Open Access Open Access  Restricted Access Subscription or Fee Access

Methylnaltrexone reduced body weight gain in ob/ob mice

Chun-Su Yuan, MD, PhD, Chong-Zhi Wang, PhD, Anoja Attele, MD, Liu Zhang, PhD


Objective: Opioids may function to regulate food intake and body weight, an activity that could be predominantly centrally mediated. In this study, the authors evaluated the effects of a peripherally acting opioid receptor antagonist, methylnaltrexone, on weight changes in adult obese ob/ob mice.
Results: After a 12-day treatment with naloxone 0.3 mg/kg, weight was reduced from 63.7 ± 1.1 g in the control group to 59.2 ± 0.9 g in the naloxone group (p < 0.05). After a 12-day treatment with methylnaltrexone 3.0 mg/kg, weight increase completely ceased. The body weight was 63.9 ± 1.0 g in the control group when compared with 55.9 ± 1.2 g in the drug group (p < 0.01). The effect of methylnaltrexone (1.0 mg to 3.0 mg/kg) on weight changes was dose-dependent (p < 0.01). Methylnaltrexone significantly reduced daily food intake (p < 0.05), but did not affect body temperature and energy expenditure. Using HPLC analysis, no detectable naltrexone levels were found in association with methylnaltrexone administration. Whether the observed methylnaltrexone effects are primarily related to the antagonism of endorphinergic system remains to be investigated.
Conclusions: Our results suggest that the peripheral opioid mechanism contributes to modulating food ingestion and methylnaltrexone may have clinical importance in obesity management.


opioid, naloxone, methylnaltrexone, body weight, food intake, body temperature, energy expenditure, ob/ob mice

Full Text:



Jeanrenaud B, Rohner-Jeanrenaud F: Effects of neuropeptides and leptin on nutrient partitioning: Dysregulations in obesity. Annu Rev Med. 2001; 52: 339-351.

Gosnell BA, Levine AS, Morley JE: The stimulation of food intake by selective agonists of mu, kappa and delta opioid receptors. Life Sci. 1986; 38: 1081-1088.

Marin-Bivens CL, Olster DH: Opioid receptor blockade promotes weight loss and improves the display of sexual behaviors in obese Zucker female rats. Pharmacol Biochem Behav. 1999; 63: 515-520.

Cozzolino D, Sessa G, Salvatore T, et al.: The involvement of the opioid system in human obesity: A study in normal weight relatives of obese people. J Clin Endocrinol Metab. 1996; 81: 713-718.

Yu WZ, Ruegg H, Bodnar RJ: Delta and kappa opioid receptor subtypes and ingestion: Antagonist and glucoprivic effects. Pharmacol Biochem Behav. 1997; 56: 353-361.

Cole JL, Leventhal L, Pasternak GW, et al.: Reductions in body weight following chronic central opioid receptor subtype antagonists during development of dietary obesity in rats. Brain Res. 1995; 678: 168-176.

Baile CA, McLaughlin CL, Della-Fera MA: Role of cholecystokinin and opioid peptides in control of food intake. Physiol Rev. 1986; 66: 172-234.

Zhang J, Frassetto A, Huang RR, et al.: The mu-opioid receptor subtype is required for the anorectic effect of an opioid receptor antagonist. Eur J Pharmacol. 2006; 545: 147-152.

Tabarin A, Diz-Chaves Y, Carmona Mdel C, et al.: Resistance to diet-induced obesity in mu-opioid receptor-deficient mice: Evidence for a “thrifty gene”. Diabetes. 2005; 54: 3510-3516.

Yuan CS: Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007; 41: 984-993.

Elia M, Livesey G: Energy expenditure and fuel selection in biological systems: The theory and practice of calculations based on indirect calorimetry and tracer methods. World Rev Nutr Diet. 1992; 70: 68-131.

Attele AS, Shi ZQ, Yuan CS: Leptin, gut, and food intake. Biochem Pharmacol. 2002; 63: 1579-1583.

Kotake AN, Kuwahara SK, Burton E, et al.: Variations in demethylation of N-methylnaltrexone in mice, rats, dogs, and humans. Xenobiotica. 1989; 19: 1247-1254.

Osinski J, Wang A, Wu JA, et al.: Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics study. J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 780: 251-259.

Arora SA: Role of neuropeptides in appetite regulation and obesity–A review. Neuropeptides. 2006; 40: 375-401.

Appleyard SM, Hayward M, Young JI, et al.: A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology. 2003; 144: 1753-1760.

Leibowitz SF: Neurochemical-neuroendocrine systems in the brain controlling macronutrient intake and metabolism. Trends Neurosci. 1992; 15: 491-497.

Hayward MD, Schaich-Borg A, Pintar JE, et al.: Differential involvement of endogenous opioids in sucrose consumption and food reinforcement. Pharmacol Biochem Behav. 2006; 85: 601-611.

Chen RZ, Huang RR, Shen CP, et al.: Chronic administration of nalmefene leads to increased food intake and body weight gain in mice. Eur J Pharmacol. 2004; 495: 63-66.

Fletcher PJ: Opiate antagonists inhibit feeding induced by 8-OH-DPAT: Possible mediation in the nucleus accumbens. Brain Res. 1991; 560: 260-267.

Boyd TA, Yuan CS: Methylnaltrexone: Investigation in treating opioid bowel dysfunction. In Yuan CS (ed.): Handbook of Opioid Bowel Syndrome. New York: Haworth Medical Press, 2005: 197-221.

Jarosz PA: The effect of kappa opioid receptor antagonism on energy expenditure in the obese Zucker rat. Biol Res Nurs. 2007; 8: 294-299.

Aung HH, Mehendale SR, Xie JT, et al.: Methylnaltrexone prevents morphine-induced kaolin intake in the rat. Life Sci. 2004; 74: 2685-2691.

Gmerek DE, Cowan A, Woods JH: Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats. J Pharmacol Exp Ther. 1986; 236: 8-13.



  • There are currently no refbacks.