Opioids Induce Renal Abnormalities in Tumor-Bearing Mice

Abstract

Background/Aims: The etiology of renal dysfunction in cancer patients is likely to be multifactorial. A large proportion of these patients receive opioid analgesics, but whether opioids contribute to renal dysfunction remains uncertain. In a murine cancer model, we examined the effects of chronic opioid administration on renal function and pathology, and the molecular mechanisms involved. Methods: C3H/HeJ mice implanted with 2472 tumor cells were treated with either morphine or hydromorphone in clinically relevant doses, or PBS (controls). Renal function was assessed by blood and urine chemistry as well as by measuring mean arterial pressure (MAP) and kidney perfusion. Pathological changes in the kidneys were examined by routine histology. Molecular changes were examined by assessing eNOS, iNOS, HO-1 and COX-2 expression in whole-kidney lysates by Western immunoblotting, and cellular colocalization of these enzymes was determined using immunofluorescence microscopy. Results:Three weeks of opioid treatment resulted in increased kidney weight, elevated BUN and proteinuria, and decreased MAP. This was accompanied by histological abnormalities including glomerular enlargement, hypercellularity, peritubular congestion, vasodilatation and tubular casts. The vasoregulatory molecules iNOS, eNOS, HO-1 and COX-2 were upregulated in the kidneys. The NOS inhibitor L-NAME prevented the morphine-induced increase in perfusion and kidney weight. Conclusions: The chronic use of clinically relevant doses of opioidsleads to structural kidney abnormalities, upregulates NOS, COX-2 and HO-1, and results in renal dysfunction in a murine model of cancer.

Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC

“…Within this scope, a number of in vitro [25,30] and in vivo [25,26] studies showed that morphine at medically relevant concentrations stimulated angiogenesis [25,26,30], and some other studies showed that chronic administration of morphine has stimulated the proliferation of tumour cells [23,24,31]. The main findings of the present study revealed that morphine at clinically relevant doses stimulated angiogenesis, and angiogenesis triggered of morphine is demonstrated with MVD and DS, but not TF.…”

“…Morphine can affect tumour growth by several mechanisms; (a) modulating the immune system [32][33][34][35][36][37], (b) directly acting on the tumour cells, (c) directly acting on the endothelial cells [26,31,38,39], (d) acting on the central nervous system-mediated secretion of cytokines and growth factors that may alter the tumour microenvironment: The morphine-induced enhancement of tumour growth could be due to a change in the milieu. Therefore, morphine by itself does not modulate tumour cell growth in culture, but administration of opiates stimulates the release of other hormones [14][15][16][17].…”

COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia

“…Earlier observations have shown that morphine induces vasodilatation by stimulating NO (Stefano et al, 1995). In addition, recent observations from our laboratory show that 3 weeks of morphine treatment stimulates the expression of the vasodilatory enzymes iNOS, eNOS, COX-2 and HO1 in the kidneys of C3H mice bearing NCTC 2472 tumours (Arerangaiah et al, 2007). Upregulation of NO by morphine may also compensate for the vasoconstrictive and hypertensive effect of celecoxib on cardiovascular haemodynamics.…”

“…Morphine stimulates NO in endothelium and chronic morphine treatment increases NO synthase (NOS), NO and cyclooxygenase-2 (COX-2) in mouse kidney (Stefano et al, 1995;Arerangaiah et al, 2007). Nitric oxide stimulates the enzymatic activity of COX (Salvemini et al, 1993), and activated COX in turn increases prostaglandin E 2 (PGE 2 ) production (Salvemini et al, 1993(Salvemini et al, , 1994Nedelec et al, 2001;Birnbaum et al, 2005).…”

Could Perioperative Opioid Use Increase the Risk of Cancer Progression and Metastases?

“…40 NO-induced COX-2 contributes to production of prostaglandin E2 (PGE2), 41 and PGE2 is known to promote angiogenesis. 42–44 We found that co-treatment with morphine and the COX-2 inhibitor celecoxib inhibits angiogenesis, tumor growth, metastasis and mortality in a mouse model of breast cancer.…”