Rationale: Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of salvinorin A has been used to develop longer acting KOPr agonists. Objectives: We evaluate two novel C-2 analogues of salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and β-tetrahydropyran Sal B (β-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side effects, pre-clinically. Methods: Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug seeking in self-administering rats. EOM Sal B and β-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and β-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FSTs), respectively. Results: EOM Sal B (0.1, 0.3 mg/kg, intraperitoneally (i.p.)) dose dependently attenuated drug seeking, and EOM Sal B (0.1 mg/kg, i.p.) and β-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST) were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B decreased time spent in the drug-paired chamber. Conclusion: EOM Sal B is more potent than Sal A and β-THP Sal B in reducing drug-seeking behaviour with fewer side effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.
|Number of pages||16|
|State||Published - Aug 1 2017|
Bibliographical noteFunding Information:
Funding was provided by the Neurological Foundation of New Zealand and the Health Research Council of New Zealand (to BMK), DA018151 (to TEP), GM008545 (to RSC) and an AFPE Pre-Doctoral Fellowship in Pharmaceutical Sciences (to RSC). A Postgraduate Research Scholarship was provided by Victoria University of Wellington (to AE). We would like to acknowledge Andrew Biggerstaff, Kelly Paton and Stephen Mathew for technical assistance. All animal use and procedures were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals and approved by the Victoria University of Wellington Animal Ethics Committee, Wellington, New Zealand.
© 2017, Springer-Verlag Berlin Heidelberg.
- Behavioural Pharmacology
- Conditioned place aversion
- Drug seeking
- Elevated plus maze
- Forced swim test
- Salvinorin A
- Sucrose self-administration
ASJC Scopus subject areas