Behavioural effects of selective ?-, ?-, and ?-opioid agonists in neonatal rats

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Abstract
The behavioural effects of selective μ-, κ- and δ-opioid agonists in 5-, 10- and 20-day-old rats were investigated by observational analysis. The predominant response to μ-agonists was behavioural depression. High doses (10 mg/kg IP) of morphine and DAGO (d-Ala2, NMe-Phe4, Glyol5-enkephalin) produced overt sedation in all the age groups and also induced catalepsy which was particularly apparent in the 5- and 10-day-old animals. These compounds did not produce any signs of behavioural activation in the neonatal rats. In contrast, rat pups treated with the κ-agonists U50,488H and PD 117,302 (1,10 mg/kg IP) exhibited marked hyperactivity with increases in wall-climbing and locomotion. Sedative effects of the highest dose of the κ-agonists began to emerge, however, as the animals grew older, resulting in significant decreases in behaviours such as gnawing and grooming at 20 days of age. The κ-agonist (+)-tifluadom (0.1–10 mg/kg), but not its corresponding (-)-isomer, produced an increase in activity in 5-day-old rats, thus extending the observations made with U50,488H and PD 117,302 and establishing the stereoselective nature of the response. The involvement of κ-receptors in opioid-induced hyperactivity was further substantiated by using a variety of opioid antagonists. In this context, the increase in activity induced by U50,488H (10 mg/kg) in 5-day-old neonates was attenuated by naltrexone (1 mg/kg IP) but not by larger doses (10 mg/kg) of either M8008 (which has low affinity for κ-receptors) or the selective δ-receptor antagonist ICI 174,864. Finally, DPDPE (d-Pen2, d-Pen5-enkephalin) which acts selectively at δ-opioid receptors, did not exert any behavioural effects in either the 5-, 10- or 20-day-old rat pups at doses of up to 10 mg/kg. These results demonstrate behavioural effects of μ- and κ-but not δ-agonists in neonatal rats. There is a clear differentiation between μ- and κ-receptor effects and both μ- and κ-mediated behaviours show dissimilarities from the adult profile.