Supraspinal antinociceptive response to [D-Pen(2,5)]-enkephalin (DPDPE) ispharmacologically distinct from that to other delta-agonists in the rat

The cloned delta -opioid receptor (DOR) is being investigated as a potentia l target for novel analgesics with an improved safety profile over mu -opio id receptor agonists such as morphine. The current study used antisense tec hniques to evaluate the role of DOR in mediating supraspinal antinociceptio n in rats. All of the opioid agonists tested (delta -selective: deltorphin II, DPDPE, pCI-DPDPE, SNC80; mu -selective: DAMGO; i.c.v.) provided signifi cant, dose-dependent antinociception in the paw pressure assay. Administrat ion of a phosphodiester antisense oligonucleotide (i.c.v.) targeted against DOR inhibited antinociception in response to SNC80, deltorphin II, and pCl -DPDPE compared with mismatch and saline-treated controls. However, antisen se treatment did not inhibit the response to DPDPE or DAMGO. In contrast, t he highly selective mu -antagonist CTOP blocked antinociception in response to ED80 concentrations of DAMGO and DPDPE, reduced the response to pCl-DPD PE, and did not alter the response to deltorphin II or SNC80. In total, the se data suggest that DOR mediates the antinociceptive response to deltorphi n II, SNC80, and pCl-DPDPE at supraspinal sites and further demonstrates th at the DOR-mediated response to deltorphin II and SNC80 is independent of m u -receptor activation. Conversely, supraspinal antinociception in response to DPDPE is mediated by a receptor distinct from DOR; this response is dir ectly or indirectly sensitive to mu -receptor blockade. The distinct pharma cological profile of DPDPE suggests that either this prototypical delta -ag onist mediates antinociception by a direct, nonselective interaction at mu -receptors or DPDPE interacts with a novel delta -subtype that, in turn, in directly activates mu -receptors in the brain.