Modulation of the potency and efficacy of mu-mediated antinociception by delta agonists in the mouse

Previous reports have shown that [Leu⁵]enkephalin or [Met⁵] enkephalin, endogenous delta receptor agonists, or synthetic analogues of these substances, can respectively produce a positive (i.e., increase) or negative (i.e., decrease) modulation of the antinociceptive potency of mu agonists such as morphine; such modulation is believed to be the result of interactions between delta and mu receptors. In spite of these studies showing modulation of mu agonist potency, it is unclear whether delta agonists can similarly modulate the antinociceptive efficacy of mu agonists. This question was addressed by using several levels of nociceptive stimulus intensity in mice. As the nociceptive stimulus intensity increased, the i.c.v. morphine dose-response line was shown to be displaced progressively to the right with decreasing maximal effect (i.e., decreased efficacy) a pattern typical of partial agonists. In contrast, the antinociceptive potency and efficacy of i.c.v. etorphine was unaffected by increasing the stimulus intensity, suggesting that this compound has higher efficacy than morphine in this nociceptive assay. Coadministration of delta opioid agonists produced leftward ([D-Pen², D-Pen⁵]enkephalin) or rightward ([Met⁵]enkephalin) displacement of the morphine dose-response line (i.e., changes in potency). When the delta agonists were coadministered with morphine under conditions of high stimulus intensity, the maximal antinociceptive effects of i.c.v. morphine were increased or decreased from studies with morphine alone (i.e., change in efficacy). Both changes in potency and efficacy produced by the delta-agonists, but not the direct antinociceptive effects of morphine, were blocked by the delta antagonists, ICI 174,864, suggesting that modulation occurred via the delta receptor. The positive modulation of morphine efficacy was also observed in mice made highly tolerant to the antinociceptive effects of morphine after 7 days of morphine pretreatment, indicating that morphine potency and efficacy can be modulated by delta agonists under conditions of tolerance. At the low stimulus intensities i.c.v. codeine produced only approximately a 40% maximal antinociceptive response, indicating that this agonist may have lower efficacy than morphine. Coadministration of the delta agonist, [D-Pen²,D-Pen⁵] enkephalin with codeine resulted in a leftward displacement of the codeine dose-response line as well as a 100% antinociceptive effect. These data demonstrate that delta agonists can produce a modulation of both potency and efficacy of mu agonists such as morphine and codeine, and that this modulatory action occurs by way of the delta receptor. The results offer implications for clinical relief of pain by suggesting that equivalent pain relief can be obtained by 1) use of a reduced dose of mu agonist, or lower efficacy mu agonists, in combination with a delta agonist, and 2) the reinstatement of analgesic efficacy in patients highly tolerant to mu opiates by use of a combination of mu agonist and delta agonist.