Isobolographic analysis of analgesic interactions between intrathecally and intracerebroventricularly administered fentanyl, morphine and D-Ala²-D-Leu⁵-enkephalin in Morphine-Tolerant and nontolerant mice

Concurrent administration of morphine sulfate i.c.v. and i.t. produces a multiplicative interaction for analgesia in the tail flick response in mice. This interaction decreases to an additive interaction in mice which are tolerant to s.c. morphine. To test the responses of opioids selective for mu or delta receptors, the present study examined the interactions between fentanyl citrate (mu agonist) and D-Ala²-D-Leu⁵ enkephalin (DADLE, a relatively selective delta agonist) administered i.c.v. and i.t. using the tail flick test in control and morphine pellet-implanted mice. A method was developed for assigning statistical significance to the resulting ED₅₀ values when analyzed isobolographically. When fentanyl or DADLE was administered i.c.v. plus i.t., an additive interaction between sites occurred in control animals, which changed to an antagonistic interaction for fentanyl and a multiplicative interaction for DADLE after morphine pellet treatment. When morphine was given i.c.v. along with i.t. fentanyl or DADLE in control animals, multiplicative interactions occurred when equipment doses were given. Thus, opioids which were more receptor-selective than morphine did not produce multiplicative interactions, but were multiplicative when given with morphine. These results suggest that activation of combinations of receptors (by morphine) was required for the multiplicative interaction. The supraspinal site involved mu receptors (which are not self-sufficient and require an additional component) and the spinal site involved mu or delta receptors. The use of isobolographic analysis required that the drugs, when administered concurrently at two sites, be given in a constant dose ratio.