Evidence for the Induction of Analgesic Cross-Tolerance Between Opioid and Apelin/APJ Systems in Male Rats

Objective: Opioids are potent pain relievers for managing severe pain. However, their effectiveness is hindered by tolerance, which causes the need for higher doses and leads to adverse effects. In a previous study, we found that prolonged use of apelin, similar to opioids, results in a tolerance to its analgesic effects. It remains unclear whether there is a cross-tolerance between morphine and apelin, meaning if the analgesic effects of one can reduce the effectiveness of the other. Method: The tail-flick test was used to assess the nociceptive threshold. All experiments were carried out on 63 male Wistar rats, which received intrathecal apelin (3 mu g/rat) or morphine (15 mu g/rat) for 7 days. To determine cross-tolerance between the analgesic effect of morphine and apelin, the analgesic property of apelin or morphine was assessed in chronic morphine- or apelin-treated groups, respectively. To determine the role of apelin and opioid receptors signaling on the development of analgesic cross-tolerance, F13-A and naloxone, as apelin and opioid receptor antagonists, were injected simultaneously with morphine or apelin. At the end of the tests, the expression levels of apelin and mu- opioid receptors were evaluated by western blotting. Results: The data indicated that chronic apelin or morphine use produced tolerance to the antinociceptive effects of each other. F13-A and naloxone could inhibit the induction of such cross-tolerance. The molecular data showed that there was a significant downregulation of apelin receptors in chronic morphine-treated rats and vice versa. Conclusions: Chronic administration of apelin or morphine induces analgesic cross-tolerance that may, in part, be mediated through receptor interactions and downregulation. The demonstrated efficacy of F13-A in these experiments highlights its potential as a novel target for improving pain management through the inhibition of the apelin/APJ signaling pathway, meriting further investigation. ( J. Stud. Alcohol Drugs, 85, 704-712, 2024)