Behavioural Pharmacology of Novel Kappa Opioid Compounds

10.26686/wgtn.17011409 ◽

2021 ◽

Author(s):

◽

Aashish Sultan Morani

Keyword(s):

Adverse Effect ◽

Adverse Effects ◽

Opioid Receptor ◽

Motor Function ◽

Serotonin Transporter ◽

Kappa Opioid ◽

Drug Seeking ◽

Behavioural Sensitization ◽

Cocaine Seeking ◽

Structural Analogues

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. Methods: 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.

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Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0910705106 ◽

2009 ◽

Vol 106 (45) ◽

pp. 19168-19173 ◽

Cited By ~ 187

Author(s):

Benjamin B. Land ◽

Michael R. Bruchas ◽

Selena Schattauer ◽

William J. Giardino ◽

Megumi Aita ◽

...

Keyword(s):

Opioid Receptor ◽

Dorsal Raphe Nucleus ◽

Dorsal Raphe ◽

Kappa Opioid Receptor ◽

Raphe Nucleus ◽

Kappa Opioid ◽

Drug Seeking ◽

Effects Of Stress ◽

Dorsal Raphé

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Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats

Pharmacology Biochemistry and Behavior ◽

10.1016/j.pbb.2009.09.002 ◽

2009 ◽

Vol 94 (2) ◽

pp. 244-249 ◽

Cited By ~ 41

Author(s):

Aashish S. Morani ◽

Bronwyn Kivell ◽

Thomas E. Prisinzano ◽

Susan Schenk

Keyword(s):

Opioid Receptor ◽

Kappa Opioid Receptor ◽

Salvinorin A ◽

Kappa Opioid ◽

Drug Seeking ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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Investigating the Effects of Novel Kappa Opioid Receptor Agonists on the Dopamine Transporter

10.26686/wgtn.16985389 ◽

2021 ◽

Author(s):

◽

Bridget Simonson

Keyword(s):

Cell Surface ◽

Dopamine Transporter ◽

Opioid Receptor ◽

Serotonin Transporter ◽

Surface Expression ◽

Kappa Opioid Receptor ◽

Cell Surface Expression ◽

Salvinorin A ◽

Kappa Opioid ◽

Opioid Receptor Agonists

Classic kappa opioid receptor (KOPr) agonists have shown anti-addictive properties in rat models of addiction (Heidbreder et al. 1998; Schenk et al. 1999; Sun et al. 2010), and this has been shown to be partially through modulation of dopamine and serotonin in the synapse (Thompson et al. 2000; Zhang et al. 2004; Zakharova et al. 2008a). However, they have side effects such as depression and dysphoria and therefore have not been moved into the clinic. The novel KOPr agonist salvinorin A has a completely different structure compared to the classic agonists, and along with its novel analogues has opened up a new family of KOPr agonists which may possess anti-addictive properties and have the potential to have decreased side effects. Salvinorin A has also demonstrated anti-addictive properties (Morani et al. 2009). In this study the novel KOPr agonist salvinorin A and its analogues DS-1-240 and DS-3-216 were investigated, along with the classic agonists U50,488H and U69,593. Their effects on the dopamine transporter (DAT) were measured using isolated rat brain tissue and cell models. The effects of U50,488H and salvinorin A on the serotonin transporter (SERT) was also measured in rat striatum using rotating disk electrode voltammetry, which was established to measure serotonin uptake in our lab during this study. We found that all of the kappa opioid receptor agonists studied in isolated rat brain tissue caused dose dependent increases in uptake of dopamine by the dopamine transporter and a decrease in uptake of serotonin by the serotonin transporter. The effect on the serotonin transporter was observed after a 15 min incubation with the agonists. Salvinorin A had a faster effect on the dopamine transporter than the other compounds investigated, with increases measured at 1 min rather than 4 min. DAT kinetics showed increases in Vmax for all agonists investigated, and both U69,593 and DS-1-240 also showed increased Km values. This demonstrates an overall increase in function, with the possibility of increased cell surface expression. Further investigation using cell models also found an increase in uptake of the fluorescent monoamine transporter substrate ASP+ by YFP tagged human DAT (YFP-hDAT). This effect was seen with all the agonists studied after incubations of less than 5 min and was YFP-hDAT trafficking-independent. The increase in uptake seen may be due to increased active YFP-hDAT found on the cell membrane as ASP+ binding studies demonstrated an increase in binding. The acute increase in YFP-hDAT function was found to be ERK1/2 dependent for all compounds studied, and was also dependent on intact lipid rafts in the cell membrane. After a 30 min incubation, salvinorin A and U50,488H still caused increased uptake of ASP+ by YFP-hDAT, whereas DS-1-240 and DS-3-216 did not. Increases in cell surface expression of YFP-hDATwas seen at this time point with salvinorin A, U69,593, and DS-3-216. Further investigation into this found that the increase in cell surface expression of YFP-hDAT after salvinorin A treatment was ERK1/2 dependent, whereas the increase seen with U69,593 appeared to be ERK1/2 independent. Overall, this data demonstrates that KOPr rapidly regulates DAT function by a trafficking-independent, ERK1/2-, and lipid raft-dependent mechanism. The classic KOPr agonist U50,488H and salvinorin A also caused a decrease in serotonin uptake by SERT, confirming that the KOPr also regulates SERT. The data from this study provides more information on how these classic and novel KOPr agonists function to regulate DAT and SERT, which may help explain some of the anti-addictive properties displayed by these compounds.

