A telemetric examination of cardiovascular function during the development of, and recovery from, opiate dependence in rats

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Abstract

Rats were subject to daily injections of morphine or saline and were then allowed to spontaneously withdraw from morphine for 4 days. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded continuously, via radiotelemetry, during the development of, and recovery from, opiate dependence. Injections of morphine produced pronounced and prolonged increases in MAP and HR which increased as morphine dose increased. There were also significant increases in MAP during the 19–23 h period after each morphine injection indicating the presence of withdrawal. Spontaneous withdrawal from morphine was associated with a pronounced (20% increase from baseline) and prolonged (72 h) increase in MAP. MAP returned to baseline levels 72–96 h after last morphine exposure. These results show that intermittent injections of morphine, and spontaneous withdrawal from these injections, are associated with profound alterations in cardiovascular function and confirm the usefulness of radiotelemetry for studying opiate dependence.

Introduction

Prolonged administrations of opiates produce the development of tolerance and withdrawal. The withdrawal syndrome from opiates in humans includes cognitive (e.g., drug craving), affective (e.g., anxiety), and behavioural (e.g., twitches) signs [16]. Changes in autonomic function are also key indicators of opiate withdrawal. These can include cardiovascular alterations (e.g., heart rate and blood pressure), changes in respiration, and changes in thermoregulation [6].

Despite the important place of autonomic changes in the opiate withdrawal syndrome, there have been few investigations into autonomic function during dependence and withdrawal from opiates using animal models [1], [2], [4], [17]. Chan et al. [4] implanted rats with radiotelemetry probes to continuously monitor blood pressure and heart rate in the freely moving animal. They also implanted rats with minipumps to continuously deliver morphine. They showed that delivery of morphine produced small increases in blood pressure which displayed tolerance across prolonged exposures. Precipitation of withdrawal via removal of the minipumps also resulted in a small but significant increase in blood pressure as well as heart rate. Similar increases in blood pressure have been reported in rats following antagonist-precipitated withdrawal [1], [2], [17] and in humans during spontaneous [10], [11], [14] and antagonist-precipitated [6] withdrawal. The relative lack of research into the autonomic correlates of opiate dependence and withdrawal in animals is surprising because investigations into the patterns of neural activation associated with opiate withdrawal consistently identify pronounced activation of central autonomic circuits. For example, it is well documented that withdrawal from opiates induces immediate early gene expression in structures such as the nucleus of the solitary tract, rostral and caudal ventrolateral medulla, A5 catecholaminergic group, parabrachial nuclei, locus coeruleus, paraventricular nucleus of the hypothalamus, amygdala and thoracic spinal cord [8], [9], [13], [15], [18], [19], [22], [23], all of which play critical roles in regulating autonomic function.

Although past studies have identified robust changes in autonomic function during opiate withdrawal, they have also left unanswered a number of important questions. First, the time course of the development of opiate-induced changes in autonomic function is unclear because none of these studies have recorded continuously across a prolonged period of opiate injections. Second, the time course of recovery from opiate-induced alterations is unclear because only one study has recorded autonomic changes continuously across a prolonged period of withdrawal from opiates [4]. Typically intervals of 24 h or less have been studied [1], [2], [17]. Thirdly, the effects of intermittent exposures to opiates, and withdrawal from these exposures, on autonomic function are unclear because prior studies have typically employed constant infusions of opiates [1], [4]. This is of considerable significance because administration regimes employing constant infusions of opiates bear little resemblance to patterns of human opiate use. The typical pattern of human opiate use is frequent, often daily, episodes of intoxication and withdrawal rather than continuous opiate exposure followed by a single episode of opiate withdrawal [7]. Finally, the effects of spontaneous withdrawal from opiates on autonomic function are unclear because these experiments have typically studied antagonist-precipitated withdrawal from opiates [1], [2], [17]. Indeed, only two prior studies have characterised autonomic parameters during spontaneous withdrawal from opiates in rats [4], [17] but the interpretation of these results is limited by the fact they involved continuous exposures to morphine to induce dependence.

The aim of the experiment reported here was to study autonomic function during intermittent exposures to opiates and during spontaneous withdrawal from these exposures. Rats, implanted with telemetric probes in the descending aorta permitting continuous recording of mean arterial blood pressure (MAP) and heart rate (HR), were injected daily for 13 days with either morphine or saline. The doses of morphine increased from 2.5 to 20 mg/kg. The rats then remained undisturbed in their home cages for a further four days to permit spontaneous opiate withdrawal.

Section snippets

Subjects

Subjects were eight male Wistar rats weighing between 300 and 325 g at the start of the experiment. They were obtained from a commercial supplier (Gore Hill Research Laboratories, Sydney, Australia). Prior to the start of the experiment, rats were housed in groups of 8 in plastic cages (67 × 40 × 22 cm [L × W × H]) maintained under natural lighting. They were handled for 5 days prior to the start of the experiment. At the commencement of the experiment rats were singly housed in plastic cages (40 × 26 × 

Results

There were no differences between groups in either HR (mean HR group Saline = 370 bpm; SEM = 6; group Morphine = 370 bpm; SEM = 5) (p > 0.05) or MAP (MAP group Saline = 100 mm Hg; SEM = 3; group Morphine 107 mm Hg; SEM = 3) (p > 0.05) averaged across the three days of baseline recordings.

Fig. 1 shows the mean and standard error of the mean (SEM) HR (top panel) and MAP (bottom panel), expressed as percentage change from baseline, across the 13 days of saline or morphine injections. Each data point represents the

Discussion

This experiment studied cardiovascular function during the development of, and recovery from, opiate dependence. The results can be summarised succinctly. Injections of morphine produced pronounced (25–40% above baseline) and prolonged increases in MAP and HR. These alterations were more pronounced as the duration and dose of opiate exposure increased. MAP also increased significantly during the 19–23 h period following each injection. These increases in MAP were also more pronounced as the

Acknowledgements

This research was supported by grant 209577 from the National Health and Medical Research Council to GPM. The authors thank Dr. Samuel Leman and Dr. Gabrielle Weidemann for their assistance with this experiment.

References (24)

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