Morphine promotes renal pathology in sickle mice

Abstract

Patients with sickle cell disease (SCD) are often treated with opioids for severe pain. Although opioids are known to have renal-specific effects, their role in nephropathy in SCD remains unknown. Because a subset of patients receives opioids for long periods of time, we examined the influence of chronic morphine treatment on mice with pre-existing renal disease expressing varying amounts of sickle hemoglobin. Morphine treatment for 3–6 weeks resulted in a variety of defects in renal morphology observed using light and electron microscopy. Notably, morphine induced glomerular pathology, resulting in increased glomerular volume, mesangial expansion, mesangial cell proliferation, parietal cell metaplasia, podocyte effacement, and microvillus transformation. Cystic tubulopathy and hemeoxygenase-1 expression and activity were also increased in morphine-treated mice. Naloxone, a non-selective opioid receptor (OR) antagonist, ameliorated these effects. Functionally, the urine albumin to creatinine ratio was increased following acute as well as chronic morphine treatment. These results suggest that clinically relevant doses of morphine induce renal pathology and that OR antagonists may be effective for ameliorating morphine-induced renal disease.

Keywords:

• mesangial cell
• morphine
• nephropathy
• pain
• podocyte
• sickle cell disease

Acknowledgments

We thank Mariya Farooqui, Tasneem Poonawala, Karl A Nath, Anthony Croatt, Stefan Kren, and Janet Parker for technical assistance. This work was funded by NIH grants, RO1 HL68802, HL103773, HL68802-06S1, HL68802-7S1 (to KG) and PO1 HL55552 (to RPH).

Authors’ contributions

MLW performed experiments and assisted with writing the manuscript; DV performed urine analysis; PEV interpreted data and wrote the manuscript; JTC and PG analyzed and interpreted histopathology and electron microscopy data; RPH conducted genotyping, provided mice, and gave advice regarding editing of the manuscript; KG conceived, designed, and supervised the study and analyzed and interpreted data as well as edited the manuscript.

Disclosure

The authors report no conflicts of interest in this work.