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Modulation of serotonin transporter function by kappa-opioid receptor ligands

Neuropharmacology ◽

10.1016/j.neuropharm.2016.10.011 ◽

2017 ◽

Vol 113 ◽

pp. 281-292 ◽

Cited By ~ 9

Author(s):

Santhanalakshmi Sundaramurthy ◽

Balasubramaniam Annamalai ◽

Devadoss J. Samuvel ◽

Toni S. Shippenberg ◽

Lankupalle D. Jayanthi ◽

...

Keyword(s):

Opioid Receptor ◽

Serotonin Transporter ◽

Kappa Opioid Receptor ◽

Receptor Ligands ◽

Kappa Opioid ◽

Opioid Receptor Ligands

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Investigating the Effects of Novel Kappa Opioid Receptor Agonists on the Dopamine Transporter

10.26686/wgtn.16985389.v1 ◽

2021 ◽

Author(s):

◽

Bridget Simonson

Keyword(s):

Cell Surface ◽

Dopamine Transporter ◽

Opioid Receptor ◽

Serotonin Transporter ◽

Surface Expression ◽

Kappa Opioid Receptor ◽

Cell Surface Expression ◽

Salvinorin A ◽

Kappa Opioid ◽

Opioid Receptor Agonists

Classic kappa opioid receptor (KOPr) agonists have shown anti-addictive properties in rat models of addiction (Heidbreder et al. 1998; Schenk et al. 1999; Sun et al. 2010), and this has been shown to be partially through modulation of dopamine and serotonin in the synapse (Thompson et al. 2000; Zhang et al. 2004; Zakharova et al. 2008a). However, they have side effects such as depression and dysphoria and therefore have not been moved into the clinic. The novel KOPr agonist salvinorin A has a completely different structure compared to the classic agonists, and along with its novel analogues has opened up a new family of KOPr agonists which may possess anti-addictive properties and have the potential to have decreased side effects. Salvinorin A has also demonstrated anti-addictive properties (Morani et al. 2009). In this study the novel KOPr agonist salvinorin A and its analogues DS-1-240 and DS-3-216 were investigated, along with the classic agonists U50,488H and U69,593. Their effects on the dopamine transporter (DAT) were measured using isolated rat brain tissue and cell models. The effects of U50,488H and salvinorin A on the serotonin transporter (SERT) was also measured in rat striatum using rotating disk electrode voltammetry, which was established to measure serotonin uptake in our lab during this study. We found that all of the kappa opioid receptor agonists studied in isolated rat brain tissue caused dose dependent increases in uptake of dopamine by the dopamine transporter and a decrease in uptake of serotonin by the serotonin transporter. The effect on the serotonin transporter was observed after a 15 min incubation with the agonists. Salvinorin A had a faster effect on the dopamine transporter than the other compounds investigated, with increases measured at 1 min rather than 4 min. DAT kinetics showed increases in Vmax for all agonists investigated, and both U69,593 and DS-1-240 also showed increased Km values. This demonstrates an overall increase in function, with the possibility of increased cell surface expression. Further investigation using cell models also found an increase in uptake of the fluorescent monoamine transporter substrate ASP+ by YFP tagged human DAT (YFP-hDAT). This effect was seen with all the agonists studied after incubations of less than 5 min and was YFP-hDAT trafficking-independent. The increase in uptake seen may be due to increased active YFP-hDAT found on the cell membrane as ASP+ binding studies demonstrated an increase in binding. The acute increase in YFP-hDAT function was found to be ERK1/2 dependent for all compounds studied, and was also dependent on intact lipid rafts in the cell membrane. After a 30 min incubation, salvinorin A and U50,488H still caused increased uptake of ASP+ by YFP-hDAT, whereas DS-1-240 and DS-3-216 did not. Increases in cell surface expression of YFP-hDATwas seen at this time point with salvinorin A, U69,593, and DS-3-216. Further investigation into this found that the increase in cell surface expression of YFP-hDAT after salvinorin A treatment was ERK1/2 dependent, whereas the increase seen with U69,593 appeared to be ERK1/2 independent. Overall, this data demonstrates that KOPr rapidly regulates DAT function by a trafficking-independent, ERK1/2-, and lipid raft-dependent mechanism. The classic KOPr agonist U50,488H and salvinorin A also caused a decrease in serotonin uptake by SERT, confirming that the KOPr also regulates SERT. The data from this study provides more information on how these classic and novel KOPr agonists function to regulate DAT and SERT, which may help explain some of the anti-addictive properties displayed by these compounds.

Download Full-text