Study on the molecular mechanism of antinociception induced by ghrelin in acute pain in mice

Ghrelin has been identified as the endogenous ligand for the GHS-R1 alpha (growth hormone secretagogue receptor 1 alpha). Our previous experiments have indicated that ghrelin (i.c.v.) induces antinociceptive effects in acute pain in mice, and the effects were mediated through the central opioid receptors and GHS-R1 alpha. However, which opioid receptor (OR) mediates the antinociceptive effects and the molecular mechanisms are also needed to be further explored. In the present study, the antinociceptive effects of ghrelin (i.c.v.) could be fully antagonized by delta-opioid receptor antagonist NTI. Furthermore, the mRNA and protein levels of delta-opioid peptide PENK and delta-opioid receptor OPRD were increased after i.c.v injection of ghrelin. Thus, it showed that the antinociception of ghrelin was correlated with the GHS-R1 alpha and delta-opioid receptors. To explore which receptor was firstly activated by ghrelin, GHS-R1 alpha antagonist [DLys(3)]-GHRP-6 was co-injection (i.c.v.) with deltorphin II (selective delta-opioid receptor agonist). Finally, the antinociception induced by deltorphin II wasn't blocked by the co-injection (i.c.v.) of [D-Lys3]-GHRP-6, indicating that the GHS-Rl a isn't on the backward position of delta-opioid receptor. The results suggested that i.c.v. injection of ghrelin initially activated the GHS-R1 alpha, which in turn increased the release of endogenous PENK to activation of OPRD to produce antinociception. (C) 2016 Elsevier Inc. All rights reserved.