Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats

Abstract

Rationale: Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan) is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists.

Objectives: This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during, and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone.

Methods: Adult male Sprague-Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32-10 mg/kg), nalbuphine (1.0 mg/kg), and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning 2 weeks after termination of morphine treatment.

Results: NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine.

Conclusions: These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence.

Figure 1

Baseline ICSS performance before, during and after chronic morphine treatment. ICSS curves were analyzed during pre-drug baseline sessions (grey dashed line), and before test drug administration during each phase of morphine exposure. 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. Right panel shows summary data for the total number of stimulations per test component expressed as a percentage of total pre-drug baseline control stimulations. Abscissa: daily morphine dose in mg/kg/day during each phase of testing. Ordinate: percent control stimulations per test component. 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. All points show mean ± SEM for the 5 rats that completed all phases of the study; one rat lost its head cap during treatment with 18 mg/kg/day morphine and is not included in this figure.

Figure 2

Effects of NAQ on ICSS before, during and after chronic morphine treatment. NAQ doses (or vehicle) were administered during treatment with repeated vehicle (a,b), repeated 3.2 mg/kg/day morphine (c,d), repeated 18 mg/kg/day morphine (e,f), or beginning two weeks after termination of morphine treatment (g,h). 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 NAQ 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 NAQ 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 as determined by analyses of frequency-rate data in the left panel, such that upward arrows indicate significant facilitation of ICSS at ≥1 frequency, and downward arrows indicate significant depression of ICSS at ≥1 frequency of the frequency-rate curve. All points show mean ± SEM for 6 rats (panels a-d) or 5 rats (panels e-h).

Figure 3

Naltrexone antagonism of NAQ effects during chronic treatment with 3.2 mg/kg/day morphine. All points show mean ± SEM for 6 rats. For description of axes and symbols, please refer to figures 1 and 2. Filled points indicate significantly different from “Vehicle.” Asterisks indicate significantly different from “0.1 NLTX + 1.0 NAQ”.

Figure 4

Effects of nalbuphine (1.0 mg/kg) and naltrexone (0.1 mg/kg) on ICSS before and during chronic morphine treatment. All points show mean ± SEM for 6 rats (panels a-d) or 5 rats (panels e,f). For description of axes and symbols, please refer to figures 1 and 2. Filled points indicate significantly different from “Vehicle.” Asterisks indicate significantly different from “0.1 NLTX + 1.0 nalbuphine”.