Relative analgesic potency of mu, delta and kappa opioids after spinal administration in amphibians

The analgesic effects of 12 opioid agonists in amphibians were measured using the acetic acid test. Spinal administration of dermorphin, [D-Ala²,NMePhe⁴,Gly-ol]-enkephalin, fentanyl and morphine (mu opioids); [D-Ser²,Leu⁵-Thr⁶]-enkephalin, [D-Ala²,D-Leu⁵]-enkephalin, [D-Pen²,D-Pen⁵]-enkephalin and deltorphin (delta opioids); and CI977 {(5R)-(544α,744α,845β)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4,5]dec-8yl]-4-benzofuranacetamide monohydrochloride, bremazocine}, U50488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate) and nalorphine (kappa opioids) produced a dose-dependent and long-lasting analgesia in the Northern grass frog, Rana pipiens. With all opioids, time course experiments showed that this analgesic effect lasted for at least 4 hr, with no untoward effects observed within each dosage range used. The analgesic effects of the 12 opioids were blocked by systemic naltrexone pretreatment. Comparison of dose-response curves demonstrated that the rank order of potency was such that, in general, mu opioids > delta opioids > kappa opioids. Dose-response curves obtained in the presence of a fixed dose of naltrexone showed the greatest shift for [D-Ser²,Leu⁵-Thr⁶]-enkephalin, less so for [D-Ala²,NMePhe⁴,Gly-ol]-enkephalin and the least shift for bremazocine. ED₅₀ values for mu and delta opioids in the amphibian acetic acid test were significantly correlated to ED₅₀ values of the same opioids reported in the literature for the rodent TF test. These results show that a spinal site of opioid analgesia is present in amphibians and supports the utility of this alternative, nonmammalian model for studies of opioid analgesia and pain research.