Behavioural Pharmacology of Novel Kappa Opioid Compounds

Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.\n\nMethods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined.

Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function.

Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.