Effect of the spinal apelin-APJ system on the pathogenesis of chronic constriction injury-induced neuropathic pain in rats

Apelin is hypothesized to serve a dual function in pain processing. Spinal administration of apelin induces hyperalgesia, while opioid receptors are implicated in the antinociceptive effects of apelin in acute nociceptive models. However, whether the apelin-apelin receptor (APJ) system is involved in neuropathic pain remains to be elucidated. The present study aimed to evaluate the impact and mechanism of the spinal apelin-APJ system in neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve produced sustained spinal apelin and APJ upregulation, which was associated with mechanical allodynia and heat hyperalgesia development in the hind-paw plantar surface. Immunofluorescence demonstrated that apelin and APJ were localized to the superficial dorsal horns. In order to further clarify the function of the apelin-APJ system, a single intrathecal administration of ML221, an APJ antagonist, was used; this transiently reduced CCI-induced pain hypersensitivity. However, apelin-13 (the isoform which binds most strongly to APJ) exhibited no effect on the nociceptive response, suggesting an essential role for the spinal apelin-APJ system in neuropathic pain sensitization. The present study demonstrated that a single application of ML221 alleviated mechanical allodynia and heat hyperalgesia 7 days following CCI, in a dose-dependent manner. Intraspinal delivery of ML221, at the onset of and in fully-established neuropathic pain, persistently attenuated CCI-induced pain hypersensitivity, indicating that the apelin-APJ system was involved in initiating and maintaining pain. It was demonstrated, using immunoblotting, that intrathecal ML221 downregulated phosphorylated extracellular signal-related kinase (ERK) in the rat spinal cord dorsal horn, suggesting that the effect of apelin on neuropathic pain may be mediated via ERK signaling. The results of the present study suggested that the spinal apelin-APJ system may drive neuropathic pain. Inhibition of APJ may provide novel pharmacological interventions for neuropathic pain.