Abrupt or precipitated withdrawal from morphine induces immunosuppression
Introduction
It is well established that morphine given acutely or subacutely is immunosuppressive as assayed by several different parameters including natural killer (NK) cell activity Weber and Pert, 1989, Band et al., 1992, T-cell mitogen responses Bayer et al., 1990, Bayer et al., 1992, and antibody responses Bussiere et al., 1992, Eisenstein et al., 1990, Eisenstein et al., 1995. There are few studies examining the effects of chronic morphine exposure on immune responses. Bryant et al., 1988a, Bryant et al., 1988b followed the kinetics of murine splenocyte proliferative responses to concanavalin A in mice implanted with a 75-mg slow-release morphine pellet. They observed profound immunosuppression, which reached a maximum at 48 h but returned to normal by 96 h after pellet implantation, although morphine levels in the sera at 48 and 96 h were equivalent. Previous studies from our laboratory examined murine splenic plaque-forming cell (PFC) responses to sheep red blood cells (SRBCs) over time after implantation of a 75-mg slow-release morphine pellet and showed comparable results, with maximal immune suppression at 48 h, and a return to normal responses by 120 h after pellet implantation (Bussiere et al., 1993). Recently, West et al. (1997) have shown that continuous administration of morphine to rats for 20 days by osmotic minipump led to tolerance in some immune assays but not others. These studies support the hypothesis that tolerance to many of the immunomodulatory effects of morphine develops after chronic exposure to the opioid.
The phenomenon of opioid tolerance is well established by standard pharmacological tests measuring behavioral, biochemical, and physiological parameters Way et al., 1969, Cicero and Meyer, 1973, Patrick et al., 1978, Bergström et al., 1984, Martinez et al., 1990, Paronis and Holtzman, 1992. The majority of these studies show that morphine is a potent analgesic, but upon repeated administration, its effects diminish. It is also well established that once tolerance develops, termination of the drug by abrupt (drug cessation) or precipitated withdrawal (with or without drug cessation plus administration of an opioid antagonist) can lead to an abstinence syndrome indicating a state of physical dependence. There are only two studies in mice and one in humans on the effects of abrupt withdrawal (AW) from morphine on immune responses Bhargava et al., 1994, Govitrapong et al., 1998, West et al., 1999, and none that we are aware of on precipitated withdrawal.
The present study examines and compares the effects of precipitated and abrupt withdrawal from morphine on splenic antibody responses in mice. It was found that abrupt withdrawal, by removal of morphine pellets from dependent animals, resulted in profound immunosuppression that was maximal at 48 h post-pellet removal and was still present at 144 h. In contrast, precipitated withdrawal resulted in a short period of immunopotentiation at 3 h post-pellet removal, followed by profound immunosuppression at 24 h post-withdrawal, with a rapid return to normal immune responses by 72 h. The results are novel, as both paradigms led to immunosuppression at 24 h post-withdrawal, but there were marked differences in the kinetics of the effects on immune responses.
Section snippets
Mice
Six-week-old C3HeB/FeJ female mice were purchased from Jackson Laboratories (Bar Harbor, ME) and housed in sterilized cages with mouse chow and water provided ad libitum. All mice were acclimated for a minimum of 1 week prior to being used in experiments.
Surgery and experimental design
Mice were anesthetized with methoxyflurane and areas of the back were shaved. A 1-cm incision was made in the skin and mice were implanted s.c. with either a 75-mg morphine pellet or a cellulose placebo pellet (The National Institute on Drug
Abrupt withdrawal (AW) results in suppression of splenic antibody responses
To examine the effect of abrupt withdrawal on immune responses, the PFC assay was carried out at various time points after pellet removal (Fig. 1). At 2 h post-withdrawal, mice that were implanted with a placebo or a morphine pellet showed approximately a 50% decrease in the number of PFCs. By 4 h, the immune response of the placebo animals had returned to normal, suggesting that the transient immunosuppression observed at 2 h was a result of the surgical procedure. In contrast, PFC responses
Discussion
This study is the first to compare the effects of both abrupt and precipitated withdrawal from morphine on immune responses in mice and shows that withdrawal, by either paradigm, results in profound immunosuppression. The present study is also the first to examine and compare the kinetics of abrupt and precipitated withdrawal on immune responses. Mice were made dependent by administration of a morphine pellet for 96 h and a morphine-abstinence syndrome was initiated by two different paradigms.
Acknowledgments
This work was supported by National Institute on Drug Abuse grants DA06650, DA11134, and DA13429-01. We also thank Dr. John P. Gaughan for assistance with statistical analyses.
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