Chronic exposure to morphine increases corticosteroid-binding globulin

Although it appears that corticosterone may play an important role in determining vulnerability to drugs of abuse, few studies have examined drug effects on factors that affect corticosterone efficacy. Thus, studies were carried out to assess the effects of morphine on corticosteroid-binding globulin (CBG), the major glucocorticoid binder in blood. Since CBG-bound hormone is thought to be physiologically inactive, changes in CBG levels could affect corticosterone action independently of hormone levels per se. We found that morphine caused a marked naltrexone-preventable increase (approximately 160%) in CBG in adult male rats. Elevated levels were seen by three days and were maximal at seven days after morphine pellet (75 mg) implantation. CBG levels remained elevated while morphine was detectable in blood and returned toward normal as the drug cleared from the system. A single morphine pellet was sufficient to induce a marked increase in the concentration of CBG and two or more pellets caused maximal upregulation. Baseline and stress levels of total corticosterone (bound and unbound) were normal after chronic exposure to morphine. However, due to the elevated level of CBG, the amount of free, physiologically active hormone was dramatically reduced. These results suggest that morphine may exert potent effects on corticosterone action that are not revealed by measurement of corticosterone alone. Furthermore, the increase in CBG resulting from chronic exposure to morphine might contribute to the perpetuation of drug use and to adverse effects of drug exposure by impairing normal functions of corticosterone.