Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor.
The nitric oxide synthase inhibitor NG-nitro-L-arginine (NO2Arg) blocks morphine tolerance in mice. After implantation of morphine pellets the analgesic response decreases from 100% on the first day to 0% on the third. Coadministration of NO2Arg along with the pellets markedly retards the development of tolerance; 60% of mice are analgesic after 3 days, and 50% of mice are analgesic after 5 days. In a daily injection paradigm the analgesic response to morphine is reduced from 60% to 0% by 5 days. Concomitant administration of morphine along with NO2Arg at doses of 2 mg/kg per day prevents tolerance for 4 weeks. A single NO2Arg dose retards morphine tolerance for several days, and dosing every 4 days is almost as effective as daily NO2Arg. NO2Arg slowly reverses preexisting tolerance over 5 days despite the continued administration of morphine along with NO2Arg. NO2Arg also reduces dependence and reverses previously established dependence. NO2Arg does not prevent tolerance to analgesia mediated by the kappa 1 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]- benzene-acetamide (U50,488H) or the kappa 3 agent naloxone benzoylhydrazone, indicating a selective action of NO in the mechanisms of mu tolerance and dependence.
Kolesnikov
Y A
YA
Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, Department of Neurology and Neuroscience, Cornell University Medical College, New York, NY 10021.
Pick
C G
CG
Ciszewska
G
G
Pasternak
G W
GW
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome; D013997:Time Factors
D000700:Analgesics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D019335:Nitroarginine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases