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Endogenous and Exogenous Opioid Role in Stress Responsivity: Impact of Recent Molecular Genetics Findings

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From our initial work at the Rockefeller Hospital in 1964, we conceptualized that addictions were diseases of the brain with behavioral manifestations and were not simply traits of a weak or antisocial personality or due to criminal behavior (Dole et al. 1966; Kreek 1996c, 2000a, 2003). Further, we hypothesized that some aspects of normal human neuroendocrine function modulating stress response might be involved in the addictions (Kreek 1973, 1978, 1996c, 1996d, 2000b; Kreek and Koob 1998; Kreek et al. 2002). Therefore, we built into our very earliest studies, both prospective and one-point-in-time studies conducted from 1964 to 1973, ways to address specific questions relating to the integrity of the neuroendocrine system after long cycles of heroin addiction and during stabilization in long-term methadone maintenance treatment (e.g., Kreek 1978, 1992). Furthermore, by the mid-1970s our laboratory hypothesized specifically that an atypical responsivity to stress and stressors may contribute to the persistence of and relapse to addiction and possibly even to the initial acquisition of addiction (e.g., Kreek 1973, 1978). Further, we hypothesized that such atypical responsivity to stress and stressors may be due to preexisting environmental factors and intrinsic genetic factors as well as drug-induced changes, which were later well documented. By 1973, we were able to directly document that whereas during cycles of heroin addiction there is profound disruption of the stress-responsive HPA axis, during methadone maintenance treatment, normalization occurs (Kreek 1973, 1978, 1992; Kreek et al. 1983, 1984, 2002). As soon as the endogenous opioid system was identified and technology allowed us to directly measure levels of -endorphin, we were further able to determine that profound disruption occurs during cycles of heroin addiction and normalization of levels and circadian rhythm of this very important, primarily opioid receptor ligand, -endorphin, occurs, along with normal responsivity during methadone maintenance treatment (Kosten et al. 1987, 1992; Kreek et al. 1983, 1984). In contrast, we were able to show that there is a profound disruption of -endorphin levels, ACTH, and cortisol levels during chronic naltrexone maintenance treatment for opiate addiction; and activation of these HPA axis hormones also occurs after administration of opioid receptor antagonists in healthy, nonaddicted volunteers (Culpepper-Morgan and Kreek 1997; Culpepper-Morgan et al. 1992; Kosten et al. 1986a, 1986b; Schluger et al. 1998). We also learned that the normal feedback control of the HPA axis function is profoundly disrupted during the cycles of heroin addiction, with resultant lowered levels of ACTH, -endorphin, and cortisol—again, all of which normalize during methadone maintenance (e.g., Cushman and Kreek 1974a, 1974b; Kreek 1973, 1978). We were able to directly document that response to negative feedback control by glucocorticoids normalizes during methadone maintenance treatment.

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