Renal effects of opioid exposure: Considerations for therapeutic use

Kalpna Gupta, PhD, Marc L. Weber, MD


In recent years, the discovery of peripheral opioid receptors has challenged the dogma of opioids interacting exclusively with the central nervous system. In this article, we describe the current understanding of the roles of opioids and opioid receptors in renal physiology and pathophysiology. The renal response to opioid exposure varies depending upon the specific opioid agonist, dose, and duration of exposure. The known acute effects of opioids on the kidney impact salt and water balance. The chronic effects of opioid exposure on kidney function are largely unknown, but collapsing glomerulopathy has been associated with chronic heroin abuse. Opioid exposure can lead to both physiological and architectural renal changes, and this may have important clinical implications. Since opioids are often used for pain management in patients with existing kidney disease, their role in kidney function warrants attention.


opioid, morphine, kidney, renal function, endothelium

Full Text:



booth M: Opium: A History. New York: St. Martin’s Press, 1998.

Dibona GF, Jones SY: Role of endogenous peripheral opioid mechanisms in renal function. J Am Soc Nephrol. 1994; 4: 1792-1797.

Neidle A, Manigault I, Wajda IJ: Distribution of opiate-like substances in rat tissues. Neurochem Res. 1979; 4: 399-410.

Quirion R, Finkel MS, Mendelsohn FA, et al.: Localization of opiate binding sites in kidney and adrenal gland of the rat. Life Sci. 1983; 33(Suppl 1): 299-302.

Stefano Gb, Hartman A, bilfinger TV, et al.: Presence of the mu3 opiate receptor in endothelial cells. coupling to nitric oxide production and vasodilation. J Biol Chem. 1995; 270: 30290-30293.

Gupta K, Kshirsagar S, chang L, et al.: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002; 62: 4491-4498.

Poonawala T, Levay-Young bK, Hebbel RP, et al.: Opioids heal ischemic wounds in the rat. Wound Repair Regen. 2005; 13: 165-174.

Weber ML HR, Hebbel RP, Gupta K: Opioids promote kidney growth. J Am Soc Nephrol. 2005; 16: 387A.

Waldhoer M, bartlett SE, Whistler JL: Opioid receptors. Annu Rev Biochem. 2004; 73: 953-990.

Wollemann M: Recent developments in the research of opioid receptor subtype molecular characterization. J Neurochem. 1990; 54: 1095-1101.

Law PY, Loh HH: Regulation of opioid receptor activities. J Pharmacol Exp Ther. 1999; 289: 607-624.

Gupta K, Stephenson EJ: Existence and modus operandi of opioid receptors in endothelium. In Aird Wc (ed.): The Endothelium: A Comprehensive Reference [in press]. cambridge: cambridge University Press, 2006.

Tian W, Zhang Z, cohen DM: MAPK signaling and the kidney. Am J Physiol Renal Physiol. 2000; 279: F593-F604.

Gutkind JS: The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades. J Biol Chem. 1998; 273: 1839-1842.

Fukuda K, Kato S, Morikawa H, et al.: Functional coupling of the opioid receptors to mitogen-activated protein kinase and arachidonate release in chinese hamster ovary cells. J Neurochem. 1996; 67: 1309-1316.

Lou L-G, Zhang Z, Ma L, et al.: Nociceptin/orphanin FQ activates mitogen-activated protein kinase in chinese hamster ovary cells expressing opioid receptor-like receptor. J Neurochem. 1998; 70: 1316-1322.

Li J-G, Luo L-Y, Krupnick JG, et al.: U50,488H-induced internalization of the human k opioid receptor involves a b-arrestinand dynamin-dependent mechanism. k receptor internalization is not required for mitogen-activated protein kinase activation. J Biol Chem. 1999; 274: 12087-12094.

Kieffer bL: Recent advances in molecular recognition and signal transduction of active peptides: Receptors for opioid peptides. Cell Mol Neurobiol. 1995; 15: 615-635.

Welters ID, Fimiani c, bilfinger TV, et al.: NF-kb, nitric oxide and opiate signaling. Med Hypotheses. 2000; 54: 263-268.

Li LY, chang KJ: The stimulatory effect of opioids on mitogen-activated protein kinase in chinese hamster ovary cells transfected to express mu-opioid receptors. Mol Pharmacol. 1996; 50: 599-602.

chuang LF, Killam KF Jr, chuang RY: Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. J Biol Chem. 1997; 272: 26815-26817.

Wetzker R, bohmer FD: Transactivation joins multiple tracks to the ERK/MAPK cascade. Nat Rev Mol Cell Biol. 2003; 4: 651-657.

Waters c, Pyne S, Pyne NJ: The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction. Semin Cell Dev Biol. 2004; 15: 309-323.

belcheva MM, Szucs M, Wang D, et al.: mu-Opioid receptormediated ERK activation involves calmodulin-dependent epidermal growth factor receptor transactivation. J Biol Chem. 2001; 276: 33847-33853.

chen c, Farooqui M, Gupta K: Morphine stimulates VEGFlike signaling in mouse retinal endothelial cells. current Neurovasc Res. 2006; 3(3), (In press).

Kapusta DR, Jones SY, Dibona GF: Renal mu opioid receptor mechanisms in regulation of renal function in rats. J Pharmacol Exp Ther. 1991; 258: 111-117.

Kapusta DR, Jones SY, Dibona GF: Effects of opioid peptides on neural control of renal function in spontaneously hypertensive rats. Hypertension. 1990; 15: 767-773.

Kapusta DR, Jones SY, Dibona GF: Opioids in the systemic hemodynamic and renal responses to stress in spontaneously hypertensive rats. Hypertension. 1989; 13: 808-816.

Mercadante S, Arcuri E: Opioids and renal function. The Journal of Pain. 2004; 5: 2-19.

Gottlieb Hb, Kapusta DR: Endogenous central kappa-opioid systems augment renal sympathetic nerve activity to maximally retain urinary sodium during hypotonic saline volume expansion. Am J Physiol Regul Integr Comp Physiol. 2005; 289: R1289-R1296.

Shirasaka T, Kunitake T, Kato K, et al.: Nociceptin modulates renal sympathetic nerve activity through a central action in conscious rats. J Physiol. 1999; 277: R1025-R1032.

Kapusta DR, Dzialowski EM: central mu opioids mediate differential control of urine flow rate and urinary sodium excretion in conscious rats. Life Sci. 1995; 56: PL243-PL248.

Kapusta DR, Obih Jc: central kappa opioids blunt the renal excretory responses to volume expansion by a renal nerve-dependent mechanism. J Pharmacol Exp Ther. 1995; 273: 199-205.

Flores O, camera LA, Hergueta A, et al.: Role of atrial natriuretic factor, hemodynamic changes and renal nerves in the renal effects of intraperitoneal morphine in conscious rats. Kidney Blood Press Res. 1997; 20: 18-24.

Kapusta DR, Obih Jc: Role of endogenous central opioid mechanisms in maintenance of body sodium balance. Am J Physiol. 1995; 268: R723-R730.

Wang YX, clarke GD, Sbacchi M, et al.: contribution of alpha-2 adrenoceptors to kappa opioid agonist-induced water diuresis in the rat. J Pharmacol Exp Ther. 1994; 270: 244-249.

Rimoy GH, bhaskar NK, Wright DM, et al.: Mechanism of diuretic action of spiradoline (U-62066E)—a kappa opioid receptor agonist in the human. Br J Clin Pharmacol. 1991; 32: 611-615.

Ooi bS, Maccarthy EP, Hsu A: beta-endorphin amplifies the effect of interleukin-1 on mouse mesangial cell proliferation. J Lab Clin Med. 1987; 110: 159-163.

