SELECTIVE-INHIBITION OF [D-ALA(2), GLU(4)]DELTORPHIN ANTINOCICEPTION BY SUPRASPINAL, BUT NOT SPINAL, ADMINISTRATION OF AN ANTISENSE OLIGODEOXYNUCLEOTIDE TO AN OPIOID DELTA-RECEPTOR

Evidence in vivo has suggested the existence of subtypes of the delta opioid receptor (DOR), which have been termed delta(1) and delta(2). T hese proposed DOR subtypes are thought to be activated by [D-Pen(2), D -Pen(5)]enkephalin (DPDPE, delta(i)) and [D-Ala(2), Glu(4)]deltorphin (delta(2)). Recent work in which an antisense oligodeoxynucleotide (ol igo) to a cloned DOR was administered by the intrathecal (i.th.) route has demonstrated a reduction in the antinociceptive actions of both i .rh. DPDPE and [D-Ala(2), Glu(4)]-deltorphin, but not of [D-Ala(2), NM Phe(4), Gly-ol]enkephalin (DAMGO, mu agonist) in mice. The present inv estigation has extended these observations by administering the same D OR antisense oligo sequence by the intracerebroventricular (i.c.v.) ro ute and evaluating the antinociceptive actions of i.c.v. agonists sele ctive for delta, mu and kappa receptors. I.th. treatment with DOR anti sense oligo, but not mismatch oligo, significantly inhibited the antin ociceptive actions of both i.th. DPDPE and [D-Ala(2), Glu(4)]deltorphi n but not of i.th. DAMGO or U69,593 (kappa agonist), confirming previo us data. In contrast, i.c.v. DOR antisense oligo, but not mismatch oli go, selectively inhibited the antinociceptive response to i.c.v. [D-Al a(2), Glu(4)]deltorphin without altering the antinociceptive actions o f i.c.v. DPDPE, DAMGO or U69,593. The data suggest that the cloned DOR corresponds to that pharmacologically classified as delta(2) and furt her, suggest that this delta receptor subtype may play a major role in eliciting spinal delta-mediated antinociception.