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Infection and Immunity, September 2006, p. 5221-5226, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00208-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Morphine Withdrawal Lowers Host Defense to Enteric Bacteria: Spontaneous Sepsis and Increased Sensitivity to Oral Salmonella enterica Serovar Typhimurium Infection

Pu Feng,1,2 Allan L. Truant,2,4 Joseph J. Meissler Jr.,1,2 John P. Gaughan,5 Martin W. Adler,1,3 and Toby K. Eisenstein1,2*

Center for Substance Abuse Research,1 Department of Microbiology and Immunology,2 Department of Pharmacology,3 Department of Pathology and Laboratory Medicine,4 Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 191405

Received 6 February 2006/ Returned for modification 31 May 2006/ Accepted 19 June 2006

Understanding the consequences of drug withdrawal on immune function and host defense to infection is important. We, and others, previously demonstrated that morphine withdrawal results in immunosuppression and sensitizes to lipopolysaccharide-induced septic shock. In the present study, the effect of morphine withdrawal on spontaneous sepsis and on oral infection with Salmonella enterica serovar Typhimurium was examined. Mice were chronically exposed to morphine for 96 h by implantation of a slow-release morphine pellet. Abrupt withdrawal was induced by removal of the pellet. In the sepsis model, bacterial colonization was examined and bacterial species were identified by necropsy of various tissues. It was found that at 48 h postwithdrawal, morphine-treated mice had enteric bacteria that were detected in the Peyer's patches (4/5), mesenteric lymph nodes (4/5), spleens (4/10), livers (6/10), and peritoneal cavities (8/10). In placebo pellet-withdrawn mice, only 2/40 cultures were positive. The most frequently detected organisms in tissues of morphine-withdrawn mice were Enterococcus faecium followed by Klebsiella pneumoniae. Both organisms are part of the normal gastrointestinal flora. In the infection model, mice were orally inoculated with S. enterica 24 h post-initiation of abrupt withdrawal from morphine. Withdrawal significantly decreased the mean survival time and significantly increased the Salmonella burden in various tissues of infected mice compared to placebo-withdrawn animals. Elevated levels of the proinflammatory cytokines were observed in spleens of morphine-withdrawn mice, compared to placebo-withdrawn mice. These findings demonstrate that morphine withdrawal sensitizes to oral infection with a bacterial pathogen and predisposes mice to bacterial sepsis.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140. Phone: (215) 707-3585. Fax: (215) 707-7920. E-mail: tke{at}temple.edu.

Editor: F. C. Fang

Infection and Immunity, September 2006, p. 5221-5226, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00208-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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