Supraspinal administration of apelin-13 induces antinociception via the opioid receptor in mice
Introduction
APJ is a G protein-coupled receptor that was originally isolated from human genomic DNA [22], subsequently cloned in mice [5] and rat [4], [14], [21]. It shares the closest identity to the angiotensin II type 1 (AT1) receptor ranging from 40% to 50% in the hydrophobic transmembrane regions, but it does not bind to angiotensin II [22]. The endogenous ligand for the APJ receptor was first isolated from bovine stomach extracts [30] and named apelin (APJ endogenous ligand). It derives from a 77 amino acid precursor, preproapelin, which can be cleaved into several molecular forms including apelin-36 and apelin-13 in different tissues [14], [15]. Apelin-13 was found to exhibit significantly higher activity at the receptor than apelin-36 [30].
To date, some physiological effects of apelin have been reported. Apelin-13 has been shown to promote the acidification rate and inhibit cAMP production in cells expressing APJ [30] and it was demonstrated to stimulate the proliferation of gastric cells and to increase the secretion of cholecystokinin from dispersed intestinal endocrine cells [32]. Intraperitoneal (i.p.) administration of apelin-13 increases drinking behavior [16], whereas intracerebroventricular (i.c.v.) administration decreases drinking behavior in dehydrated animals [25]. It has also been implied that apelin-13 was involved in the regulation of blood pressure [27], [31], vasopressin release [25], [29] and modulation of immune response [3], [13]. However, to our knowledge, there have been no published papers about the nociceptive effect of apelin to date.
The apelinergic system is widely distributed in both central system and periphery, particularly in the heart, kidney, lung, and mammary gland [9], [14], [15], [16], [21], [25]. In the CNS, the distribution of apelin and its receptors in the amygdala, hypothalamus, dorsal raphe nucleus (DRN) and spinal cord suggests a possible role for apelin in nociception. Thus, the present study aimed to: (1) evaluate the effects of i.c.v. administration of apelin-13 on pain modulation and morphine-induced analgesia, and (2) investigate the mechanisms involved in the effect.
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Materials and methods
All experiments were carried out according to protocols approved by the Ethics Committee of Animal Experiments at Lanzhou University and in accordance with guidelines from the China Council on Animal Care and the International Association for the Study of Pain Committee for Research and Ethical Issues. Every effort was made to minimize the numbers and any suffering of the animals used in the following experiments.
In vivo effect of apelin-13 on the nociception after i.c.v. administration
Fig. 1 illustrates the dose- and time-related analgesic effect of i.c.v. administration of apelin-13 in 48.5 °C warm-water tail immersion test in conscious mice. The i.c.v. administration of apelin-13 (0.3, 0.5, 0.8 and 3 μg/mouse) produced a significant dose-related increase in tail withdrawal latencies. This effect reached a maximum at 15 min and terminated about 40 min after i.c.v. injection. The percent change of TWL at 15 min after i.c.v. administration of 0.3, 0.5, 0.8 and 3 μg/mouse apelin-13
Discussion
The study presents evidence that apelin-13, a novel neuropeptide, plays a significant role in the modulation of pain response at the supraspinal level in mice. Our results also suggest that the analgesic effect of apelin-13 was mediated by the activation of the APJ receptor and endogenous opioid system.
The structure and anatomical distribution similarities between APJ/apelin and the AT1/angiotensin II may provide clues about the physiological functions of the apelin system. Antinociception
Acknowledgments
This study was supported by grants from the National Nature Science Foundation of China (No. J0630644). The authors would like to thank the other members of the group for their suggestions and help in the research.
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2021, NeuropeptidesCitation Excerpt :Biological researches show that apelin 13 has the highest biological activity among the other isoforms. This peptide sequence, which has 13 amino acids at its C-terminal, has been completely conserved during the evolution in all species (Xu et al., 2009; Lv et al., 2012). In addition, pyroglutamate apelin-13 ([pyr-1]-apelin-13) is created by post-translational modification in the N-terminal glutamate of apelin-13, is more protected against degradation by exopeptidase (Habata et al., 1999).
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Both authors contributed equally to this work.