oxadiazoles and Opioid-Related-Disorders

Previous studies have shown that activation of N-methyl-D-aspartate (NMDA) receptors and formation of nitric oxide (NO) contributes to the hyperactivity of locus coeruleus (LC) noradrenergic neurons and behavioural symptoms seen during opioid withdrawal. However, the role of soluble guanylyl cyclase (sGC), the 'physiological' target of NO, in this phenomenon is unclear. In this study, the effect of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a highly selective sGC inhibitor, on the naloxone-precipitated morphine withdrawal was examined using differential normal pulse voltammetry (DNPV) to measure LC activity, in vivo microdialysis to measure glutamate/aspartate release response, and behavioural assessment to evaluate withdrawal symptoms. In halothane-anaesthetized rats, acute intracerebroventricular (i.c.v.) morphine (10 microg) reduced the catecholamine oxidation current (CA.OC) (54.5+/-4.9% of baseline). Naloxone (2 mg/kg, i.v.) reversed this action of morphine and produced a rebound increase in CA.OC (136.1+/-6.0% of baseline), representing acute morphine withdrawal. Administration of ODQ (200 nmol, i.c.v.) blocked this response without affecting acute morphine action. In animals chronically treated with morphine (15 microg/microl/h, i.c.v., 5 days), naloxone significantly increased both the CA.OC signal (270.0+/-19.6% of baseline) and the release of L-glu (193+/-30.4%) and L-asp (221.5+/-28.4%) above baseline. These responses were attenuated in animals pretreated with ODQ. In unanaesthetized chronic morphine dependent rats, ODQ treatment suppressed the signs of withdrawal precipitated by naloxone (10 mg/kg). Taken together, the results of this study suggest that sGC plays an intermediary role in the genesis of LC neuronal hyperactivity and behavioural signs of morphine withdrawal.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Cyclic GMP; Enzyme Inhibitors; Excitatory Amino Acids; Guanylate Cyclase; Locus Coeruleus; Male; Morphine; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Oxadiazoles; Quinoxalines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome