Abstract

When the opioid agonist morphine is given chronically and systemically to mice by pellet implantation for 3 days, the animals develop substantial tolerance to the antinociceptive effect of a test dose of morphine given systemically. When the test dose is administered to the spinal cord, however, very little tolerance is observed. We tested six strains of mice differing in the degree to which they develop systemic tolerance to morphine and found that none of them developed significant tolerance to spinal morphine. However, most of these strains did develop substantial spinal tolerance to antinociception induced by the selective μ-agonist [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO) and by the selective δ-agonist [d-Pen²,d-Pen⁵]-enkephalin (DPDPE). Moreover, in naı̈ve animals, the antinociceptive effect of both DAMGO and DPDPE was blocked byd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH₂, a selective μ-antagonist, indicating that both agonists mediate antinociception in the spinal cord through μ-receptors. In addition to directly mediating antinociception, however, DPDPE potentiated the antinociceptive activity of DAMGO in the spinal cord of naı̈ve animals, and this antinociception was blocked by the δ-antagonist H-TyrTicPsi[CH₂NH]Phe-Thr-OH (TIPPψ), indicating mediation through δ-receptors. In contrast, in tolerant animals, TIPPψ enhanced the antinociception of DAMGO. These results thus demonstrate not only that μ- and δ-opioid receptors interact in naı̈ve animals, but that the nature of this interaction changes during tolerance, from a potentiation to an inhibition. The lack of tolerance to spinal morphine may result from the ability of morphine to act as a partial antagonist at δ-receptors.