Blockade of Tolerance to Morphine but not to κ Opioids by a Nitric Oxide Synthase Inhibitor

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-06, Vol.90 (11), p.5162-5166
• Main Authors: Kolesnikov, Yuri A., Pick, Chaim G., Ciszewska, Grazyna, Pasternak, Gavril W.
• Format: Article
• Language: English
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amino Acid Oxidoreductases - antagonists & inhibitors; Analgesia; Analgesics; Analgesics - pharmacology; Animals; Arginine - administration & dosage; Arginine - analogs & derivatives; Arginine - pharmacology; Biological and medical sciences; Blood pressure; Dosage; Drug Administration Schedule; Drug Tolerance; Male; Medical sciences; Mice; Mice, Inbred Strains; Morphine; Morphine - administration & dosage; Morphine - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nitric Oxide Synthase; Nitroarginine; Opioid analgesics; Oxides; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology; Pharmacology. Drug treatments; Pyrrolidines - pharmacology; Receptors, Opioid, kappa - antagonists & inhibitors; Substance Withdrawal Syndrome; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.11.5162

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 κ1agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]- benzene-acetamide (U50,488H) or the κ3agent naloxone benzoylhydrazone, indicating a selective action of NO in the mechanisms of μ tolerance and dependence.