Hyperalgesic Activity of Kisspeptin in Mice

Abstract

BackgroundKisspeptin is a neuropeptide known for its role in the hypothalamic regulation of the reproductive axis. Following the recent description of kisspeptin and its 7-TM receptor, GPR54, in the dorsal root ganglia and dorsal horns of the spinal cord, we examined the role of kisspeptin in the regulation of pain sensitivity in mice.ResultsImmunofluorescent 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.ConclusionThese 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 modulates the activity of the stress system and associated behaviours, the body temperature and nociception

“…This is in accordance with previous findings in hot plate and formalin tests conducted by Spampinato et al [206] and recent results that of Elhabazi et al [50]. In our experiments no linear dose-response curve, but rather an inverted bell-shaped response was observed, which is well known in the literature, and has already been described in case of endomorphins [22] and other neuropeptides [146].…”

“…Second, in chronic inflammatory pain model kisspeptin and KISS1R up-regulation was detected at the level of the dorsal root ganglia and dorsal horn neurones [140]. Third, Spampinato et al reported that the KISS1R antagonist, kisspeptin-234 exhibits a clearly analgesic effect in formalin test [206]. Fourth, the NPFFR agonist, NPFF in numerous studies caused analgesia when the route of administration was intrathecal instead of icv.…”

The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters

“…A few data indicate that KP has other actions besides that on reproduction. The hyperalgesic action of KP has been reported in mice [26]. KP directly regulates neuropeptide Y synthesis in hypothalamic neurons [27].…”

Lipid Nanoparticle Inclusion Prevents Capsaicin-Induced TRPV1 Defunctionalization

“…The capsaicin TRPV1 receptor is a non-selective ligand-gated cation channel that formed by six membrane-spanning domains assembled as homo or hetero-tetramers activated by heat, low pH, and endogenous lipids [2][3][4]. TRPV1 receptors are widely expressed in areas that are involved in pain transmission, both in the central and peripheral nervous system [5,6]. In the brain, TRPV1 receptors are also involved in the modulation of synaptic plasticity as well as in epilepsy and cognition [7].…”