Neuropharmacology and Analgesia
Hydromorphone efficacy and treatment protocol impact on tolerance and μ-opioid receptor regulation

https://doi.org/10.1016/j.ejphar.2008.08.025Get rights and content

Abstract

This study examined the antinociceptive (analgesic) efficacy of hydromorphone and hydromorphone-induced tolerance and regulation of μ-opioid receptor density. Initially s.c. hydromorphone's time of peak analgesic (tail-flick) effect (45 min) and ED50 using standard and cumulative dosing protocols (0.22 mg/kg, 0.37 mg/kg, respectively) were determined. The apparent analgesic efficacy (τ) of hydromorphone was then estimated using the operational model of agonism and the irreversible μ-opioid receptor antagonist clocinnamox. Mice were injected with clocinnamox (0.32–25.6 mg/kg, i.p.) and 24 h later, the analgesic potency of hydromorphone was determined. The τ value for hydromorphone was 35, which suggested that hydromorphone is a lower analgesic efficacy opioid agonist. To examine hydromorphone-induced tolerance, mice were continuously infused s.c. with hydromorphone (2.1–31.5 mg/kg/day) for 7 days and then morphine cumulative dose response studies were performed. Other groups of mice were injected with hydromorphone (2.2–22 mg/kg/day) once, or intermittently every 24 h for 7 days. Twenty-four hours after the last injection, mice were tested using morphine cumulative dosing studies. There was more tolerance with infusion treatments compared to intermittent treatment. When compared to higher analgesic efficacy opioids, hydromorphone infusions induced substantially more tolerance. Finally, the effect of chronic infusion (31.5 mg/kg/day) and 7 day intermittent (22 mg/kg/day) hydromorphone treatment on spinal cord μ-opioid receptor density was determined. Hydromorphone did not produce any change in μ-opioid receptor density following either treatment. These results support suggestions that analgesic efficacy is correlated with tolerance magnitude and regulation of μ-opioid receptors when opioid agonists are continuously administered. Taken together, these studies indicate that analgesic efficacy and treatment protocol are important in determining tolerance and regulation of μ-opioid receptors.

Introduction

The mechanisms that mediate tolerance to opioid agonists have been extensively studied. The results of many studies suggest that agonist efficacy may play an important role in the magnitude of tolerance (Duttaroy and Yoburn, 1995, Paronis and Holtzman, 1992, Pawar et al., 2007). For example, at equi-effective doses, a higher efficacy opioid agonist (e.g., etorphine) produces less tolerance than lower efficacy agonists (e.g., morphine, oxycodone) after chronic infusion treatment (Duttaroy and Yoburn, 1995, Stafford et al., 2001, Pawar et al., 2007). The regulation of μ-opioid receptor density also appears to be correlated with agonist efficacy. Higher efficacy agonists induce μ-opioid receptor internalization and downregulation in in vitro and in vivo studies (e.g., Patel et al., 2002, Whistler et al., 1999, Yoburn et al., 2004, Zaki et al., 2000); whereas, lower efficacy agonists are typically ineffective (e.g., Keith et al., 1996, Stafford et al., 2001; however see Haberstock-Debic et al., 2005). Nevertheless, while μ-opioid receptor downregulation is usually not observed in vivo with lower efficacy opioid agonists (Patel et al., 2002, Yoburn et al., 2004), downregulation contributes to the magnitude of tolerance (e.g., Stafford et al., 2001). Taken together, opioid agonist efficacy appears to play a role in both tolerance and opioid receptor regulation (Duttaroy and Yoburn, 1995, Paronis and Holtzman, 1992, Stevens and Yaksh, 1989, Walker and Young, 2001, Pawar et al., 2007).

Efficacy can be defined as the property of a drug that causes a receptor to change its behavior towards the host cell (Kenakin, 2002). Recent formulations of efficacy suggest that ligands acting at a given receptor can have multiple efficacies (e.g., Kenakin, 2007, Galandrin and Bouvier, 2006). In earlier studies examining the role of efficacy in tolerance and μ-opioid receptor regulation, opioid agonist efficacy had been considered as a parameter that characterizes the drug itself, rather than the drug and a particular effect (e.g., Stafford et al., 2001). Using the operational model of agonism in a previous study, morphine and oxycodone were found to have relatively low τ values for analgesia (i.e., antinociception), whereas etorphine was identified as a higher analgesic efficacy opioid (Pawar et al., 2007). This quantitative estimate of analgesic efficacy supported previous suggestions that efficacy can be used to predict μ-opioid receptor regulation and the magnitude of tolerance (e.g., Duttaroy and Yoburn, 1995, Paronis and Holtzman, 1992, Stafford et al., 2001).

In the present study, we used the irreversible μ-opioid receptor antagonist clocinnamox and the operational model of agonism (Black and Leff, 1983, Black et al., 1985, Leff et al., 1990) to estimate the analgesic efficacy of the opioid agonist hydromorphone. Hydromorphone is an opioid analgesic that is commonly used to manage pain and is abused (e.g., Cicero et al., 2005, Kumar and Lin, 2007, Murray and Hagen, 2005); and studying efficacy may enhance clinical effectiveness and lead to strategies to minimize tolerance, abuse and dependence. Based on the estimated low analgesic efficacy of this drug, we predicted that hydromorphone would produce substantial tolerance, but would not regulate the density of μ-opioid receptors. In addition, we have reported that the magnitude of tolerance was similar among several opioid analgesics when the drugs were administered intermittently rather than continuously infused (Duttaroy and Yoburn, 1995). In other words, opioid analgesic efficacy did not appear to be a major factor in predicting the magnitude of tolerance using an intermittent treatment protocol. Therefore, in this study we also examined tolerance and μ-opioid receptor regulation following intermittent as well as acute treatment with hydromorphone.

Section snippets

Subjects

Male Swiss Webster mice, weighing 22–30 g, obtained from Taconic Farms (Germantown, NY) were used throughout. Animals were housed 10 per cage with food and water ad libitum. Mice were used only once. All protocols and procedures were approved by the St. John's University Institutional Animal Care and Use Committee.

Drugs and chemicals

Hydromorphone HCl was obtained from Spectrum Chemicals Inc. (Gardena, CA). Morphine sulfate and placebo pellets were obtained from the Research Triangle Institute (Research Triangle

Results

The time of peak analgesic effect for hydromorphone was estimated as 45 min (Fig. 1). Throughout the rest of this study, all testing was conducted at 45 min following hydromorphone administration. ED50 values for hydromorphone were determined using standard and cumulative dose response protocols (Fig. 2). The mean ED50 (95% CL) for the standard dosing protocol was estimated as 0.22 mg/kg (0.20–0.24 mg/kg), while that for the cumulative dosing protocol was estimated as 0.37 mg/kg

Discussion

It has been proposed that the magnitude of tolerance produced by opioid agonists after chronic infusion treatment is related to the analgesic efficacy of the agonist (e.g., Duttaroy and Yoburn, 1995, Pawar et al., 2007). Continuous infusions of lower analgesic efficacy opioid agonists (e.g., morphine, oxycodone) produce more tolerance compared to higher efficacy opioid agonists (e.g., etorphine) when these drugs are administered at equi-analgesic doses (Duttaroy and Yoburn, 1995, Paronis and

Acknowledgements

The authors are grateful to Dr. M.T. Turnock who provided continuous encouragement during this study. Quiyu Zhang provided technical support. Priyanka Madia reviewed the manuscript and provided helpful comments. Supported in part by a grant from the National Institute on Drug Abuse (DA 19959, to BCY).

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