Elsevier

Peptides

Volume 30, Issue 6, June 2009, Pages 1153-1157
Peptides

Supraspinal administration of apelin-13 induces antinociception via the opioid receptor in mice

https://doi.org/10.1016/j.peptides.2009.02.011Get rights and content

Abstract

The effect of apelin-13 on pain modulation at the supraspinal level was investigated in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of apelin-13 (0.3, 0.5, 0.8 and 3 μg/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A), indicating an APJ receptor-mediated mechanism. Furthermore, naloxone, β-funaltrexamine and naloxonazine, could reverse the analgesic effect. However, naltrindole or nor-binaltorphimine could not reverse the effect, suggesting that μ opioid receptor (primarily μ1 opioid receptor subtype) is involved in the analgesic response evoked by apelin-13. Moreover, i.c.v. administration of apelin-13 potentiated the analgesic effect induced by morphine (i.c.v., 5 μg/kg) and this potentiated effect can be also reversed by naloxone.

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.

Section snippets

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.

References (32)

Cited by (52)

  • Chronic administration of [Pyr<sup>1</sup>] apelin-13 attenuates neuropathic pain after compression spinal cord injury in rats

    2017, Neuropeptides
    Citation Excerpt :

    Stock solutions were prepared with 0.9% sterile saline and then stored at − 20 °C until use. Stock solution thawed and diluted before injection on a daily basis (Xu et al., 2009). Apelin and vehicle were intrathecally administered in a volume of 10 μl within 60 s using a Hamilton syringe (Ray et al., 2011) once a day from day 1 post SCI and continued for a week.

  • Induction of antinociceptive tolerance to the chronic intrathecal administration of apelin-13 in rat

    2016, Neuropeptides
    Citation Excerpt :

    Recently, it has been shown that apelin has central antinociceptive effects. In addition, μ-opioid receptor potentially involved in the analgesic effect of apelin (Lv et al., 2012b; Xu et al., 2009). Although, many studies have been demonstrated the unwanted side effect of analgesic tolerance in human and animals (Furlan et al., 2006), it has still remained unspecified whether antinociceptive tolerance can be induced by chronic administration of apelin-13.

View all citing articles on Scopus
1

Both authors contributed equally to this work.

View full text