Investigating the analgesic properties of Kurkinorin, a novel mu-opioid receptor analogue of Salvinorin A

Background: The mu-opioid receptor (MOPr) activating drugs such as morphine, fentanyl, etorphine and methadone are used to treat moderate to severe pain. However, their long-term use produces serious adverse effects such as respiratory depression, sedation, tolerance, nausea, dependence, and constipation and this signifies the search for an alternate pain therapeutic agent. Here we report the investigation of antinociceptive and side effect profiles of a structurally unique MOPr-activating drug, kurkinorin from Salvinorin A (Sal A) that was compared with morphine and herkinorin. Methods: Adult male B6-SJL mice (22-29 g) were used to investigate the antinociceptive effects of kurkinorin, herkinorin and morphine utilising the 50° C warm-water tail-withdrawal assay. The 2% intra-dermal formalin assay was used to evaluate acute nociceptive and inflammatory pain and paw oedema. The side effect profiles were evaluated by measuring core-body temperature and utilising behavioural tests of motor co-ordination (accelerating rotarod test). Kurkinorin’s rewarding properties were assessed using the conditioned place preference (CPP) assay in male Sprague-Dawley rats (240-350 g). Results: Kurkinorin produced significant antinociceptive effects in the tail-withdrawal assay at both 5 (p<0.01, 10 min, p<0.001, 15-60 min) and 10 mg/kg (p<0.001, 5-90 min, p<0.01, 120 min) and attenuated both nociceptive and inflammatory pain in the 2% intra-dermal formalin model in mice. The analgesic effects of kurkinorin at 10 mg/kg were similar to the analgesic effects of morphine at the same dose. The decrease in pain score in the intra-dermal formalin assay with kurkinorin and morphine produced a corresponding reduction of paw oedema. In comparison, herkinorin had reduced analgesic effects in the tail-withdrawal assay (10 mg/kg, p<0.05, 30 min) and attenuated inflammatory pain in the intra-dermal formalin assay (10 mg/kg, p<0.001) with reduced paw oedema (10 mg/kg, p<0.05). Morphine produced significant motor incoordination effects from 15-60 min post injection whereas kurkinorin produced no significant motor impairment. Kurkinorin and herkinorin (5 mg/kg, i.p) did not produce rewarding effects, whereas morphine produced a significant, rewarding effect in the CPP assay. Kurkinorin produced no change in the core body temperature while morphine significantly reduced the body temperature. Conclusions: Kurkinorin is central acting and is as potent as morphine in attenuating acute nociceptive and inflammatory pain. It produced no significant sedative and rewarding effects. Therefore, kurkinorin has been identified as a structurally new class of mu-opioid analgesic, displaying improvements compared to morphine.