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Vol. 286, Issue 2, 812-824, August 1998
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard
Medical School, Belmont, Massachusetts
There is accumulating evidence that kappa opioid
agonists attenuate cocaine's behavioral effects, and we recently
reported that the kappa opioid agonists
ethylketocyclazocine (EKC) and U50-488 decreased cocaine
self-administration by rhesus monkeys. In the present study, we first
examined the effects of acute intramuscular administration of six
kappa opioid agonists on responding maintained by food
under an FR30 schedule. Each kappa agonist produced
dose-dependent decreases in schedule controlled behavior, and the
relative potencies were enadoline 
bremazocine > Mr2033 cyclazocine = spiradoline > PD117302. We then
studied the effects of chronic administration of these
kappa agonists in monkeys responding under a second
order schedule of food delivery and cocaine self-administration. The effects of 10 days of intravenous treatment with three arylacetamides [enadoline (0.00032-0.0032 mg/kg/hr), (
) spiradoline (0.0032-0.018 mg/kg/hr), PD117302 (0.032-0.32 mg/kg/hr)] and three benzomorphans [bremazocine (0.00032-0.0032 mg/kg/hr), Mr2033 (0.0032-0.032
mg/kg/hr), cyclazocine (0.001-0.10 mg/kg/hr)] were compared with
saline treatment. Enadoline (0.001 and 0.0032 mg/kg/hr), bremazocine
(0.0032 mg/kg/hr) and Mr2033 (0.01 and 0.0032 mg/kg/hr) significantly
decreased cocaine self-administration (0.01 mg/kg/injection) (P < .05-.01). Cyclazocine (0.001-0.10 mg/kg/hr), () spiradoline
(0.0032-0.018 mg/kg/hr) and PD117302 (0.032-0.32 mg/kg/hr) had no
significant effects on cocaine self-administration across the
dose-range studied. When gradually increasing doses of enadoline
(0.00032-0.01 mg/kg/hr) or Mr2033 (0.0032-0.032 mg/kg/hr) were
administered over 28 consecutive days, cocaine self-administration was
dose-dependently decreased in all monkeys. Food-maintained responding
was usually decreased at doses that decreased cocaine
self-administration. Adverse side effects (emesis and sedation) were
transient, and laboratory indices of hematology and blood chemistry
were normal throughout chronic enadoline and Mr2033 treatment. These
data extend our earlier findings with EKC and U50,488 and suggest that
kappa opioid agonists may be a useful approach to the
development of new pharmacological treatments for cocaine dependence.
The extent to which undesirable side effects may limit their clinical
usefulness remains to be determined.
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