A non-invasive gating device for continuous drug delivery that allows control over the timing and duration of spontaneous opiate withdrawal

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Abstract

Opiate dependence in laboratory animals is commonly induced by two methods: (1) subcutaneous (s.c.) insertion of morphine pellets, and (2) daily injections of increasing doses of opiates. While both of these methods reliably induce opiate dependence, they do not allow one to discontinue, and subsequently reestablish steady state opiate plasma levels with minimal invasive procedures. We developed an “ON–OFF” gating device for repeatedly and non-invasively turning ON or OFF opiate delivery by standard osmotic minipumps. The reliability of this “device” was tested utilizing naloxone (NAL)-precipitated somatic signs of withdrawal, and body mass index (BMI) as measures of withdrawal. Rats were implanted with osmotic minipumps equipped with the gating device, containing heroin (2.66 mg per day). Three days after surgery, somatic signs of withdrawal were precipitated every 48 h by NAL (0.3 mg/kg), with minipumps gated ON or OFF. For BMI, spontaneous withdrawal was repeatedly (three times) induced by turning OFF and ON the gating devices every 48 h. Body weights were measured every 4 h from 06:00 to 22:00 h daily. Results show that NAL precipitated intense somatic signs of withdrawal when gating devices were ON. This effect was almost abolished when gating devices were OFF. BMI rapidly decreased after the gating devices were turned OFF with maximum weight loss occuring 12 h post-OFF position, and gradually returning to baseline values after gating devices were turned back ON. These results demonstrate the validity of the “ON–OFF” gating device for non-invasively and repeatedly inducing physical dependence to opiates over a prolonged time.

Introduction

Over the past century, methods of chronic opiate administration in laboratory animals have greatly contributed to our current knowledge of the neurobiology of unconditioned and conditioned opiate dependence (Bechara et al., 1998, Koob et al., 1992, Williams et al., 2001). Despite some earlier attempts, however, comparatively little research has focused on the role of opiate withdrawal in driving the increased need to take drugs associated with the transition to addiction (Goldberg et al., 1969, Nichols et al., 1956, Wikler and Pescor, 1967). This situation is probably due—at least partly—to the lack of appropriate methods that allow the experimenter to mimic in the laboratory the succession of withdrawal-abstinence-relapse that characterizes the natural history of opiate addiction. More specifically, no simple, non-commercial device currently exists that allows one to discontinue, and subsequently reestablish in a repeated manner, steady state opiate blood levels with minimal invasive procedures and with minimal time and effort.

Opiate withdrawal has commonly been precipitated by experimenter-administered selective opiate antagonists, such as naloxone and naltrexone, in previously opiate-dependent animals (Gellert and Holtzman, 1978, Goldberg et al., 1971, Gold et al., 1994). While antagonist-induced drug withdrawal in dependent animals was very useful in the mapping of the neural substrates of opiate dependence (Koob et al., 1989, Maldonado et al., 1992a, Stinus et al., 1990, Walker et al., 2000), it may not adequately reproduce the functional state associated with spontaneous withdrawal following the normal termination of opiate action, which more closely resembles the experience of a human opiate user (Del Arco et al., 2002, Walker et al., 2000). Pharmacologically precipitated withdrawal induces a very rapid and highly intense change in the organism state that tends in most experimental situations to non-specifically ongoing behavior, including opiate self-administration itself (Gellert and Sparber, 1977, Goldberg et al., 1971, Young, 1986, Walker et al., 2000). This apparently paradoxical phenomenon may have contributed to the belief that opiate dependence and withdrawal do not play the critical role that was once attributed to them in the transition to and perpetuation of opiate addiction (e.g. Stewart and Wise, 1992). Finally, another disadvantage of antagonist-precipitated opiate withdrawal is that repeated administration of opiate antagonists may induce long-lasting changes in opiate receptor function that may complicate the interpretation of the data (Diaz et al., 2002, Lesscher et al., 2003, Unterwald et al., 1995).

The present study is an attempt to develop and validate a simple, non-commercial gating device for repeatedly and non-invasively turning ON or OFF opiate delivery by standard subcutaneous osmotic minipumps. In the present investigation, heroin—rather than morphine—was used to induce dependence because heroin is often the opiate drug used and eventually abused by humans (Hartnoll, 1994, Hunt et al., 1984). After induction of heroin dependence, the efficacy and reliability of the gating device was tested in two separate experiments. In the first experiment, naloxone (NAL)-precipitated somatic signs of withdrawal were utilized to rapidly and easily validate whether turning ON and OFF the gating device was effectively accompanied by the initiation and cessation of heroin delivery, respectively. In the second experiment, body mass index (BMI) was measured at short and regular intervals after turning OFF the subcutaneous (s.c.) delivery of heroin to characterize the onset and time-course of spontaneous withdrawal. The present data establish our gating device as a valid tool for repeatedly and non-invasively discontinuing s.c. drug administration and for triggering spontaneous withdrawal in dependent animals. This device may prove very useful in future studies aimed at testing the contribution of spontaneous opiate withdrawal in driving the increased motivation to take drugs that marks the transition to addiction.

Section snippets

Animals

Wistar-derived male rats (300–380 g) were housed in groups of three and maintained in a temperature-controlled environment on a 12 h:12 h light cycle (lights on from 06:00 h–18:00 h), upon arrival to the laboratory. Animals were given free access to food and water during a 1-week habituation period to the laboratory. Animals used in the research studies were handled, housed, and sacrificed in accordance with the current NIH guidelines regarding the use and care of laboratory animals, and all

Experiment 1

Results from this experiment revealed that, overall, when the gating device is in the ON position, a single dose of 0.3 mg/kg naloxone produced a significant difference in the total number of counted and graded naloxone-precipitated somatic signs of withdrawal, compared to those values obtained when gating was in the OFF position (F[3,24]=216, P<0.01). As evident from the one-way repeated measures ANOVA, with factor gating position, rats receiving 2.66 mg per day of heroin produced a robust

Discussion

The device reported in this study is a non-commercial, implantable gating device capable of controlling the timing and duration of delivery of pharmacological agents when connected to standard osmotic minipumps. These characteristics make it a unique device for experimental studies that cannot be achieved with current commercially available infusion pumps. The present study demonstrated the efficacy of this device for controlling the timing and duration of subcutaneous administration of heroin,

Acknowledgements

This research was supported by National Institutes of Health grant DA04043 from the National Institute on Drug Abuse. Serge Ahmed and Luis Stinus were supported by CNRS (France). Both M. Azar and S. Ahmed contributed equally to this work. Additionally, the authors would like to thank Mike Arends for his assistance with manuscript preparation. This is publication number 15921-NP from The Scripps Research Institute.

References (23)

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