Vol. 295, Issue 3, 1135-1141, December 2000

Supraspinal Antinociceptive Response to [D-Pen^2,5]-Enkephalin (DPDPE) Is Pharmacologically Distinct from That to Other -Agonists in the Rat¹

Graeme L. Fraser² , Amynah A. Pradhan, Paul B. S. Clarke and Claes Wahlestedt³

AstraZeneca R & D Montréal, Québec, Canada (G.L.F., C.W.); and Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (G.L.F., A.A.P., P.B.S.C., C.W.)

The cloned -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 (-selective: deltorphin II, DPDPE, pCl-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 pCl-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 pCl-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 pCl-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 -agonist mediates antinociception by a direct, nonselective interaction at µ-receptors or DPDPE interacts with a novel -subtype that, in turn, indirectly activates µ-receptors in the brain.