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Vol. 299, Issue 2, 629-637, November 2001

Studies of Tolerance and Dependence with the delta -Opioid Agonist SNC80 in Rhesus Monkeys Responding under a Schedule of Food Presentation

Michael R. Brandt1 , M. Scott Furness, Kenner C. Rice, Bradford D. Fischer and S. Stevens Negus

Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, Massachusetts (M.R.B., B.D.F., S.S.N.); and Laboratory of Medicinal Chemistry, National Institute of Diabetics and Digestive and Kidney Diseases and National Institutes of Health, Bethesda, Maryland (M.S.F., K.C.R.)

Tolerance and dependence after acute or chronic administration of the selective delta -opioid agonist SNC80 were assessed in rhesus monkeys (Macaca mulatta) responding under a schedule of food presentation. SNC80 dose dependently decreased response rates. These effects waned after 5 h. When administered as an acute 24-h pretreatment, SNC80 (1.0-10.0 mg/kg) produced tolerance as evidenced by dose-dependent rightward shifts in the SNC80 dose-effect curve. Pretreatments of 3.2 or 10.0 mg/kg SNC80 increased the SNC80 ED50 by 4- or 25-fold, respectively. Tolerance to acute SNC80 was also time-dependent as evidenced by increased ED50 values when administered as a 5-h (14-fold), 24-h (25-fold), or 3-day (11-fold) pretreatment. The SNC80 dose-effect curve was similar to control after a 7-day pretreatment. The selective delta -antagonist naltrindole (1.0 mg/kg) partially blocked tolerance to acute SNC80. Chronic SNC80 (1.0-10.0 mg/kg/day) also produced dose-dependent rightward shifts in the SNC80 dose-effect curve. Chronic SNC80 was more effective than acute SNC80 in producing tolerance. Moreover, tolerance to chronic SNC80 waned more slowly than to acute SNC80. Acute or chronic SNC80 (10.0 mg/kg/day) also produced cross-tolerance to the rate-decreasing effects of other delta -agonists (SNC162 and SNC243A) but not to µ- (morphine) or kappa  (U-50,488)-agonists. Changes in response rates or behavioral signs of withdrawal were not observed after the administration of opioid antagonists (i.e., naltrindole or naltrexone) in monkeys treated with SNC80. These data suggest that a pharmacologically selective tolerance develops to delta -agonists after both acute and chronic administration of SNC80 with little or no dependence.

1 Current Address: Wyeth-Ayerst Research, Wyeth Neuroscience, CN-8000, Princeton, NJ 08543-8000. E-mail: brandtm{at}war.wyeth.com

0022-3565/01/2992-0629$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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