Pharmacological evidence for the role of nitric oxide in the modulation of stress-induced anxiety by morphine in rats

The present study evaluated the effects of the opioid agonist, morphine on stress induced anxiogenesis and the possible involvement of nitric oxide (NO) in such effects in rats. Acute restraint stress consistently induced an anxiety-like response in the elevated plus maze test, i.e. reduced number of open arm entries and time spent in the open arms as compared to controls. Pretreatment with morphine (1 and 5 mg/kg), attenuated the restraint stress induced anxiogenic response in a dose related manner. Restraint stress induced neurobehavioral suppression was associated with reductions in brain NO oxidation products (NOx) levels, which were also reversed with morphine. Interaction studies showed that sub-effective doses of morphine and L-arginine (a NO precursor) had synergistic effects on stress induced elevated plus maze activity and brain NOx, whereas, L-NAME (a NO synthase inhibitor) neutralized these effects of morphine. Repeated restraint stress (x5) induced adaptative changes as evidenced by normalization of behavioral suppression and elevations in brain NOx, as compared to acute stress. Pretreatment with morphine in combination with repeated stress (x5) showed potentiating effects in the induction of behavioral adaptation in the elevated plus maze and elevations in brain NOx, as compared to repeated stress alone. Further, L-NAME, when administered prior to morphine, blocked this effect of morphine on stress adaptation. These results suggest differential morphine-NO interactions during acute and repeated restraint stress. (C) 2011 Elsevier B.V. All rights reserved.