Effects of morphine on sprouting of locus coeruleus fibers in the neonatal rat

Acutely (by 48 h), as well as after one month survival, morphine (20 mg/kg) significantly potentiated the extent of noradrenergic degeneration in the forebrain of newborn rats caused by 50 mg/kg of 6-hydroxydopamine (6-OHDA) s.c. This was associated with increased regenerative sprouting in the cerebellum and pons-medulla as determined by measurements of norepinephrine (NE) concentration and [³H]NE uptake. This potentiating effect of morphine was not seen in either forebrain, brainstem, or cerebellum if it was administered to newborn rats with a 24-h delay following 6-OHDA. Clonidine (0.1 mg/kg) which, like morphine, decreases locus coeruleus activity, acutely tended to enhance the acute degenerative effects of 6-OHDA, whereas yohimbine (5 mg/kg), an α₂-antagonist which increases locus coeruleus activity, significantly attenuated the acute effect of 6-OHDA in the forebrain. In order to determine whether morphine directly alters the regenerative growth of neurons independently of its acute interaction with 6-OHDA, we explored its effect on the collateral sprouting of locus coeruleus projections induced by midcollicular hemisection. Unilateral midcollicular hemisection in neonates resulted, at 2 months of age, in a 91% reduction of NE concentration in the ipsilateral forebrain and an increase in the ipsilateral cerebellar hemisphere to over 200% of control. Significant increases of a slightly smaller magnitude were found in the cerebellar vermis, pons-medulla and the colliculi. Morphine given simultaneously with the lesion significantly attenuated this collateral sprouting in the cerebellar hemisphere and colliculi. These results indicate that morphine potentiates the initial toxicity of 6-OHDA, perhaps by altering activity of locus coeruleus neurons. Because of the well-known reciprocal relationship between denervation of noradrenergic fibers in the forebrain and sprouting of their collaterals in the cerebellum and pons-medulla, the combined treatment results in increased innervation to these hindbrain regions. However, as shown in the hemisection experiment, it is apparent that morphine also prevents axonal sprouting by locus coeruleus neurons from achieving its full extent.