EFFECT OF SUPRASPINAL ANTISENSE OLIGODEOXYNUCLEOTIDE TREATMENT ON DELTA-OPIOID RECEPTOR MESSENGER-RNA LEVELS IN MICE

Studies in vivo demonstrate that antisense oligodeoxynucleotide (ODN) treatment specifically reduces the functions mediated by numerous cent ral nervous system (CNS) receptors, including opioid receptors. Howeve r, the effects of antisense ODN on the opioid receptor mRNA target, it self are rarely examined. In the present study, the effect of supraspi nal antisense ODN administration on delta-opioid receptor (DOR) mRNA l evels in selected CNS regions, was investigated in mice. ODN targeting a 20-nucleotide sequence of the DOR mRNA transcript was administered by intracerebroventricular (i.c.v.) injection twice daily for 3 days. First, to confirm that antisense ODN treatment decreases DOR function in this system, antinociception produced by DOR-selective agonist [D-A la(2)]deltorphin II was assessed on day 4. A 2-fold reduction in [D-Al a(2)]deltorphin II potency was revealed in antisense ODN-treated mice compared to mice receiving control treatments. DOR mRNA levels in sele cted CNS regions which either mediate antinociception; medial thalamus (MThal), periaqueductal gray (FAG), frontal cortex (FCtx) and spinal cord (SpC) or exhibit relatively high levels of DOR mRNA; nucleus accu mbens (Acb) and caudate-putamen (CPu) were then quantitated by solutio n hybridization. Levels of DOR mRNA in antisense ODN-treated mice were not different from levels in mice treated with saline vehicle, which ranged from 0.07 pg/mu g total RNA in MThal and PAG to 0.26 pg/mu g to tal RNA in CPu. These results are both consistent with previous report s that antisense oligodeoxynucleotide (ODN) treatment down-regulates D OR protein in vivo and indicate that this down-regulation is not assoc iated with altered DOR mRNA levels. (C) 1997 Elsevier Science B.V.