Effect of Morphine on the Neuropathogenesis of SIVmac Infection in Indian Rhesus Macaques

Abstract

Morphine is known to prevent the development of cell-mediated immune (CMI) responses and enhance expression of the CCR5 receptor in monocyte macrophages. We undertook a study to determine the effect of morphine on the neuropathogenesis and immunopathogenesis of simian immunodeficiency virus (SIV) infection in Indian Rhesus Macaques. Hypothetically, the effect of morphine would be to prevent the development of CMI responses to SIV and to enhance the infection in macrophages. Sixteen Rhesus Macaques were divided into three experimental groups: M (morphine only, n = 5), VM (morphine + SIV, n = 6), and V (SIV only, n = 5). Animals in groups M and VM were given 2.5 mg/kg of morphine sulfate, four times daily, for up to 59 weeks. Groups VM and V were inoculated with SIVmacR71/17E 26 weeks after the beginning of morphine administration. Morphine prevented the development of enzyme-linked immunosorbent spot-forming cell CMI responses in contrast to virus control animals, all of which developed CMI. Whereas morphine treatment had no effect on viremia, cerebrospinal fluid viral titers or survival over the time course of the study, the drug was associated with a tendency for greater build-up of virus in the brains of infected animals. Histopathological changes in the brains of animals that developed disease were of a demyelinating type in the VM animals compared to an encephalitic type in the V animals. This difference may have been associated with the immunosuppressive effect of the drug in inhibiting CMI responses.

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

“…To the best of our knowledge, this is the first time that advanced and endstage plexiform lesions characteristic of pulmonary arteriopathy associated with severe PAH have been observed in SIVinfected macaques. As reported earlier, no significant differences were found in the CD4 or CD8 counts or plasma viral load between the V and VM groups (18). However, in other studies of SIV/SHIV-infected macaques, exposure to chronic morphine had a significant and dramatic effect on viral replication in cerebral tissues, resulting in early mortality (29,30).…”

“…Based on these findings, we hypothesized that simian immunodeficiency virus (SIV)-infected rhesus macaques exposed chronically to morphine would demonstrate an accentuated pulmonary vascular arteriopathy. To test this hypothesis, we analyzed archival lung tissues from macaques used earlier to study the effect of morphine abuse on the neuropathogenesis and immune pathogenesis of SIV infection (18). Here we show enhanced pulmonary arteriopathy with the presence of complex lesions in the SIV plus morphine group compared with either the morphine or SIV group.…”

“…The paraffin-embedded archival lung sections from 11 male SIVinfected rhesus macaques exposed (virus 1 morphine [VM] group, n ¼ 6) or unexposed (virus only [V] group, n ¼ 5) to morphine for up to 59 weeks were assessed for histological evidence of pulmonary vascular lesions and compared with morphine-exposed uninfected control animals (morphine [M] only group, n ¼ 5) (18). Briefly, 26 weeks of morphine injections (2.5 mg/kg, intramuscular, four times daily) were administered to macaques in the M and VM groups, and sham injections of saline were given to macaques in the V group.…”

“…No hemodynamic measurements were obtained on any of the macaques. For more details, please refer to previous publication by Marcario and colleagues (18). Hematoxylin and eosin (H&E), Verhoeff von Gieson (VVG), Masson's trichrome, and immunohistochemical staining of paraffin-embedded lung sections was performed as previously described (20).…”

Opioidinduzierte Immunsuppression

“…Diese letztgenannten drei Studien stammen jedoch von einer Arbeitsgruppe und beziehen sich wahrscheinlich immer auf dieselben 6 infizierten Affen, sodass sie nicht als unabhängige Ergebnisse gewertet werden kön-nen. In einer anderen Studie wurden keine Unterschiede zwischen morphin-und placebobehandelten Tieren (n=6 Tiere/ Gruppe) hinsichtlich der Virusreplikation im Serum, im Liquor und des Überle-bens gefunden [14]. Insgesamt ist die Anzahl der untersuchten Tiere niedrig, und die bisherigen Ergebnisse sind widersprüchlich.…”