title: The role of nitric oxide in the development of opioid withdrawal induced by naloxone after acute treatment with mu- and kappa-opioid receptor agonists.
abstract: The present study investigated the possible role of nitric oxide (NO) in the development of the withdrawal contractures of guinea pig isolated ileum after acute activation of mu- and kappa-opioid receptors. After a 4-min in vitro exposure to morphine (mu-opioid receptor preferring, but not selective, agonist), [D-Ala2-N-methyl-Phe4-Gly5-ol-]enkephalin (DAMGO; highly selective mu-opioid receptor agonist), or trans(+/-)-3,4-dichloro-N-methyl-N-2(1-pyrrolidynyl)cyclohexyl-ben zeneacetamide (U50-488H; highly selective kappa-opioid receptor agonist), the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. L-N(G)-nitro arginine methyl ester (3-300 microM) injected 10 min before the opioid receptor agonists was able dose dependently to reduce the naloxone-induced contraction after exposure to mu- and kappa-opioid receptor agonists whereas D-N(G)-nitro arginine methyl ester at the same concentrations did not affect it. The inhibitory effect of L-N(G)-nitro arginine methyl ester on morphine, DAMGO and U50-488H withdrawal was dose dependently reversed by L-arginine (3-300 microM) but not by D-arginine. Finally, glyceryl trinitrate on its own (3-300 microM) significantly increased the naloxone-induced contraction after exposure to mu- and kappa-opioid receptor agonist and it was also able to reverse the inhibition of opioid withdrawal caused by L-N(G)-nitro arginine methyl ester. These results provide evidence that NO has a role in the development of opioid withdrawal and that mu- or kappa-opioid receptors are involved.
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, Italy. annacap@ponza.dia.unisa.it
authors.forename: A
authors.initials: A
authors.lastname: Capasso
authors.forename: L
authors.initials: L
authors.lastname: Sorrentino
authors.forename: A
authors.initials: A
authors.lastname: Pinto
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000009:adverse effects; D000109:Acetylcholine / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000009:adverse effects; D009119:Muscle Contraction / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D009270:Naloxone / Q000009:adverse effects / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D009294:Narcotics / Q000009:adverse effects*; D009569:Nitric Oxide / Q000502:physiology*; D005996:Nitroglycerin / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013375:Substance Withdrawal Syndrome / Q000209:etiology* / Q000517:prevention & control; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D004745:Enkephalins; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014665:Vasodilator Agents; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009569:Nitric Oxide; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D005996:Nitroglycerin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester