ANTISENSE OLIGODEOXYNUCLEOTIDES TO OPIOID MU-RECEPTOR AND DELTA-RECEPTOR REDUCED MORPHINE-DEPENDENCE IN MICE - ROLE OF DELTA-2 OPIOID RECEPTORS

Repeated intracerebroventricular injections of antisense oligodeoxynuc leotides (ODNs) were used to selectively restrict the expression of cl oned mu and delta opioid receptors (OR) in the mouse brain. Reduction of mu and delta OR-like immunoreactivity was observed in brain structu res of experimental mice. A random-sequence ODN used as a control show ed no effect. ODNs to OR decreased radiolabeling of neural structures after intracerebroventricular injection of I-125-immunoglobulins G dir ected to mu or delta OR, The potencies of opioids binding the mu OR, [ D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin and morphine were significant ly attenuated in mice injected with ODNs to this receptor, an effect n ot seen for the delta OR-binding agonists, [D-Pen(2,5)]enkephalin and [D-Ala(2)]deltorphin II. In morphine-dependent mice, ODNs to mu OR red uced the incidence of naloxone-precipitated withdrawal jumping, body w eight loss and diarrhea. The ODN directed to nucleotides 7-26 of the d elta OR mRNA selectively impaired antinociception induced by [D-Ala(2) ]deltorphin II (delta-2), but not that of [D-Pen(2,5)]enkephalin (delt a-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 de pendence. The involvement of delta-2 OR in the development and/or expr ession of morphine dependence is suggested.