Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents

Abstract

Rationale: TRV130 (oliceridine; N-[(3-methoxythiophen-2-yl)methyl]-2-[(9 R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine) is a novel mu opioid receptor (MOR) agonist that preferentially activates G-protein versus β-arrestin signaling pathways coupled to MORs. Prevailing evidence suggests that TRV130 and other G-protein-biased MOR agonists may produce therapeutic analgesic effects with reduced adverse effects compared to existing MOR agonists.

Objectives: This study compared the effects of acute and repeated TRV130 administration on measures of antinociception, gastrointestinal function, and abuse liability in rodents. We hypothesized that TRV130 would produce robust and sustained antinociception and abuse-related effects during repeated treatment, but that tolerance would develop to gastrointestinal inhibition.

Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in mice. Gastrointestinal function was assessed in mice using an in vivo measure of fecal output and in vitro assays of colonic propulsion and of colon and ileum circular muscle contraction. Abuse liability was assessed in rats using an intracranial self-stimulation (ICSS) procedure. (+)-TRV130 was administered with acute and repeated dosing regimens, and (-)-TRV130 was also examined in the ICSS procedure to assess stereoselectivity.

Results: Acute (+)-TRV130 treatment produced robust antinociception, complete inhibition of gastrointestinal function, and weak abuse-related effects. Repeated (+)-TRV130 treatment failed to produce tolerance to antinociception or gastrointestinal inhibition, and abuse-related effects were enhanced by repeated treatment. Effects of acute and repeated (+)-TRV130 in these procedures resemble effects of morphine, with the exception that TRV130 antinociception was more resistant to tolerance. (-)-TRV130 was inactive.

Conclusions: These results suggest that TRV130 retains undesirable constipating and abuse-related effects during repeated treatment despite its bias for G-protein signaling.

Keywords: TRV130; abuse liability; analgesia; constipation; gastrointestinal inhibition; intracranial self-stimulation.

Figure 1

Comparison of effects produced by (+)-TRV130 and morphine on in vivo antinociception and fecal output (A,B) and in vitro colonic propulsion (C,D). In Panels A and B, abscissae show treatments, and ordinates show measures of antinociception (percent maximum possible effect, %MPE, Panel A) or fecal output over 60 min (expressed as a fraction of food consumption over the previous 24h; Total Corrected Fecal Output, Panel B). Bars show mean ± SEM in 5 mice. Asterisks indicate a significant difference between the designated treatments as indicated by a significant one-way ANOVA in Panel A [F(3,16)=33.78, P<0.0001] and Panel B [F(3,16)=15.74, P<0.0001] followed by Bonferroni’s post hoc test (**, P<0.01; ***, P<0.001). In Panel C, the abscissa shows treatment, and the ordinate shows distance traveled by an artificial pellet (expressed as a percentage of baseline pellet propulsion in the presence of Krebs solution for each colon). Bars show mean ± SEM in 5–10 colons. Asterisks indicate a significant difference from Krebs Baseline as indicated by a significant one-way ANOVA [F(5,29)=14.01, P<0.0001] followed by Bonferroni’s post hoc test (***, P<0.001). Panel D shows representative spatiotemporal maps from a 10 min video recording of colon inserted with an artificial pellet (black band). Distance along Y axis indicates time and the oral to anal gradient is represented on the X-axis. Note the absence of pellet propulsion in the presence of (+)-TRV130 (100 nM) and morphine (1 uM). Each symbol represents the same mouse in the two assays.

Figure 2

Circular muscle contractions elicited by repeated treatment with 100 nM (+)-TRV130 treatment in mouse colon (A; N=4) and ileum (B; N=3). Abscissae: Exposure number (4 sequential exposures). Ordinates: Percent of contraction elicited by the initial exposure (% Contraction). Representative raw traces are shown above each panel. Bars show mean ± SEM, and points show data for individual experiments. Asterisk indicates significant difference from contraction during exposure 1 determined by repeated measures ANOVA in Panel B [F(3,6)=14.72, P<0.01] followed by Bonferroni’s post hoc test (**, P<0.01). The ANOVA in Panel A was not significant [F(3,9)=1.875, P=0.20142].

