The role of nitric oxide in the development of opioid withdrawal induced by naloxone after acute treatment with μ- and k-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 μ- and k-opioid receptors. After a 4-min in vitro exposure to morphine (μ-opioid receptor preferring, but not selective, agonist), [d-Ala2-N-methyl-Phe4-Gly5-ol-]enkephalin (DAMGO; highly selective μ-opioid receptor agonist), or trans(±)-3,4-dichloro-N-methyl-N-2(1-pyrrolidynyl)cyclohexyl-benzeneacetamide (U50-488H; highly selective k-opioid receptor agonist), the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. l-NG-nitro arginine methyl ester (3–300 μM) injected 10 min before the opioid receptor agonists was able dose dependently to reduce the naloxone-induced contraction after exposure to μ- and k- opioid receptor agonists whereas d-NG-nitro arginine methyl ester at the same concentrations did not affect it. The inhibitory effect of l-NG-nitro arginine methyl ester on morphine, DAMGO and U50-488H withdrawal was dose dependently reversed by l-arginine (3–300 μM) but not by d-arginine. Finally, glyceryl trinitrate on its own (3–300 μM) significantly increased the naloxone-induced contraction after exposure to μ- and k-opioid receptor agonist and it was also able to reverse the inhibition of opioid withdrawal caused by l-NG-nitro arginine methyl ester. These results provide evidence that NO has a role in the development of opioid withdrawal and that μ- or k- opioid receptors are involved.