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Introduction
The apelin receptor (APJ), a novel G-protein-coupled receptor, shares homology with the angiotensin II type 1 receptor and was considered an ‘orphan’ receptor prior to the discovery of apelin in 1998 (1,2). Apelin is a product of the 77-amino acid precursor preproapelin, which yields numerous isoforms, including apelin-12, apelin-13, apelin-17 and apelin-36 (3,4). Apelin-13 is composed of 13 amino acids at the C-terminus of preproapelin, and is highly conserved (5); it exhibits the strongest binding to APJ among all the isoforms (3). Following the pairing of apelin peptides with cognate ligands, they have been identified to serve various roles in physiological and pathophysiological states, including effects on the cardiovascular system (6–8), fluid equilibrium (9,10), the adipoinsular signaling pathway (11,12), the immune system (13) and neuroprotection (14).
The apelin-APJ system is located in the central and peripheral nervous systems (3,15). In the central nervous system (CNS), apelin and its receptors were detected in pain-associated regions, indicating that apelin may affect nociception (4,16). Previous studies have indicated that apelin-13, when administered at the supraspinal level, inhibits acute or visceral pain (17,18). Intracerebroventricular apelin-13 administration promotes antinociception in mice, an effect markedly antagonized by coagulation factor XIII A chain (an APJ antagonist) and naloxone, suggesting that apelin is involved in opioid receptor signaling and corroborating reports that apelin is located in opioid-rich brain areas, including the arcuate nucleus of the hypothalamus and the spinal trigeminal nucleus (19). However, a previous study proposed that an intrathecal injection of apelin-13 produces hyperalgesia, not antinociception, in the second phase of a formalin test (20). The discrepancies between previous studies may result from the involvement of multiple receptor systems in apelin-13-induced pain behavior in acute and tonic pain models. Although apelin-13 produces aberrations in acute nociceptive models, it possibly serves an agonistic role at low concentrations, with these effects reversed at increased concentrations (20). Alternatively, apelin-13 may costimulate receptors aside from known opioid binding molecules, compromising its antinociceptive activity (17). Recent clinical results also indicated that the ratio of apelin to the endothelin-1 precursor has a positive correlation with increased vaso-occlusive pain in pediatric patients with sickle cell disease (21), indicating that the role of the apelin-APJ system in pain modulation requires further research.
Pain following nerve injury, also termed neuropathic...