Hypothalamic-Pituitary-Adrenocortical (HPA) Axis Response and Biotransformation of Oral Naltrexone Preliminary Examination of Relationship to Family History of Alcoholism

Abstract

We examined HPA axis response to 50 mg oral naltrexone compared with placebo in 17 healthy male and female nonalcoholic subjects, approximately half of whom had a positive family history of alcoholism (FH ϩ ) and half of whom who did not (FH Ϫ)The endogenous opioid system plays a role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis (Cushman and Kreek 1974;Johnson et al. 1992;Kreek 1972Kreek , 1973Kreek , 1978. Opioid antagonist administration blocks the tonic opioid inhibition of HPA axis activity, thereby resulting in release of POMC-derived hormones in the pituitary and cortisol from the adrenal gland. Indeed, numerous studies have demonstrated acute increases in adrenocorticotropin (ACTH) and cortisol levels in man after intravenous infusion of the opioid antagonists naloxone (Cohen et al. 1983;Conaglen et al. 1985;Delitala et al. 1994;Naber et al. 1981;Martin del Campo et al. 1994;Morley et al. 1980;Schluger et al. 1998;Volavka et al. 1979a) and nalmefene . However, few studies have examined acute neuroendocrine response to the opioid antagonist naltrexone, which, in contrast to naloxone and nalmefene, is not available for intravenous administration.The two published studies on the acute HPA axis effects of orally administered naltrexone have both been conducted with relatively small sample sizes (n р 10). NO . 6 Naltrexone, HPA Axis, and Biotransformation 779The first study (Volavka et al. 1979b), conducted in ten normal male subjects, showed that oral naltrexone significantly increased cortisol levels two hours after administration and directionally (but nonsignificantly) increased ACTH levels one hour after administration. However, due to the small sample studied, the power may not have been sufficient to detect differences. The results may also have been confounded by the co-occurrence of pain sensitivity testing (i.e., 2-min cold pressor task) during the protocol, which may have produced independent HPA axis responses. A more recent study in six abstinent alcoholic patients (Farren et al. 1999) showed significant increases in cortisol and ACTH to three doses of oral naltrexone (25, 50, and 100mg) with no dose-dependent effects (Farren et al. 1999). It has been hypothesized that alterations in HPA axis function may play a role in various stages of addiction, including initiation, maintenance, and relapse (Kreek 1992). Naltrexone (50 mg oral) has shown efficacy in the treatment of alcohol dependence (Volpicelli et al. 1992(Volpicelli et al. , 1997O'Malley et al. 1992;Anton et al. 1999), which led to its FDA-approval for adjunctive treatment of alcoholism. Studies examining HPA axis response after oral naltrexone administration might be of potential clinical relevance as neuroendocrine changes and sensitivity to naltrexone could relate to individual differences and treatment response. Hypothetically, the effects of an opioid antagonist, such as naltrexone, in modulating tonic inhibition of the opioid system at various receptors, including primarily , but also ␦ and , may relate to tr...

Increased Attributable Risk Related to a Functional μ-Opioid Receptor Gene Polymorphism in Association with Alcohol Dependence in Central Sweden

“…Both blunted cortisol response (Schuckit et al, 1987) and enhanced ACTH and b-endorphin response to alcohol have been reported in nondependent offspring of alcoholic subjects (Gianoulakis et al, 1996). More consistently, increased HPA response to the m-preferring opiate antagonists naloxone or naltrexone has been found in nonalcoholic offspring of alcoholics (King et al, 2002;King et al, 1997;Wand et al, 1998;Wand et al, 2001). Interestingly, naltrexone also attenuated the subjective effects of alcohol in the family history positive social drinkers but not in the family history negative group (King et al, 1997).…”

Relationships Among Ventral Striatal Dopamine Release, Cortisol Secretion, and Subjective Responses to Amphetamine

“…Findings from human laboratory studies have further shown that stress increases drug craving (Sinha et al, 1999(Sinha et al, , 2000(Sinha et al, , 2003 alters subjective responses to alcohol (Soderpalm and de Wit, 2002) and increases alcohol consumption (de Wit et al, 2003;Hull and Young, 1983). There is also evidence that genetic influences on stress reactivity may be associated with individual differences in risk for alcoholism (Bau et al, 2000;Dai et al, 2002a, b;King et al, 2002;Madrid et al, 2001;Ohannessian et al, 1994;Schuckit et al, 1996;Waltman et al, 1994;Wand et al, 2001Wand et al, , 1998Wand et al, , 1999a and that the dynamics of the physiological stress response may be deranged in drug dependent individuals (Errico et al, 2002;Kemper et al, 1990;Kreek and Koob, 1998).…”

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

“…In the case of the addictive diseases, these alterations are primarily due to the pharmacological effects of drugs of abuse but are also influenced by developmental, environmental, and genetic factors. As an example of the latter, nonalcoholic sons of alcoholic fathers have altered HPA responsiveness to alcohol and mu opioid receptor antagonism compared to sons of nonalcoholic fathers (King et al, 1998;Schuckit et al, 1987;Wand et al, 1998). In fact, up to 50% of interindividual differences in basal and stress-induced cortisol levels in healthy human volunteers may be explained by genetic factors (Federenko et al, 2004;Linkowski et al, 1993).…”