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

The cloned δ-opioid receptor (DOR) is being investigated as a potential target for novel analgesics with an improved safety profile over μ-opioid receptor agonists such as morphine. The current study used antisense techniques to evaluate the role of DOR in mediating supraspinal antinociception in rats. All of the opioid agonists tested (δ-selective: deltorphin II, DPDPE, pCI-DPDPE, SNC80; μ-selective: DAMGO; i.c.v.) provided significant, dose-dependent antinociception in the paw pressure assay. Administration of a phosphodiester antisense oligonucleotide (i.c.v.) targeted against DOR inhibited antinociception in response to SNC80, deltorphin II, and pCI-DPDPE compared with mismatch and saline-treated controls. However, antisense treatment did not inhibit the response to DPDPE or DAMGO. In contrast, the highly selective μ-antagonist CTOP blocked antinociception in response to ED₈₀ concentrations of DAMGO and DPDPE, reduced the response to pCI-DPDPE, and did not alter the response to deltorphin II or SNC80. In total, these data suggest that DOR mediates the antinociceptive response to deltorphin II, SNC80, and pCI-DPDPE at supraspinal sites and further demonstrates that the DOR-mediated response to deltorphin II and SNC80 is independent of μ-receptor activation. Conversely, supraspinal antinociception in response to DPDPE is mediated by a receptor distinct from DOR; this response is directly or indirectly sensitive to μ-receptor blockade. The distinct pharmacological profile of DPDPE suggests that either this prototypical δ-agonist mediates antinociception by a direct, nonselective interaction at μ-receptors or DPDPE interacts with a novel (δ-subtype that, in turn, indirectly activates μ-receptors in the brain.