Morphine tolerance in spinal cord is due to interaction between mu- and delta-receptors

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 mu-agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) and by the selective delta-agonist [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE). Moreover, in naïve animals, the antinociceptive effect of both DAMGO and DPDPE was blocked by D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2), a selective mu-antagonist, indicating that both agonists mediate antinociception in the spinal cord through mu-receptors. In addition to directly mediating antinociception, however, DPDPE potentiated the antinociceptive activity of DAMGO in the spinal cord of naïve animals, and this antinociception was blocked by the delta-antagonist H-TyrTicPsi[CH(2)NH]Phe-Thr-OH (TIPPpsi), indicating mediation through delta-receptors. In contrast, in tolerant animals, TIPPpsi enhanced the antinociception of DAMGO. These results thus demonstrate not only that mu- and delta-opioid receptors interact in naïve 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 delta-receptors.