain.Kisspeptin is a 54-amino acid peptide originally discovered for its activity as metastasis-suppressor [1]. It is encoded by the Kiss1 gene as a 145-amino acid precursor protein and cleaved to a 54-amino acid protein as well as into shorter products (kisspeptin-10,-13,-14) known to play a critical role in the neuroendocrine regulation of reproduction [2-5].In the brain, kisspeptin is localized not only in areas involved in gonadotropin secretion, but also in other regions such as the amygdala, hippocampus, and the periacqueductal gray [6,7].Its action is mediated by a 7-TM receptor named GPR54, also known as KISS1R, which is coupled to polyphosphoinositide hydrolysis via a Gq/11 GTP binding protein [2,8].Loss-of-function mutations of GPR54 cause a non-Kallman variant of hypogonadotropic/hypogonadism in humans (i.e. hypogonadotropic/hypogonadism without anosmia) [2,9]. Interestingly, the expression of kisspeptin and GPR54 is not restricted to the hypothalamus. Relatively high levels of kisspeptin and GPR5

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