Effect of opioid receptor antagonists on hypothalamic–pituitary–adrenal activity in rhesus monkeys
Introduction
Endogenous opioids appear to modulate different hormones secreted by the pituitary. This modulation has been inferred from the finding that opioid antagonists increase plasma levels of pituitary hormones. For example, the opioid antagonist naloxone increased the release of adrenocorticotropic hormone (ACTH) and luteinizing hormone in humans (Morley, 1983, Grossman et al., 1986, Jackson et al., 1995). Although naloxone increases these hormones, the opioid receptor that mediates the release of these hormones is not clear.
A comparison of the naloxone and naltrexone (NTX) doses that are selective for different opioid receptors may help to clarify the receptor mechanism modulating the release of ACTH and cortisol. Naloxone and NTX are selective for mu-receptors only at low doses; as the doses are increased, kappa- and then delta-receptors are occupied. For example, in humans, low doses of naloxone 0.4–0.8 mg (0.006–0.01 mg/kg), given intravenously, primarily block respiratory depression caused by mu-agonists (Reisine and Pasternak, 1996). Similar naloxone doses increased luteinizing hormone without affecting cortisol (Grossman et al., 1986, Delitala et al., 1983, Del Pozo et al., 1980). In sheep, low doses of naloxone block the ability of mu-agonists to increase prolactin and decrease luteinizing hormone levels (Walsh and Clarke, 1996). In contrast, high naloxone doses (>8 mg or 0.1 mg/kg) are required to increase ACTH and cortisol plasma levels and diminish the ability of opioid agonists to decrease ACTH and cortisol plasma levels in humans (Allolio et al., 1987, Martin del Campo et al., 1994). These data suggest that prolactin and luteinizing hormone responses to opioid agonists are modulated by the mu-receptor, whereas ACTH and cortisol responses are modulated by the kappa-receptor, the delta-receptor, or some combination of the three opioid receptor types.
In addition to naloxone and NTX, receptor-selective antagonists can be used to determine the role of the different opioid receptor types on antinociceptive and behavioral effects. Clocinnamox (CCAM), a mu-selective irreversible antagonist, can be used to discriminate between opioid effects at the mu-receptor and those at the kappa- and delta-receptor. In rhesus monkeys, CCAM (0.1 mg/kg) antagonized the suppression of food-reinforced responding caused by mu-agonists but not delta- or kappa-agonists (Butelman et al., 1996). CCAM’s long duration of action is demonstrated by its ability to reduce the potency of and suppress the maximum antinociceptive effect of the mu-agonist alfentanil for 2–4 weeks (Zernig et al., 1994). Kappa-receptors can be selectively blocked by nor-binaltorphimine (nor-BNI). In an antinociception assay with rhesus monkeys, a 24-h pretreatment with 3.2 mg/kg nor-BNI reduced the potency of kappa-selective agonists, but not those of mu- or delta-agonists (Butelman et al., 1993). Similar to CCAM, nor-BNI altered the antinociceptive response to opioid agonists for several weeks. To selectively block the delta-receptor, naltrindole can be used. In rhesus monkeys, naltrindole (up to 3.2 mg/kg) blocked the decrease of food-reinforced responding caused by the delta-agonist BW373U86, but not by mu- or kappa-agonists (Negus et al., 1994). Thus, these antagonists have been shown to block the antinociceptive and behavioral effects of selective opioid agonists in rhesus monkeys.
The purpose of the current experiment was to test the ability of opioid receptor-selective antagonists to increase the ACTH and cortisol plasma levels in monkeys. If mu-, kappa-, or delta-receptors modulate ACTH and cortisol release, then increases in release by highly selective opioid receptor antagonists should allow an inference as to which opioid receptor is involved.
Section snippets
Subjects
Eight adult rhesus monkeys (Macaca mulatta), four females weighing 6.4–8.9 kg and four males weighing 8.1–13.3 kg, were used in these experiments. The monkeys received food and water ad libitum and were treated according to the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). These monkeys had never received opioid antagonists before these experiments and their adrenal glands and gonads were intact.
Apparatus
The monkeys were housed individually in stainless steel cages
Results
The time-course data for ACTH plasma levels (Fig. 1) show that the antagonists increased ACTH concentrations to varying degrees depending upon the antagonist. The baseline values just prior to each antagonist injection series were 10–50 pg/ml across all time points. Although 50 pg/ml is unusually high, this level was reached only prior to the nor-BNI injection series; all other baselines were below 30 pg/ml. ACTH concentrations increased above that after a vehicle injection for 0.1–1.0 mg/kg
Discussion
A major finding of the experiment was that NTX increases HPA axis activity in rhesus monkeys; the dose range of activity and type of effect is very similar to that shown in humans (Teoh et al., 1988, Farren et al., 1999, O’Malley et al., 2002), which raises the possibility that similar mechanisms may be involved. In this experiment, opioid modulation of ACTH and cortisol levels does not appear to be mediated solely by the mu-, kappa-, or delta-receptor. Opioid modulation of HPA activity may
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