Abuse-related effects of µ-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure

Abstract

Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be varied rapidly to maintain a wide range of baseline response rates, and drugs' effects can be evaluated simultaneously on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS 'facilitation' indicates drug-induced increases in low ICSS rates and is often considered an abuse-related effect, whereas ICSS 'depression' indicates decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of µ-agonist efficacy and of previous µ-agonist exposure as determinants of µ-agonist effects on ICSS in rats with electrodes implanted into the medial forebrain bundle. The high-efficacy, intermediate-efficacy, and low-efficacy µ agonists methadone, fentanyl, and nalbuphine were tested during escalating regimens of morphine exposure (vehicle, 3.2, and 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that µ-agonist exposure increases the expression of abuse-related ICSS facilitation by µ agonists with a broad range of efficacies at µ receptors.

Fig. 1

ICSS performance before, during and after chronic morphine treatment. ICSS curves were analyzed during pre-drug baseline sessions (grey dashed line), daily baseline components from test sessions during phases 1-3, and day 3 after termination of chronic morphine treatment (WD3: Withdrawal Day 3) for subjects that finished all three phases. The left panel shows 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 lower than those observed during the pre-drug baseline components, as determined by the Holm-Sidak post-hoc test following a significant two-way ANOVA. Summary data in the right panel show the total number of stimulations per test component expressed as a percentage of total pre-drug baseline control stimulations. Abscissae: phase of the treatment. Ordinates: percent control stimulations per test component. Downward arrows indicate the presence and direction of significant differences from pre-drug baseline as determined by analyses of frequency-rate data in the left panel, such that downward arrows indicate significant depression of ICSS at ≥1 frequency of the frequency-rate curve. ANOVA results were as follows: Significant main effect of frequency [F(9,126)=158.1; P<0.001], significant main effect of phase [F(3,42)=11.0; P<0.001], and significant phase X frequency interaction [F(27,378)=4.9; P<0.001]. All points show mean ± SEM for 15 rats.

Fig. 2

Effects of methadone on ICSS before and during chronic morphine treatment. Methadone doses (or vehicle) were administered during treatment with repeated vehicle (phase 1; a,b), repeated 3.2 mg/kg/day morphine (phase 2; c,d), and repeated 18 mg/kg/day morphine (phase 3; e,f). Left panels show full frequency-rate curves. Left abscissae: frequency of electrical brain stimulation in hertz (log scale). Left ordinates: ICSS rate expressed as percent maximum control rate (%MCR). Filled symbols indicate frequencies at which ICSS rates after methadone were different than those observed after vehicle, as determined by the Holm-Sidak post-hoc test following a significant two-way ANOVA. Summary data in the right panels show the total number of stimulations per test component expressed as a percentage of total pre-drug baseline control stimulations. Abscissae: dose of methadone in mg/kg. Ordinates: percent control stimulations per test component. Upward and/or downward arrows indicate the presence and direction of significant differences from vehicle treatment as determined by analyses of frequency-rate data in the left panels. All points show mean ± SEM for 5-8 rats. For description of axes and symbols, please refer to figure 1. ANOVA results were as follows: Chronic vehicle: Significant main effect of frequency [F(9,63)=31.4; P<0.001], significant main effect of dose [F(3,21)=9.9; P<0.001], and significant dose X frequency interaction [F(27,189)=9.1; P<0.001]. Repeated 3.2 mg/kg/day morphine: Significant main effect of frequency [F(9,54)=67.2; P<0.001], no significant main effect of dose [F(3,18)=2.6; P=0.086], and significant dose X frequency interaction [F(27,162)=11.2; P<0.001]. Repeated 18 mg/kg/day morphine: Significant main effect of frequency [F(9,36)=91.5; P<0.001], no significant main effect of dose [F(4,16)=1.2; P=0.365], and significant dose X frequency interaction [F(36,144)=10.4; P<0.001].

Fig. 3

Effects of fentanyl on ICSS before and during chronic morphine treatment. Fentanyl doses (or vehicle) were administered during treatment with repeated vehicle (phase 1; a,b), repeated 3.2 mg/kg/day morphine (phase 2; c,d), and repeated 18 mg/kg/day morphine (phase 3; e,f). All points show mean ± SEM for 5-6 rats. For description of axes and symbols, please refer to figures 1 and 2. ANOVA results were as follows: Chronic vehicle: Significant main effect of frequency [F(9,45)=93.2; P<0.001], significant main effect of dose [F(3,15)=4.3; P=0.022], and significant dose X frequency interaction [F(27,135)=5.6; P<0.001]. Repeated 3.2 mg/kg/day morphine: Significant main effect of frequency [F(9,45)=30.6; P<0.001], significant main effect of dose [F(4,20)=15.7; P<0.001], and significant dose X frequency interaction [F(36,180)=10.0; P<0.001]. Repeated 18 mg/kg/day morphine: Significant main effect of frequency [F(9,36)=37.7; P<0.001], significant main effect of dose [F(4,16)=12.1; P<0.001], and significant dose X frequency interaction [F(36,144)=5.3; P<0.001].

Fig. 4

Effects of nalbuphine on ICSS before and during chronic morphine treatment. Nalbuphine doses (or vehicle) were administered during treatment with repeated vehicle (phase 1; a,b), repeated 3.2 mg/kg/day morphine (phase 2; c,d), and repeated 18 mg/kg/day morphine (phase 3; e,f). All points show mean ± SEM for 5-6 rats. For description of axes and symbols, please refer to figures 1 and 2. ANOVA results were as follows: Chronic vehicle: Significant main effect of frequency [F(9,45)=63.0; P<0.001], significant main effect of dose [F(5,25)=6.6; P<0.001], and significant dose X frequency interaction [F(45,225)=3.0; P<0.001]. Repeated 3.2 mg/kg/day morphine: Significant main effect of frequency [F(9,45)=18.9; P<0.001], significant main effect of dose [F(5,25)=14.9; P<0.001], and significant dose X frequency interaction [F(45,225)=2.9; P<0.001]. Repeated 18 mg/kg/day morphine: Significant main effect of frequency [F(9,36)=13.2; P<0.001], significant main effect of dose [F(5,20)=9.0; P<0.001], but no significant dose X frequency interaction [F(45,180)=1.0; P=0.532].

Fig. 5

Effects of 0.1 naltrexone on ICSS during chronic 18 mg/kg/day morphine treatment (phase 3). All points show mean ± SEM for 15 rats from all groups. For description of axes and symbols, please refer to figures 1 and 2. There was significant main effect of frequency [F(9,126)=74.0; P<0.001], significant main effect of treatment [F(1,14)=6.7; P=0.021], and significant dose X frequency interaction [F(9,126)=3.7; P<0.001].

Fig. 6

Effects of methadone and nalbuphine on ICSS after termination of repeated morphine treatment. Methadone (a,b) and nalbuphine (c,d) were tested after 3 weeks of morphine abstinence. All points show mean ± SEM for 5 rats. For description of axes and symbols, please refer to figures 1 and 2. ANOVA results were as follows: Methadone: Significant main effect of frequency [F(9,36)=22.6; P<0.001], no significant main effect of dose [F(3,12)=2.6; P=0.097], and significant dose X frequency interaction [F(27,108)=5.7; P<0.001]. Nalbuphine: Significant main effect of frequency [F(9,36)=7.8; P<0.001], significant main effect of dose [F(5,20)=11.3; P<0.001], and significant dose X frequency interaction [F(45,180)=2.0; P<0.001].