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

Stress Responsivity and the Addictions…

From Our initial work al 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 (Doleet 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, I996d. 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 alter 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 lo 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 HFA axis, during methadone maintenance treatment, normalization occurs (Kreck 1973, 1978, 1992; Kreek ctal. 1983,1984,2002). As soon as the endogenous opioid system was identitled and technology allowed us lo directly measure levels of P-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 u opioid receptor lig.ind, ft-cndorplnn, occurs, along with normal responsivity during methadone maintenance treatment (Kostcn ct al. 1987, 1992; Kreck ct al. 1983,1984). In contrast, we were able to show that there is a profound disruption of |l-cndorphin levels, ACTH.and Cortisol levels during chronic naltrexone maintenance treatment for opiate addiction; and activation of these 11 PA axis hormones also occurs after administration of u. opioid receptor antagonists in healthy, nonaddictcd volunteers (Culpepper-Morgan and Kreek 1997; Culpepper-Morgan ct al. 1992; Kosten ct al. 1986a, 1986b; Schlugcrct 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, ß-endorphin, and with resultant lowered levels of ACTH, [J-cndorphin, 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 lo negative feedback control by glucocorticoids normalize*, during methadone maintenance treatment.

To further assess the disruption of the normal modulation by negative feedback of the glucocorticoid steroid Cortisol by the chronic use of the short-acting opiate heroin, we conducted studies using melyrapone. a compound that temporarily blocks I Ip-hydroxylalion, the las! step of Cortisol synthesis in the adrenal cortex. In these studies we found that while there is prolound disruption ol melyrapone response during cycles of heroin addiction, normalization occurs during methadone maintenance treatment iKreek 1973, 1978; Kreek et al. 1984; Schluger el al. 2003). We also found thai when melyrapone was given to well-stabilized, non-drug-abusing patients who have been receiving long-term methadone maintenance treatment, signs and symptoms of opiate withdrawal would ensue transiently, probably because of the internal physiological cues provided by surges ofcorticotro-pin-releasing factor (CRI-) and. in turn, levels of ACI’H; activation of both of these peptide hormones occurs in the opiate withdrawal cascade and thus signals for the former heroin addict the onset of narcotic abstinence syndrome (Kennedy et al. 1990). We were also able to show that very small amounts of the opioid antagonist naloxone, which resulted in modest elevation of ACTH and Cortisol levels, actually preceded the signs and symptoms of opiate withdrawal or occurred with no subsequent signs and symptoms (Culpepper-Morgan and Kreek 1997; Culpepper-Morgan et al. 1992; Schluger ct al. 1998). In many other studies, we were able to clearly define that administration of a specific opiate antagonist—such as naloxone, naltrexone, or nalmefcnc—leads to a dose-dependent increase in both ACTH and Cortisol levels in healthy volunteers as well as in opiate-dependent individuals (e.g., Kostcn ct al. 1986a, 1986b; Schluger ct al. 1998).

In our earlier animal studies, wc showed that intermittent morphine administration in the rat (as had been reported by others earlier) acutely and subacutely activates HPA axis hormones (X.M. Wanget al. 1999). However, when a different type of stressor (modest water restriction) was superimposed, administration of morphine actually attenuated the opiate-induced activation (Zhou ct al. 1999). Other studies, including our own, have shown that after chronic administration of a short-acting opiate such as morphine or heroin to rodents, depression of the HPA axis hormone is observed, just as it is observed from the first expo-sureofan opiate in humans. Furthermore, inn rodent model where methadone was administered by pump to achieve a long-acting profile like that naturally occurring in humans (in the rat the half-life of methadone is only 90 minutes and in the mouse only 60 minutes, whereas in humans, the half-life of the raccmic mixture is 1\ hours and that of the active ciianliomer is 28 hours), w-c found that steady-stale methadone docs not change mRNA levels (i.e., gene expression) of CR1* or pro-opioinelaiiocorlin, nor does il change I ll’A axis hormone levels (Zhnuct al. 1996b). Numerous studies have shown that following opiate withdrawal in rodents, as well as in humans, there is profound activation of each of the components of the UFA axis.

There have now been many studies reaffirming that during cycles of heroin addiction there is a lowering, and therefore a disruption, of 11 PA axis hormones; yet, whenever self-administration of a short-acting opiate, such as heroin, docs not promptly follow, there is onset of signs and symptom* of opiate withdrawal, preceded (as staled above) by activation of the HPA axis, with elevation of levels of ACTH and corlisol.lt has been established now that the elevation of HPA axis hormones precedes, and thus helps drive, the noxious signs and symptoms of withdrawal, leading lo a dysphoric state coupled with a craving to self-administer an opiate (e.g., Culpepper-Morgan and Kreek 1997;Oilpepper-Morgan ct al. 1992). Alcohol and cocaine both activate H PA axis hormones, but attenuation of this response occurs during chronic administration in rodent models and in humans (Zhou et al. 1996a), There is increasing evidence that alcoholic individuals, and possibly also individuals addicted to cocaine, like and seek modcsl activation of the HPA axis, which wc have shown is facilitated by naltrexone treatment (O’Malley et al. 2002). Heroin addicts, however, do not like such activation because it is reminiscent ot (a physiological cue for) opiate withdrawal signs and symptoms (Kennedy el al. 1990).

Just as it has been shown in rodent models and in humans that both cocaine and alcohol activate the HPA axis, it has been shown in healthy volunteers that a specific opiate antagonist, such as naloxone, nalmefcnc, or naltrexone, activates this axis (Schluger ct al. 1998). We hypothesized that during naltrexone treatment, there would be the expected modest early (•1-6 hours) activation of HPA axis hormones after oral naltrexone and a subsequent return of those levels lo baseline, but that during a time when naltrexone was still active (2-1 hours or longer), there would be a relative disinhibition of the normal u. opioid receptor inhibition of the HPA axis. A modest amount of alcohol would then be expected to cause significant activation of this axis. In contrast, we found lhai a significantly greater amount of alcohol did not cause activation of the HPA axis in a chronic alcoholic individual receiving placebo (O’Malley ct al. 2002). Furthermore, after the activation of the HPA axis hormones following consumption of alcohol, the alcoholic individuals had nohirlher urge lo drink. In contrast, ihe alcoholic subjects who were treated with placebo drank over twice as much alcohol and had much lower levels of ACTH and Cortisol following alcohol consumption, coupled with an urge lo drink (O’Malley el al. 2002).

Innumerable studies have shown that in animals trained to self-administer morphine or heroin, as in animals (hat are trained to sclf-adniinister cocaine, relapse will occur after re-introduction of the drug, introduction of a stressor, or signaling of a cue that has been used to create a conditioned response (e.g., Goedcrs 2002; Shalev ct al. 2002; Shippenbcrg and Plrncr 1998). The most potent of the three precipitators of relapse is a small amount of (he drug itself. However, the second most potent precipitator of relapse is the imposition of a stressor. Many studies have been conducted by different groups to see if this response can be blocked either at the HPA axis or in other part* oflhe brain, possibly by a CRT antagonist, hirther, il has been established by many groups that stress response systems in many other parts of the brain are affecled by chronic exposure to short-acting opiales in rodent models and thus may be involved in the role of stressors in specific addictive disease?., it is quite clear also that the HPA axis and its hormones play a major role, and this role can be directly studied in human subjects.

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