Pleiotrophin and midkine are two recently discovered growth factors that promote survival and differentiation of catecholaminergic neurons. Chronic opioid stimulation has been reported to induce marked alterations of the locus coeruleus–hippocampus noradrenergic pathway, an effect that is prevented when opioids are coadministered with the α2-adrenoceptor antagonist yohimbine. The present work tries to examine a possible link between yohimbine reversal of morphine effects and pleiotrophin/midkine activation in the rat hippocampus by studying the levels of expression of pleiotrophin and midkine in response to acute and chronic administration of morphine, yohimbine and combinations of both drugs. Pleiotrophin gene expression was not altered by any treatment; however midkine mRNA levels were increased after chronic treatment with morphine. Chronic administration of yohimbine alone also increased midkine expression levels, whereas yohimbine and morphine administered together exhibited summatory effects on the upregulation of midkine expression levels. The data suggest that midkine could play a role in the prevention of opioid-induced neuroadaptations in hippocampus by yohimbine.