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In view of the co-localization of spinal δ- and κ-opioid receptors, we have investigated the interaction of selective opioid receptor agonists and antagonists in the spinal cord of mice in order to determine if these receptors are organized as heteromers. The finding that norbinaltorphimine (κ) antagonized [d-Pen2,5]enkephalin (δ1), but not deltorphin II (δ2), strongly suggests that the putative δ1-subtype is a δ–κ heteromer. Studies with selective opioid receptor (ant)agonists support this conclusion. [Copyright &y& Elsevier]

We have determined the effect of naltrexone, naloxone, [D-Ala2,D-Leu5]enkephalin (DADLE), and morphine on the mu-S196A opioid receptor knock-in and mu-opioid receptor knockout mouse vas deferens preparations. The antagonists, naltrexone and naloxone, exhibited agonist activity and possessed IC50 values that were 14- and 37-fold greater than morphine on the S196A preparation. Morphine was found to be threefold more potent at S196A relative to wild-type mu-opioid receptor. The mouse vas deferens data suggest that S196 in transmembrane helix 4 of the mu-opioid receptor modulates efficacy. It is proposed that this may be due to decreased dimerization of the receptor. Identical IC50 values of DADLE obtained on the wild-type, S196A knock-in, and mu-opioid receptor knockout preparations support the absence of mu-delta heterodimers in the mouse vas deferens.

In view of the co-localization of spinal delta- and kappa-opioid receptors, we have investigated the interaction of selective opioid receptor agonists and antagonists in the spinal cord of mice in order to determine if these receptors are organized as heteromers. The finding that norbinaltorphimine (kappa) antagonized [D-Pen(2,5)]enkephalin (delta(1)), but not deltorphin II (delta(2)), strongly suggests that the putative delta(1)-subtype is a delta-kappa heteromer. Studies with selective opioid receptor (ant)agonists support this conclusion.