Role of Efficacy as a Determinant of Locomotor Activation by Mu Opioid Receptor Ligands in Female and Male Mice

Santos, Edna J.; Banks, Matthew L.; Negus, S. Stevens

doi:10.1124/jpet.121.001045

Cited by 13 publications

(40 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study builds on these previous findings by demonstrating that climbing is highly sensitive to disruption by MOR agonists and has a very low MOR efficacy requirement. Specifically, previous work in our lab has used fixed-proportion fentanyl/naltrexone mixtures as a strategy to quantify the efficacy requirements for a wide range of MOR agonist-induced behavioral endpoints in mice, rats, and rhesus monkeys ( 36 , 38 – 40 ). Application of this approach in the present study revealed that climbing in mice is the most sensitive behavioral effect we have evaluated in any species.…”

Section: Discussionmentioning

confidence: 99%

“…Step 2 evaluated effects produced by a series of fixed-proportion fentanyl/naltrexone mixtures. We have reported previously that the proportion of fentanyl in fentanyl/naltrexone mixtures can be manipulated such that decreasing fentanyl proportions result in decreasing net efficacy of the mixture ( 36 , 38 – 40 ). Here, we examined 10:1, 3.2:1, and 1:1 mixtures of fentanyl/naltrexone.…”

Section: Methodsmentioning

confidence: 99%

“…A significant ANOVA was again followed by a Holm-Sidak post hoc test. Lastly, data from experiments with fentanyl/naltrexone mixtures administered alone were used to determine the efficacy requirement for opioid effects on climbing as we have described previously ( 36 , 38 – 40 ). Briefly, data from each mixture were transformed to a percent of the maximum effect produced by fentanyl alone using the equation [(vehicle - mixture) ÷ (vehicle – fentanyl)] ×100, where “vehicle” equals the mean vehicle control data in a group, “mixture” equals the time climbing in a given mouse after a given dose of a mixture, and “fentanyl” equals the mean maximum effect of fentanyl alone in the fentanyl treatment group.…”

Section: Methodsmentioning

confidence: 99%

“…MOR efficacy may be especially relevant for opioid effects in assays of pain-depressed behavior, where opioids can produce competing effects that include both analgesia (which alleviates pain-related behavioral depression and increases rates of the target behavior) and motor impairment (which can reduce rates of the target behavior and obscure analgesic restoration of pain-depressed behavior) ( 19 , 34 , 35 ). Accordingly, we manipulated MOR efficacy by testing both (a) a set of single-molecule opioids with decreasing MOR efficacy (fentanyl > buprenorphine > naltrexone) ( 34 , 36 , 37 ), and (b) a series of fixed-proportion fentanyl/naltrexone mixtures that vary in net MOR efficacy as described previously ( 36 , 38 – 40 ). We hypothesized that low-efficacy single-molecule opioids or fentanyl/naltrexone mixtures would have sufficient efficacy to alleviate pain-related depression of climbing without affecting motor behavior.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

et al. 2023

Self Cite

View full text Add to dashboard Cite

This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, and “Time Climbing” was scored by observers blind to treatments. Initial validation studies demonstrated that baseline climbing was stable across repeated days of testing and depressed by intraperitoneal injection of dilute lactic acid (IP acid) as an acute pain stimulus. Additionally, IP acid-induced depression of climbing was blocked by the positive-control non-steroidal anti-inflammatory drug (NSAID) ketoprofen but not by the negative control kappa opioid receptor agonist U69593. Subsequent studies examined effects of single-molecule opioids (fentanyl, buprenorphine, naltrexone) and of fixed-proportion fentanyl/naltrexone mixtures (10:1, 3.2:1, and 1:1) that vary in their efficacy at the mu opioid receptor (MOR). Opioids administered alone produced a dose- and efficacy-dependent decrease in climbing, and fentanyl/naltrexone-mixture data indicated that climbing in mice is especially sensitive to disruption by even low-efficacy MOR activation. Opioids administered as a pretreatment to IP acid failed to block IP acid-induced depression of climbing. Taken together, these findings support the utility of climbing in mice as an endpoint to evaluate candidate-analgesic effectiveness both to (a) produce undesirable behavioral disruption when the test drug is administered alone, and (b) produce a therapeutic blockade of pain-related behavioral depression. The failure of MOR agonists to block IP acid-induced depression of climbing likely reflects the high sensitivity of climbing to disruption by MOR agonists.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…This opioidinduced hyperlocomotion is dependent on dopaminergic activation [31][32][33] , namely the activation of MORs expressed on GABA afferents onto VTAdopamine neurons 34 . Additionally, locomotor activation can distinguish between full and partial MOR agonists, with partial agonists producing graded increases dependent on e cacy 35 . We found that (R,S)-MTD and (R)-MTD increased locomotion, but (S)-MTD did not (Fig.…”

Section: Divergent Pharmacodynamic Effects Of (R)-mtd and (S)-mtd At ...mentioning

confidence: 99%

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

Michaelides¹,

Levinstein

Oliveira

et al. 2023

Preprint

View full text Add to dashboard Cite

(R,S)-methadone ((R,S)-MTD) is a racemic µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers used for the treatment of opioid use disorder (OUD) and pain. (R)-MTD is used as an OUD treatment, has high MOR potency, and is believed to mediate (R,S)-MTD’s therapeutic efficacy. (S)-MTD is in clinical development as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. In opposition to this purported mechanism of action, we found that (S)-MTD does not occupy NMDARs in vivo in rats. Instead, (S)-MTD produced MOR occupancy and induced analgesia with similar efficacy as (R)-MTD. Unlike (R)-MTD, (S)-MTD was not self-administered and failed to increase locomotion or extracellular dopamine levels indicating low abuse liability. Moreover, (S)-MTD antagonized the effects of (R)-MTD in vivo and exhibited unique pharmacodynamic properties, distinct from those of (R)-MTD. Specifically, (S)-MTD acted as a MOR partial agonist with a specific loss of efficacy at the MOR-galanin 1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use, as well as those of (R,S)-MTD.

show abstract

Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Santos

Nassehi

Bow³

et al. 2023

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

Low‐efficacy mu‐opioid receptor (MOR) agonists represent promising therapeutics, but existing compounds (e.g., buprenorphine, nalbuphine) span a limited range of low MOR efficacies and have poor MOR selectivity. Accordingly, new and selective low‐efficacy MOR agonists are of interest. A novel set of chiral C9‐substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high‐to‐low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand‐stimulated [35S]GTPɣS binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high‐efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower‐efficacy MOR agonists. In the ligand‐stimulated [35S]GTPɣS binding assay, seven phenylmorphans had graded levels of sub‐buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and ≥1 h duration of effects, evidence for MOR mediation, and minor sex differences. Tianeptine functioned as a high‐efficacy MOR agonist. Overall, these in vitro and in vivo studies support the characterization of these compounds as MOR‐selective ligands with graded MOR efficacy and utility for further behavioral studies in mice.

show abstract

Role of Efficacy as a Determinant of Locomotor Activation by Mu Opioid Receptor Ligands in Female and Male Mice

Cited by 13 publications

References 44 publications

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Contact Info

Product

Resources

About