Figure 3

Effects of (+)-TRV130 (A,B) and (−)-TRV130 (C,D) on ICSS in rats. Left panels (A,C) show ICSS frequency-rate curves. Abscissae: frequency of electrical brain stimulation in hertz (log scale). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Filled symbols indicate frequencies at which ICSS rates were significantly different from those observed after vehicle administration. Only the highest dose of (−)-TRV130 is shown in Panel C for clarity. Right Panels (B,D) show summary data for the total number of stimulations per test component expressed as a percentage of total pre-test baseline stimulations. Panel B also shows effects of 0.1 mg/kg naltrexone (NLTX) pretreatment on depression of ICSS produced by 1.0 mg/kg (+)-TRV130 (compared with effects 1.0 mg/kg (+)-TRV130 alone by t test), and Panel D also shows effects of 10 mg/kg cocaine (compared with effects of vehicle by t-test). Abscissae: dose of drug. Ordinates: percent control stimulations per test component. * Asterisks indicate significant effect compared to vehicle. # Number sign indicates significantly different from 1.0 mg/kg (+)-TRV130 alone. Statistical results were as follows (only interaction results are reported for two-way ANOVAs): (A) significant dose × frequency interaction [F(27,135)=23.45; P<0.0001]. (B) Significant effect of (+)-TRV130 dose [F(3,15)=117.0; P<0.0001]; significant effect of naltrexone (t=14.1, P<0.0001). (C) No significant dose × frequency interaction. (D) No significant main effect of (−)-TRV130 dose; significant effect of cocaine (t=4.8, P=0.005). All points show mean ± SEM for 6 rats.

Figure 4

Effect of cumulative (+)-TRV130 on ICSS in rats. For this study, (+)-TRV130 was administered by cumulative dosing in a single test session rather than as separate doses on different test days. For description of axes and symbols, please refer to Fig. 1. ANOVA results were as follows (only interaction results are reported for the two-way ANOVA): (A) Significant dose × frequency interaction [F(27,405)=21.3; P<0.0001]. (B) Significant effect of dose [F(3,45)=53.5; P<0.0001]. All points show mean ± SEM for 16 rats.

Fig. 5

Modulation of (+)-TRV130 effects on ICSS after repeated treatment with vehicle, 1.0 mg/kg/day (+)-TRV130, or 3.2 mg/kg/day morphine. Subjects were injected with saline (A,B,C), 1.0 mg/kg/day (+)-TRV130 (D,E,F), or 3.2 mg/kg/day morphine (G,H,I) for 7 days, and the effect of cumulative doses of (+)-TRV130 on ICSS was determined before and after repeated administration. For description of axes and symbols, please refer to Figure 1. * Asterisks indicate significant effect compared to within-day vehicle, whereas # number signs indicate significant effect between days for the same dose. ANOVA results were as follows: (A) Significant dose × frequency interaction [F(27,108)=7.9; P<0.0001]. (B) Significant dose × frequency interaction [F(27,108)=13.4; P<0.0001]. (C) No significant dose × day interaction, but a significant main effect of dose [F(3,12)=36.8; P<0.0001]. (D) Significant dose × frequency interaction [F(27,108)=6.0; P<0.0001]. (E) Significant dose × frequency interaction [F(27,108)=3.6; P<0.0001]. (F) Significant dose × day interaction [F(3,12)=5.4; P=0.0137]. (G) Significant dose × frequency interaction [F(27,135)=10.7; P<0.0001]. (H) Significant dose × frequency interaction [F(27,135)=12.5; P<0.0001]. (I) Significant dose × day interaction [F(3,15)=5.2; P=0.0113]. All points show mean ± SEM for 5–6 rats.