Apelin signalling in the periaqueductal grey matter alleviates capsaicin-evoked pulpal nocifensive behaviour and capsaicin-induced spatial learning and memory impairments in rat

Aim: Pulpal pain is a common orofacial health issue that has been linked to cognitive impairment. Because of its prominent role in pain modulation and cognitive impairment, apelin (Apl) is regarded as a promising target for clinical pain management. The role of Apl in orofacial pain, however, is unknown. The purpose of this study was to determine the effects of intra-periaqueductal grey matter (PAG) administrations of Apl-13 on capsaicin-evoked pulpal nocifensive behaviour and capsaicin-induced spatial learning and memory impairments in rats. Methodology: Forty-nine male Wistar rats (200–250 g) were randomly divided into seven groups (n = 7 per group). The groups included: untreated intact, capsaicin (Caps) only, three Caps+Apl groups that received different dosages of intra-PAG injection of Apl-13 (1, 2 and 3 μg/rat) 20 min prior to capsaicin application, and two Apl+antagonist groups that received Apl receptor antagonist or naloxone (a μ opioid receptor) 20 min before Apl injection. Learning and memory were assessed using the Morris water maze test. One-way analysis of variance followed by Tukey post hoc tests was used for statistical analysis. Results: Intra-PAG administration of Apl-13 significantly reduced the capsaicin-induced nocifensive behaviour (p <.01). This antinociception effect was inhibited by F13A and naloxone. Apl-13 inhibited nociception-induced learning and memory deficits (p <.01). The cognitive effects were also blocked by pre-treatment administration of F13A (3 μg/rat). Conclusions: These findings indicated that Apl-13, via Apl receptors (AR or APJ) and μ opioid receptors, alleviated capsaicin-induced dental nocifensive behaviour and protected against nociception-induced learning and memory impairments. As a result of our findings, Apl appears to be a promising analgesic option for further research in orofacial pain models and clinical trials.