Changes in responsiveness to mu and kappa opiates following a series of convulsions

Abstract

After a series of seven electroconvulsive shocks, mice (C57BL/6J) showed a marked change in their response to opiates. Although very large doses of mu agonists induce convulsions in normal control mice, our evidence indicated that this was accomplished through nonopiate mechanisms: they could not be blocked by naltrexone and the pattern of drug potencies (codeine greater than morphine greater than levorphanol) was not consistent with an opiate response. In contrast, after electroconvulsive shock small doses of mu agonists induced convulsions that could be blocked by naltrexone and the pattern of drug potency (levorphanol greater than morphine greater than codeine) was consistent with an opiate mechanism. Kappa drugs, on the other hand, produced convulsions in both control and ECS animals, although there was an enhanced responsiveness in the latter. Furthermore, the convulsions produced by kappa drugs were blocked by naltrexone and showed stereoselectivity in both control and ECS animals. The changes in responsiveness to mu and kappa opiates cannot be explained on the basis of a general increase in seizure susceptibility, as sensitivity to the nonopiate convulsant, strychnine, was not enhanced after electroconvulsive shock. The results point to a qualitative change in response to mu agonists after electroconvulsive shock, but only a change in sensitivity to kappa agonists.

Convulsions may alter the specificity of kappa-opiate receptors

“…This conclusion is supported by the finding of a morphine-EKC cross-tolerance in ECS-treated mice and not in normal animals. In addition, as our work demonstrates (18)(19)(20), the convulsions induced by mu-opiates in normal animals are not receptor-mediated, whereas those observed to follow ECS are receptor-specific. In normal mice, mu-agonists produce convulsions that are not reversible by naltrexone, usually lethal, and not altered by chronic morphine treatment.…”

“…In addition to these findings, we recently found that mu-and kappa-agonists produce convulsions via different mechanisms in the mouse (20). Mu-agonists produced convulsions only at lethal doses, could not be blocked by naltrexone, and their order of potency was not consistent with established opiate receptor responses.…”