Immunomodulatory effects of morphine withdrawal in the rat are time dependent and reversible by clonidine.
BACKGROUND
It is well established that opioids can modulate the immune status following both acute and chronic administration and that tolerance develops to some of these immunomodulatory effects. Few studies, however, have investigated opioid withdrawal-induced immunomodulation and the mechanism by which that process may be mediated.


OBJECTIVE
The present study examines the immunomodulatory properties of morphine withdrawal alone and in the presence of the alpha(2)-adrenergic agonist, clonidine.


METHODS
Rats drank a morphine solution for 20 days; withdrawal was induced on day 21 by replacing the morphine solution with plain tap water. Measurements of withdrawal-induced weight change and immunomodulation were obtained at several time points after withdrawal induction. Immune status was assessed by determining concanavalin A (Con-A), toxic shock syndrome toxin (TSST-1), and lipopolysaccharide (LPS)-stimulated splenocyte proliferation, splenic ConA-stimulated interferon (IFN)-gamma production, and splenic natural-killer (NK) cell activity. In a separate series of experiments, systemic injections of clonidine (0.001-0.01 mg/kg) were administered during a 12-h withdrawal episode and all measures of immune status were reassessed.


RESULTS
Weight change was time dependent, with peak decreases in weight occurring 24 h following withdrawal induction. Rats also exhibited a time-dependent suppression of immune status in all assays except LPS-stimulated proliferation; immunomodulation was most evident 12 h following withdrawal induction. Clonidine dose dependently prevented withdrawal-induced suppression of Con-A and TSST-1-stimulated splenocyte proliferation, Con-A-stimulated splenocyte IFN-gamma production, and splenic NK cell activity.


CONCLUSIONS
These findings demonstrate that opioid withdrawal significantly suppresses a subset of immune parameters and that these effects can be prevented by clonidine.
West
J P
JP
Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27599-3270, USA.
Dykstra
L A
LA
Lysle
D T
DT
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007107:Immune System / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D010913:Pituitary-Adrenal System / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013375:Substance Withdrawal Syndrome / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
D009020:Morphine; D007371:Interferon-gamma; D003000:Clonidine