Ultralong lasting single-dose tolerance to chloroxymorphamine (COA), an opioid receptor alkylating agonist

T. P. Caruso, A. E. Takemori, D. L. Larson, Philip S Portoghese

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Like chlornaltrexamine (CNA), but unlike oxymorphone (OX) or naltrexone (NX), COA (6 x 10-7 M) produced an inhibition (83.9%) of 3H-NX binding in 100 mM NaCl solution, which was only slightly reduced (49.3%) by subjecting the homogenate to centrifugation, resuspension, and 8 hr of dialysis. Icv COA (4mol/mouse) evoked an analgesic response that peaked at 1 hr after injection and lasted for 4 hr; whereas, the analgesic effect of an equipotent dose of OX (4mol/mouse) lasted for only 1 hr. When analgesia was tested 1 hr after icv COA an ED50 of 1.8 mol/mouse was obtained. Naloxone (N) (1 mg/kg) sc, 10 min prior to icv COA significantly increased the ED50 to 4.8 mol/mouse. COA also significantly increased the morphine ED50 for up to 3 days. This increase in morphine ED50 may be due to either antagonism or X-tolerance. The increase in morphine ED50 induced by COA and CNA is probably not due to an effect on morphine distribution since brain levels of morphine were unaffected 24 hr after icv COA or CNA. N was given sc at 6, 12, 24, and 72 hr after COA and withdrawal jumping was determined for 15 min after injection. Jumping was caused by N injections at 24 and 72 hr after COA. Our evidence suggests that COA produces a long lasting state of tolerance and dependence after a single dose.

Original languageEnglish (US)
JournalFederation Proceedings
Issue number3 I
StatePublished - Jan 1 1979


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