The role of nitric oxide in the development of opioid withdrawal induced by naloxone after acute treatment with mu- and kappa-opioid receptor agonists.
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.
Capasso
A
A
Department of Pharmaceutical Sciences, University of Salerno, Italy. annacap@ponza.dia.unisa.it
Sorrentino
L
L
Pinto
A
A
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
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