Role of agonist efficacy in exposure-induced enhancement of mu opioid reward in rats

Abstract

The abuse potential of opioid analgesics in humans appears to increase rapidly during initial regimens of opioid exposure. Previous work using intracranial self-stimulation (ICSS), a preclinical procedure useful for studying rewarding drug effects in drug-naïve animals, has similarly shown that rewarding effects of mu opioid receptor (MOR) agonists increase rapidly in rats during initial regimens of opioid administration. The goal of the present study was to evaluate the role of MOR agonist efficacy as a determinant in eliciting this trajectory of increased rewarding effects during initial opioid exposure in opioid-naïve rats. Separate groups of adult, male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure and received repeated daily treatment with vehicle or one of five MOR agonists that ranged from low to high efficacy (NAQ, nalbuphine, buprenorphine, fentanyl, methadone). Two additional groups were used to evaluate effects of repeated treatment with non-opioids (the cannabinoid CP55940 or the monoamine releaser amphetamine). Morphine was tested after each repeated treatment. In opioid-naïve rats tested before repeated dosing, MOR agonists produced primarily dose- and efficacy-dependent decreases in ICSS. Following repeated treatment, all MOR agonists except NAQ produced tolerance to opioid-induced rate-decreasing effects and enhanced expression of ICSS facilitation (indicative of opioid reward) by both the repeatedly administered drug and morphine. Repeated treatment with CP55940 and amphetamine produced different effects. Collectively, these results provide evidence to suggest that enhanced expression of opioid reward after initial regimens of opioid exposure has a low requirement for MOR agonist efficacy and is pharmacologically selective.

Keywords: Efficacy; Intracranial self-stimulation; Morphine; Mu opioid receptor; Repeated dosing.

Figure 1.

Effects of saline (left panels) and NAQ (right panels) on ICSS frequency-rate curves in rats before (top panels) and after (bottom panels) seven-day treatment with saline or 10 mg/kg/day NAQ, respectively. Abscissae: electrical brain stimulation frequency in Hertz (Hz, log scale). Ordinates: ICSS reinforcement rate expressed as a percentage of the maximum control rate (% MCR). Filled symbols indicate statistical significance (p<0.05) as compared to saline. All points show mean ± S.E.M. for n=6 rats.

Figure 2.

Effects of nalbuphine (left panels) and buprenorphine (right panels) on ICSS frequency-rate curves in rats before (top panels) and after (bottom panels) seven-day treatment with 10 mg/kg/day nalbuphine or 0.032 mg/kg/day buprenorphine, respectively. Abscissae: electrical brain stimulation frequency in Hertz (Hz, log scale). Ordinates: ICSS reinforcement rate expressed as a percentage of the maximum control rate (% MCR). Filled symbols indicate statistical significance (p<0.05) as compared to saline. All points show mean ± S.E.M. for n=6 rats.

Figure 3.

Effects of fentanyl (left panels) and methadone (right panels) on ICSS frequency-rate curves in rats before (top panels) and after (bottom panels) seven-day treatment with 0.032 mg/kg/day fentanyl or 1.0 mg/kg/day methadone, respectively. Abscissae: electrical brain stimulation frequency in Hertz (Hz, log scale). Ordinates: ICSS reinforcement rate expressed as a percentage of the maximum control rate (% MCR). Filled symbols indicate statistical significance (p<0.05) as compared to saline. All points show mean ± S.E.M. for n=6 rats.

Figure 4.

Effects of CP 55940 (left panels) and amphetamine (right panels) on ICSS frequency-rate curves in rats before (top panels) and after (bottom panels) seven-day treatment with 0.32 mg/kg/day CP 55940 or 0.32 mg/kg/day amphetamine, respectively. Abscissae: electrical brain stimulation frequency in Hertz (Hz, log scale). Ordinates: ICSS reinforcement rate expressed as a percentage of the maximum control rate (% MCR). Filled symbols indicate statistical significance (p<0.05) as compared to saline. All points show mean ± S.E.M. for n=6 rats.

Figure 5.

Effects of morphine on ICSS frequency-rate curves in rats following the second dose-effect determination for a given drug after seven-day treatments as indicated in Table 1. Abscissae: electrical brain stimulation frequency in Hertz (Hz, log scale). Ordinates: ICSS reinforcement rate expressed as a percentage of the maximum control rate (% MCR). Filled symbols indicate statistical significance (p<0.05) as compared to saline. All points show mean ± S.E.M. for n=6 rats.

Figure 6.

Relationship between MOR agonist efficacy and effects on ICSS. MOR agonists tested in this study range in efficacy from methadone at the high end to NAQ at the low end of the efficacy continuum. A-Efficacy range to produce ICSS depression in opioid-naïve rats. B-Efficacy range to trigger adaptations that promote opioid-induced ICSS facilitation after repeated treatment. C-Efficacy range to facilitate ICSS in rats already sensitized to opioid-induced ICSS facilitation.