Antisense oligodeoxynucleotides to opioid mu and delta receptors reduced morphine dependence in mice: role of delta-2 opioid receptors.

Repeated intracerebroventricular injections of antisense oligodeoxynucleotides (ODNs) were used to selectively restrict the expression of cloned mu and delta opioid receptors (OR) in the mouse brain. Reduction of mu and delta OR-like immunoreactivity was observed in brain structures of experimental mice. A random-sequence ODN used as a control showed no effect. ODNs to OR decreased radiolabeling of neural structures after intracerebroventricular injection of 125I-immunoglobulins G directed to mu or delta OR. The potencies of opioids binding the mu OR, [D-Ala2,N-MePhe4,Gly-ol5]enkephalin and morphine were significantly attenuated in mice injected with ODNs to this receptor, an effect not seen for the delta OR-binding agonists, [D-Pen2,5]enkephalin and [D-Ala2]deltorphin II. In morphine-dependent mice, ODNs to mu OR reduced the incidence of naloxone-precipitated withdrawal jumping, body weight loss and diarrhea. The ODN directed to nucleotides 7-26 of the delta OR mRNA selectively impaired antinociception induced by [D-Ala2]deltorphin II (delta-2), but not that of [D-Pen2,5]enkephalin (delta-1) or morphine. It also diminished the incidence of withdrawal signs precipitated by naloxone in morphine-dependent mice. Thus, the cloned mu OR mediates morphine-evoked antinociception as well as physical dependence. The involvement of delta-2 OR in the development and/or expression of morphine dependence is suggested.