Interactions between selective opioid agonists acting at spinal μ-, δ-, and κ-opioid receptors were evaluated by co-administering a low-antinociceptive dose of the selective δ-agonist, DPDPE, or the selective κ-agonist, U50,488H, with sequentially increasing doses of the selective β-agonist, DAMGO, intrathecally. Antinociceptive synergy (i.e., a more than additive antinociceptive effect) was observed with both combinations of opioid agonists tested. The demonstration of antinociceptive synergy suggests that the subtypes of spinal opioid receptors can act, at least in part, through a common neural circuit.
Since our measure of antinociception, the Randall-Selitto paw-withdrawal test, is dependent on a normally functioning motor system, we also evaluated the effects of these same combinations of opioid peptides on motor coordination using a rotarod treadmill. A low-antinociceptive dose of DPDPE or U50,488H co-administered intrathecally, with sequentially increasing doses of DAMGO, did not worsen the decrement in rotarod performance observed with the same doses of DAMGO administered as a single agent. In fact, the low-antinociceptive dose of DPDPE significantly attenuated the decrease in rotarod performance produced when the same dose of DAMGO was administered as a single agent.
The results of this study suggest that intrathecal combinations of selective μ- with both δ- or κ-selective opioid agonists can produce antinociceptive synergy without producing an increase in motor side effects. In addition, the results of a secondary analysis, that compared the antinociceptive data from this study with data from our previous studies of intrathecal combinations of sequentially increasing doses of U50,488H with low doses of DPDPE or DAMGO and sequentially increasing doses of DPDPE with low doses of DAMGO or U50,488H, demonstrate distinct differences in the magnitude of the antinociceptive interactions. The most prominent finding from the secondary analysis was that administration of the μ-opioid agonist, DAMGO, as a component of any combination regimen, resulted in the largest enhancement in antinociceptive effects.