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    • So in this study our results firstly demonstrated

    2021-11-26

    So in this Amoxapine study, our results firstly demonstrated that i.c.v. injection of ghrelin(1–7)-NH2 played a significant role in the modulation of the acute heat pain at the supraspinal level in mice. Our results showed that i.c.v. injection of ghrelin(1–7)-NH2 produced dose- and time- dependent antinociceptive effects. The antinociceptive effects were completely antagonized by [D-Lys3]-GHRP-6 which is the selective antagonist of GHS-R1α. This phenomenon indicated that ghrelin(1–7)-NH2 could bind to GHS-R1α and was the agonist of GHS-R1α. These results were consistent with that the N-terminus heptapeptide was the small active core of ghrelin (Matsumoto et al., 2001). Therefore, ghrelin(1–7)-NH2 should possess other physiological and pathological functions which are similar to ghrelin. Further studies are needed to explore more physiological and pathological functions of ghrelin(1–7)-NH2. Secondly, the antinociceptive effects of ghrelin(1–7)-NH2 (i.c.v.) were completely antagonized by the classical nonselective OR antagonist naloxone. It showed that the antinociceptive effects were mediated through the central opioid receptors. Our previous studies showed that ghrelin produced antinociceptive effects through GHS-R1α and OPRD (Liu et al., 2016). Furthermore, ghrelin(1–7)-NH2 is the best active sequence of ghrelin. So, we explored which OR mediated the antinociceptive effects evoked by ghrelin(1–7)-NH2 in the test. Our results showed that β-FNA, NLXZ and NTI obviously abolished the antinociceptive effects induced by ghrelin(1–7)-NH2, while the antinociceptive effects were not abolished by nor-BNI in the tail withdrawal test. These effects showed that the antinociceptive effects induced by ghrelin(1–7)-NH2 was mediated through the OPRM (primary μ1-opioid receptor) and OPRD. Comparing the antinociception of ghrelin through GHS-R1α and OPRD, ghrelin(1–7)-NH2 (i.c.v.) induced antinociception through GHS-R1α, OPRM (primary μ1-opioid receptor) and OPRD. Among the ORs, OPRM is the most important OR in connection with antinociception. So, these perhaps are the reasons for ghrelin(1–7)-NH2(i.c.v.) inducing good antinociceptive effects. Thirdly, the molecular mechanisms of ghrelin(1–7)-NH2(i.c.v.) were explored using the technologies of qRT-PCR and Western blot in mice. Our present results indicated that the ghrelin(1–7)-NH2’s antinociception was mediated through the activation of GHS-R1α. So the mRNA expression levels and protein expression levels of GHS-R were explored. The results revealed that the mRNA expression levels of the GHS-R increased significantly compared with the control group at 5 min after i.c.v. injection of ghrelin(1–7)-NH2. However, the protein expression levels of the GHS-R scarcely changed between the ghrelin(1–7)-NH2 treated group and the control group. Furthermore, the ghrelin expressions at the levels of transcription were not evidently altered at all the time after i.c.v. injection of ghrelin(1–7)-NH2 compared with the control group in the test. All of these present results suggested that the molecular mechanisms of antinociception after i.c.v. injection of ghrelin(1–7)-NH2 maybe in the activation of the GHS-R1α instead of changing the protein expression levels of ghrelin and GHS-R1α. The present results, in addition to GHS-R1α, OPRM (primary μ1-opioid receptor) and OPRD were involved in the antinociceptive effects of ghrelin(1–7)-NH2. We examined the mRNA and protein expression levels of various ORs and their endogenous opioid peptides. Our present results showed that both the OPRD and the PENK (the endogenous ligand of OPRD) increased obviously at the levels of mRNA and protein compared with the control group. These results showed that the antinociceptive effects induced after i.c.v. injection of ghrelin(1–7)-NH2 were via the release of more endogenous PENK, as well as via the increase expression levels of OPRD, to induce antinociception. These results were similar to our previous studies that the antinociception of ghrelin was induced through the release of PENK and the increase expression levels of OPRD (Liu et al., 2016). This phenomena indicated that ghrelin(1–7)-NH2 as the active sequence of ghrelin should have more physiological and pathological functions like ghrelin. Further investigation is required to discover other functions of ghrelin(1–7)-NH2.