Morphine Treatment in Neonate Rats Increases Exploratory Activities: Reversal by Antagonist D2 Receptor

Abstract

Aims: Morphine treatment in early life is a practice widely used in paediatric intensive care units. However, the consequences of this treatment on behavioural responses throughout life have been poorly studied. It is well known that behavioural symptoms after morphine exposure are presumed to depend on certain changes in the dopaminergic system, and there is a strong evidence of the involvement of D2 receptor. In this way, our objective was to evaluate whether 5 µg morphine administration, once daily for 7 days in 8-day-old rats (P8), alters exploratory and anxiolitic-like behaviours over short- (P16) and medium-term (P30) periods in the open-field (OF) and elevated-plus maze (EPM) tests, and to verify the involvement of the D2 receptor in the behaviour changes. Place of Study: All experiments were performed at Animal Experimentation Unit of Hospital de Clínicas de Porto Alegre. The experimental protocol was approved by the Institutional Committee for Animal Care and Use (GPPG-HCPA protocol No: 08345). Methodology: Wistar rats with 8-day-old (P8) received 5 µg of morphine administration, once daily for 7 days. The exploratory and anxiolitic-like behavious were analyzed in P16 and P30 by OF and EPM tests. At the ages where we observed significant differences in behaviour responses in both tests, the control and morphine groups were subdivided into three groups, each one designed to evaluate the effect of 0.2 mg/kg, 0.5 mg/kg or vehicle of i.p. administration of a dopamine D2 antagonist receptor (Haloperidol). Results: At short-term (P16) morphine group showed an increase in grooming, as well increase in exploratory behaviours at P30 in the OF test. In addition, anxiolytic-like behaviours were observed in the morphine group, such as increase of percentage of open arms behaviours and non-protected head dipping at medium-term in the EPM test. At the ages at which differences in behaviours were observed, both groups (control and morphine) received D2 antagonist receptor (haloperidol) 30 min before each test. All behaviours changes seen in the morphine group at P30 were totally reversed by haloperidol administration. Conclusion: Our findings demonstrate that morphine treatment in neonate period promotes behavioural changes in OF and EPM at P16 and P30. However, only alterations observed at P30 depend, at least in part, of dopaminergic system, particularly of the D2 receptor.