Enhanced immune sensitivity to stress following chronic morphine exposure.

Chronic administration of escalating doses ofmorphine leads to neuroadaptive changes precipitating development of tolerance to many of the acute effects of morphine, such as analgesia, activation of the hypothalamic-pituitary-adrenal (HPA) axis and suppression of immune cell activities. Interestingly, morphine tolerance has also been shown to be accompanied by heightened immunosuppressive effects of restraint stress using a rodent model. These observations have led to the hypothesis that the altered neuronal state accompanying opioid tolerance may contribute to this enhanced immune sensitivity to stress. To further test this hypothesis using different stressors, Sprague-Dawley rats were treated chronically with morphine for at least 8 days and then challenged with either psychological (water stress) or systemic stressors [morphine withdrawal, lipopolysaccharide (10 mug/kg i.p. challenge)]. It was found that, independent of the type of stress employed, morphine-tolerant animals displayed significantly lower mitogen-stimulated blood lymphocyte responses when compared to the responses of similarly treated saline controls. To determine whether direct activation of central stress pathways may also lead to enhanced immune sensitivity, morphine-tolerant animals were centrally injected with IL-1beta (1 ng/mul i.c.v.), a cytokine that activates the HPA axis by central mechanisms. Similar to the other types of stress, this direct central challenge was also found to be more immunosuppressive in morphine-tolerant animals compared to controls. Collectively, these studies demonstrate that morphine-tolerant animals have an enhanced susceptibility to the debilitating effects of a variety of stressors on immune cell function, an effect that is likely due to the neuroadaptive changes that develop during chronic morphine exposure.

HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) persists despite a vigorous virus-specific host immune response, and causes adult T-cell leukemia and lymphoma in approximately 2% of infected individuals. Here we report that HTLV-1 has evolved a genetic function to restrict its own replication by a novel post-transcriptional mechanism. The HTLV-1-encoded p30(II) is a nuclear-resident protein that binds to, and retains in the nucleus, the doubly spliced mRNA encoding the Tax and Rex proteins. Because Tex and Rex are positive regulators of viral gene expression, their inhibition by p30(II) reduces virion production. p30(II) inhibits virus expression by reducing Tax and Rex protein expression.

Immune cell activity during the initial stages of withdrawal from chronic exposure to cocaine or morphine.

The immunosuppression accompanying illicit drug use has been shown to contribute to a decreased resistance to a variety of pathogens; however, there is relatively little information on how long these effects persist following withdrawal from chronic drug exposure. To begin to address this question, Sprague-Dawley male rats were administered either cocaine (10 mg/kg, i.p., b.i.d.) for 7 days or morphine (escalating doses up to 40 mg/kg, s.c., b.i.d.) for a 10-day period. Control groups of animals received similar saline injections for equivalent time periods. Drug administration was abruptly discontinued and animals were sacrificed at 2, 24, 72 or 96 h following the last dose. At these time points, proliferation responses of peripheral blood T-lymphocytes stimulated by concanavalin A (Con A) and plasma levels of corticosterone were measured. Plasma corticosterone levels of cocaine- or morphine-treated animals were found to be significantly elevated 24 h following drug cessation as compared to saline animals. At this time, proliferation responses were significantly decreased and were further suppressed during cocaine and morphine withdrawal at 96 and 72 h, respectively. These results suggest that abrupt cessation of cocaine or morphine administration leads to activation of stress-related pathways that may contribute to an increased susceptibility of infection during the initial withdrawal phase.

Antagonism of N-methyl-D-aspartate receptors reduces the vulnerability of the immune system to stress after chronic morphine.

It has been shown that morphine-tolerant animals have an altered immunological sensitivity to stress. Although the glutamatergic system has been implicated in the neuroadaptive process underlying this tolerant state, its potential role in development of the altered immunological sensitivity consequent to chronic morphine treatment is not known. To determine this, a morphine-tolerant state was induced by 10-day administration of an escalating dose of morphine from 10 to 40 mg/kg (s.c., b.i.d.), and lymphocyte proliferative response to a T-cell mitogen was measured. Morphine challenge (10 mg/kg s.c.) after days of treatment was gradually less immunosuppressive, and this tolerance progression was delayed by concurrent administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 mg/kg s.c.) with chronic morphine. The effect was independent of glucocorticoid level changes and was not a result of an acute interaction of the drugs or the prolonged presence of the antagonist alone. Subsequent to chronic treatment, animals were subjected to opioid withdrawal and water stress. Both stressors induced 50% immunosuppression in morphine-tolerant animals compared with saline-treated controls. Increased immunological sensitivity to these stressors was attenuated when MK-801 was administered with chronic morphine as demonstrated by an accelerated recovery rate and lack of immunosuppression from opioid withdrawal and water stress, respectively. Together, these findings provide the first evidence that the neuroadapted state of the immune response after chronic morphine can be modified by NMDA receptor antagonism, as illustrated by a temporal deceleration of the development of immunological tolerance during chronic treatment that is associated with an attenuation of the immunological vulnerability of morphine-tolerant animals to stress.

Opioids, immunology, and host defenses of intravenous drug abusers.

Overall, it is apparent that opioids do affect host defense mechanisms. Heroin users present with an altered and functionally impaired immune system and have a higher prevalence of infectious diseases than do nonaddicts. Individuals exposed to opioid treatment for pain management during surgical procedures or maintained on oral methadone for treatment of drug addiction show either no effect or a suppressed immune system, depending on dosage and, in the case of methadone-maintained patients, duration of drug treatment. Confounding factors in these studies undermine definitive conclusions about the mechanisms by which opioids induce their immunomodulatory effects. Animal models have provided the means by which investigators can study the effects of opioids in a complex, biologic system that is easily manipulated and controlled. Findings from these studies have confirmed human data associating a pathogenic susceptibility with opioid use. Animal models have shown the complexity of this association. Interaction of the CNS, the autonomic nervous system, and the HPA axis is required for the varied effects of opioids on the immune system. By implication, exogenous opioids may be mimicking pathways by which endogenous opioids are involved in regulating immune defenses. To minimize the increased incidence of infectious diseases in heroin users and individuals clinically exposed to opioids, it will be important to determine the individual and collective effects of the opioid-induced activation of these pathways and the consequences of that activation to the immune system.