Elias AN, Vaziri ND, Maksy M: Plasma beta-endorphin and beta-lipotropin in patients with end-stage renal disease—effects of hemodialysis. Nephron. 1986; 43: 173-176.

Aronin N, Krieger DT: Plasma immunoreactive beta-endorphin is elevated in uraemia. Clin Endocrinol (Oxf). 1983; 18: 459-464.

Trelewicz P, Grzeszczak W, Drabczyk R: Serum beta-endorphin in non-dialysed and haemodialysed patients with chronic renal failure. Int Urol Nephrol. 1994; 26: 117-123.

Flores O, camera LA, Hergueta A, et al.: Role of atrial natriuretic factor, hemodynamic changes and renal nerves in the renal effects of intraperitoneal morphine in conscious rats. Kidney Blood Press Res. 1997; 20: 18-24.

Walker LA, Murphy Jc: Antinatriuretic effect of acute morphine administration in conscious rats. J Pharmacol Exp Ther. 1984; 229: 404-408.

Leander JD: A kappa opioid effect: Increased urination in the rat. J Pharmacol Exp Ther. 1983; 224: 89-94.

Leander JD: Further study of kappa opioids on increased urination. J Pharmacol Exp Ther. 1983; 227: 35-41.

Sezen SF, Kenigs VA, Kapusta DR: Renal excretory responses produced by the delta opioid agonist, bW373U86, in conscious rats. J Pharmacol Exp Ther. 1998; 287: 238-245.

Hadrup N, Petersen JS, Praetorius J, et al.: Opioid receptorlike 1 stimulation in the collecting duct induces aquaresis through vasopressin-independent aquaporin-2 downregulation. Am J Physiol Renal Physiol. 2004; 287: F160-F168.

Johnson JE Jr, White JJ Jr, Walovitch Rc, et al.: Effects of morphine on rat kidney glomerular podocytes: A scanning electron microscopic study. Drug Alcohol Depend. 1987; 19: 249-257.

Patel J, Manjappa N, bhat R, et al.: Role of oxidative stress and heme oxygenase activity in morphine-induced glomerular epithelial cell growth. Am J Physiol Renal Physiol. 2003; 285: F861-F869.

Singhal Pc, Sharma P, Gibbons N, et al.: Effect of morphine on renomedullary interstitial cell proliferation and matrix accumulation. Nephron. 1997; 77: 225-234.

Kilcoyne MM, Gocke DJ, Meltzer JI, et al.: Nephrotic syndrome in heroin addicts. Lancet. 1972; 1: 17-20.

Salomon MI, Poon TP, Goldblatt M, et al.: Renal lesions in heroin addicts. A study based on kidney biopsies. Nephron. 1972; 9: 356-363.

Atici S, cinel I, cinel L, et al.: Liver and kidney toxicity in chronic use of opioids: An experimental long term treatment model. J Biosci. 2005; 30: 245-252.

Michael AF, Keane WF, Raij L, et al.: The glomerular mesangium. Kidney Int. 1980; 17: 141-154.

Pesce cM, Striker LJ, Peten E, et al.: Glomerulosclerosis at both early and late stages is associated with increased cell turnover in mice transgenic for growth hormone. Lab Invest. 1991; 65: 601-605.

Wikstrom b, Gellert R, Ladefoged SD, et al.: Kappa-opioid system in uremic pruritus: Multicenter, randomized, doubleblind, placebo-controlled clinical studies. J Am Soc Nephrol. 2005; 16: 3742-3747.

bosch-Marce M, Poo JL, Jimenez W, et al.: comparison of two aquaretic drugs (niravoline and OPc-31260) in cirrhotic rats with ascites and water retention. J Pharmacol Exp Ther. 1999; 289: 194-201.

United States Renal Data System: USRDS 2000 Annual Data Report. bethesda: The National Institutes of Health, National Institute of Diabetes and Digestive Diseases, 2001.



  • There are currently no refbacks.