Neuronal nitric oxide modulates morphine antinociceptive tolerance by enhancing constitutive activity of the mu-opioid receptor
Heinzen EL, Booth RG, Pollack GM.
Division of Drug Delivery and Disposition,
School of Pharmacy,
University of North Carolina,
Chapel Hill, NC 27599-7360, USA.
Biochem Pharmacol. 2005 Feb 15;69(4):679-88.


NO is a key mediator of morphine antinociceptive tolerance. This work was conducted to evaluate the specific effects of NO on mu-opioid receptor activity. To investigate the effects of morphine- and L-arginine (the NO precursor)-induced increases in NO, five groups of rats were treated with saline, l-arginine (100-, 300-, or 500-mg/kg/h), or morphine 3-mg/kg/h for 8h on Day 1; brain tissue was collected on Day 2. To evaluate the effects of additional increases in NO on morphine-induced alterations of the mu-opioid receptor, six groups of rats were treated with 8-h intravenous infusions for two consecutive days as per the following scheme (Day 1:Day 2): saline:saline (control); saline:morphine 3-mg/kg/h (tolerant); L-arginine 500-mg/kg/h:saline (NO control); L-arginine 100-mg/kg/h:morphine 3-mg/kg/h; L-arginine 300-mg/kg/h:morphine 3-mg/kg/h; and L-arginine 500-mg/kg/h:morphine 3-mg/kg/h (supertolerant). Brain tissue was collected at the end of Day 2. The time course of effects on morphine-induced receptor alterations due to increased NO also was evaluated. Brain tissue was analyzed for changes in radioligand (agonist and antagonist) binding and [(35)S]GTPgammaS binding (agonist and antagonist). In the absence of agonist exposure, NO produced an alteration in the mu-opioid receptor that increased receptor activity. In the presence of agonist, NO increased constitutive activation of the mu-opioid receptor and reduced the ability of a selective mu-opioid agonist to activate the mu-opioid G-protein-coupled receptor; these molecular effects occurred in a time course consistent with the development of antinociceptive tolerance. This work establishes important NO-induced alterations in mu-opioid receptor functionality, which directly lead to the development of opioid antinociceptive tolerance.
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