Effects of heroin and its metabolites on schedule-controlled responding and thermal nociception in rhesus monkeys: sensitivity to antagonism by quadazocine, naltrindole and ß-funaltrexamine

Abstract

Recent studies have reported differences in the receptor mechanisms and intrinsic efficacies of heroin and its metabolites 6-acetylmorphine and morphine in rodents. The present study examined the generality of these findings to rhesus monkeys using two behavioral procedures. In an assay of schedule-controlled behavior, response rates were recorded under a fixed-ratio 30 schedule of food presentation. In an assay of thermal nociception, tail-withdrawal latencies were measured from warm water (42–58 °C). Heroin, 6-acetylmorphine and morphine produced dose-dependent rate-decreasing and antinociceptive effects. Antagonism studies were conducted with the competitive mu-selective antagonist quadazocine, the competitive delta-selective antagonist naltrindole, and the irreversible mu-selective antagonist ß-funaltrexamine (ß-FNA). Quadazocine dose-dependently antagonized the effects of all three opioids. Quadazocine pA2 values were similar across drugs and assays (7.4–7.8) and similar to quadazocine pA2 values for antagonism of other mu agonists. In contrast, naltrindole did not alter the effects of any of the opioids. ß-FNA antagonized the rate-decreasing and antinociceptive effects of heroin and morphine. Dose-effect data for heroin- and morphine-induced antinociception alone and after ß-FNA treatment were used to estimate in vivo apparent efficacy values (tau). Tau values (95% confidence limits) were 8.1 (6.9–9.6) for heroin and 2.6 (2.5–2.9) for morphine, but this difference is relatively small. These results suggest that the rate-decreasing and antinociceptive effects of heroin, 6-acetylmorphine and morphine are mediated by pharmacologically similar populations of mu opioid receptors in rhesus monkeys. The in vivo apparent efficacy of heroin at mu receptors was similar to or only slightly greater than that of morphine.

Introduction

Heroin (3,6-diacetylmorphine), a derivative of the prototypical mu opioid agonist morphine, is one of the most widely abused illicit drugs in the US and is also used clinically as an analgesic in some other countries (Kaiko et al., 1981, Sawynok, 1986, Gutstein and Akil, 2001). Heroin produces behavioral and physiological effects similar to those produced by morphine (see Gutstein and Akil, 2001, for review), although systemically-administered heroin is usually effective at lower doses (i.e. is more potent) and has a more rapid rate of onset and shorter duration of action than morphine (e.g. Kaiko et al., 1981, Umans and Inturissi, 1981, Hartvig et al., 1984, Negus et al., 1998). Heroin's relatively high potency and rapid onset of action have been attributed to its high lipophilicity and its consequent ability to cross the blood-brain barrier more rapidly than morphine (Oldendorf et al., 1972, Hartvig et al., 1984). Heroin itself displays relatively low affinity for opioid receptors, but it is rapidly deacetylated both peripherally and in the central nervous system to 6-acetylmorphine and morphine, and these metabolites have relatively high affinity for mu opioid receptors (Inturissi et al., 1983, Bertalmio et al., 1992). On the basis of these findings, it has been suggested that heroin may function as a highly lipophilic prodrug for the active metabolites 6-acetylmorphine and morphine (Way et al., 1960, Inturissi et al., 1983, Inturrisi et al., 1984).

In addition to these pharmacokinetic differences between heroin, 6-acetylmorphine and morphine, more recent studies have identified potential differences in the pharmacodynamics of these compounds in rodents. First, a growing literature suggests that heroin and 6-acetylmorphine may act on different receptor populations than morphine to produce antinociception in rodents, and these pharmacological differences may be genotype dependent (Rady et al., 1991, Rady et al., 1994, Rady et al., 1999). In Swiss Webster mice, for example, the mu-selective antagonist ß-funaltrexamine (ß-FNA) blocked the antinociceptive effects of morphine but not of heroin or 6-acetylmorphine, whereas the delta-selective antagonist naltrindole blocked the effects of heroin and 6-acetylmorphine but not of morphine (Rady et al., 1991, Rady et al., 1994). These results were interpreted to suggest that mu receptors mediated morphine antinociception and delta receptors mediated heroin and 6-acetylmorphine antinociception in Swiss Webster mice. Second, another recent study found that heroin, 6-acetylmorphine and morphine had different degrees of intrinsic efficacy at mu opioid receptors (Selley et al., 2001). Specifically, both heroin and 6-acetylmorphine produced slightly greater maximal effects than morphine in an in vitro assay of G-protein activation using membranes from both rat thalamus and C6 glioma cells expressing human mu opioid receptors. Morphine produced a partial antagonism of 6-acetylmorphine, which provided further evidence to suggest that 6-acetylmorphine and morphine were competing for the same binding sites, but that morphine had lower efficacy at those sites (Selley et al., 2001).

These differences in the pharmacodynamics of heroin, 6-acetylmorphine and morphine could conceivably contribute to quantitative or qualitative differences in their effects in vivo. For example, heroin produced a greater maximal effect than morphine in a model of neuropathic pain in rats (Martin et al., 1998). The mechanisms underlying this difference were not explored, but it was suggested that heroin might have acted at both mu and delta receptors, whereas morphine acted primarily at mu receptors (Martin et al., 1998). It is also possible that the higher maximal effect of heroin reflected the higher intrinsic efficacy of heroin at mu receptors described by Selley and colleagues (Selley et al., 2001).

Given the clinical relevance of heroin and morphine as drugs of abuse and analgesics, these provocative findings in rodents suggest that there may be clinically relevant differences in the pharmacodynamics of heroin and morphine in humans. However, there are species differences in opioid populations (Mansour et al., 1988), and the degree to which the pharmacodynamics of heroin, 6-acetylmorphine and morphine can be distinguished in humans or non-human primates has not been extensively studied. For example, it is well-established that these opioids produce similar profiles of behavioral and physiological effects in monkeys (e.g. Harrigan and Downs, 1978, Young et al., 1981, Moerschbaecher et al., 1985, Bertalmio et al., 1992, Negus et al., 1998, Kishioka et al., 2000), but few studies have directly compared the effects of receptor-selective antagonists on the behavioral effects of heroin, 6-acetylmorphine and morphine in non-human primates (cf. Dykstra et al., 1987, Vivian et al., 1998, Rowlett et al., 2000, Bowen et al., 2002). In particular, the potential role of delta receptors in mediating the antinociceptive effects of heroin in monkeys has not been examined, and the relative efficacies of heroin and its metabolites have not been directly compared. Accordingly, the present study used selective antagonists to further compare the pharmacological mechanisms that mediate the behavioral effects of heroin, 6-acetylmorphine and morphine in rhesus monkeys.