Robert V House Peter T Thomas and Hemendra N Bhargava introduction

Drug abuse is a problem of increasing worldwide significance. In addition to the obvious socioeconomic problems associated with the use of so-called street drugs, the abuse of ethical pharmaceuticals may also result in serious untoward health effects depending upon a wide range of variables (Chiang and Goldfrank 1990). One possible medical complication of drug abuse is modulation of the immune system, or immunotoxicity (Pillai and Watson 1990). The immune system is a highly regulated organ system that presents a variety of potential targets for modulation by drugs. This modulation may take the form of immunosuppression, leading to an enhanced susceptibility to infection or neoplasia; conversely, it may take the form of immunostimulation, resulting in hypersensitivity (allergy) or autoimmunity (Luster and Rosenthal 1993). Closely associated with drug abuse in recent years has been the emergence of the acquired immunodeficiency syndrome (AIDS), a retroviral infection spread by sexual contact or hematogenously by the sharing of needles among intravenous (IV) drug abusers. One of the hallmarks of AIDS is a profound and irreversible suppression of immune competence, usually resulting in death of the host from opportunistic infections. Thus, the combination of drug abuse and human immunodeficiency virus (HIV) infection represents a formidable challenge to the immune system. Although the scientific literature is replete with studies describing drug-related immunosuppression, the sheer number of abused drugs precludes detailed examination using traditional methodology. Moreover, as new therapeutics are developed for the treatment of drug abuse, an efficient screening approach will be required to assess their immunomodulatory potential.

The studies described herein were performed under the aegis of National Institute on Drug Abuse (NIDA) contract 271-91-9201, entitled "Immunomodulatory Effects of Drugs of Abuse and Potential Medications." The purpose of the these studies was the evaluation of the potential for a number of drugs of abuse, opioid peptides, and established and experimental therapeutic agents to alter immune function associated with host defense. This was approached in a twofold manner. First, test materials were evaluated in vitro using murine splenic lymphocytes from B6C3F1 (C57BL/6 X C3H) hybrid mice. This hybrid strain was chosen because of the large database that exists of drug and chemical effects on immunity. The panel of immune function assays was carefully chosen to represent relevant host defense mechanisms and be adaptable to drug screening. Second, standard in vivo pharmacological models of tolerance/abstinence were validated in this strain and then used for in vitro multidrug exposure studies as above.

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