Nitric oxide synthase inhibitors attenuate acute and chronic morphine withdrawal response in the rat locus coeruleus: an in vivo voltammetric study

Abstract

Previous studies have demonstrated that activation of N-methyl-d-aspartate (NMDA) and non-NMDA receptors contributes to the hyperactivity of noradrenergic neurons of the locus coeruleus (LC) associated with opioid and non-opioid drug withdrawal syndromes. Using an in vivo voltammetric approach, we have examined the role of nitric oxide (NO), which mediates NMDA receptor function, in this withdrawal-induced LC hyperactivity. In the anaesthetized rat, acute morphine treatment (10 μg, i.c.v.) suppressed (55.7 ± 4.4% of baseline) the catechol oxidation current (CA-OC) recorded from the LC using differential normal pulse voltammetry (DNPV). A subsequent intravenous injection of naloxone (2 mg/kg, i.v.) reversed the drug-induced inhibition of LC response and produced an increase (118.9 ± 2.3% of baseline) in CA-OC above baseline, indicative of an acute withdrawal response. Systemic (100 mg/kg) and intracerebroventricular (i.c.v.) (100 μg) pretreatment of animals with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) blocked the naloxone-induced LC withdrawal response without influencing the inhibitory effect of morphine on LC activity. In animals chronically infused with morphine (15 μg/h, i.c.v., 5 days) a naloxone challenge (2 mg/kg, i.v.) produced significant increase (253.7 ± 19.3% of baseline) in CA-OC signal. This LC withdrawal response was significantly reduced by pretreatment with l-NAME (100 μg, i.c.v.) or Nω-nitro-l-arginine (l-NOARG 10 μg, i.c.v.). In unanaesthetized animals pretreated with chronic morphine, systemic (100 mg/kg) and central l-NAME (100 μg) pretreatment suppressed some of the behavioural signs of withdrawal precipitated by naloxone (10 mg/kg) injection. As doses of the NOS inhibitors used in this study have previously been reported to produce significant inhibition of brain NOS activity, their effect on opioid withdrawal response most likely is due to NOS inhibition. The results of this study indicate that NO plays an intermediary role in the LC neuronal hyperactivity associated with both acute and chronic morphine withdrawal.