The anticonvulsant effect of opioids and opioid peptides against maximal electroshock seizures in rats.

Opioids and opioid peptides influence the threshold to a seizure which is a model of petit mal epilepsy (Cowan, Geller and Adler, 1979). The present authors investigated representative opioid compounds in a model of a grand mal seizure, maximal electroshock (MES). Although all of the opioids and opioid peptides tested blocked tonic hindlimb extension, they divided into two groups, based on their ability to decrease the total length of the tonic component of the maximal electroshock seizure and their sensitivity to blockade by naloxone. The first group contained morphine, meperidine, methadone, ethylketocyclazocine (EK), D-ala2-met-enkephalinamide, D-ala2-leu5-enkephalin and beta-endorphin. The compounds in this group caused a decrease in the length of the tonic component that was dose-related, with the maximum decrease amounting to approx. 40%. The effect was blocked by the prior administration of 1 mg/kg of naloxone. The second group contained the partial agonists, pentazocine and cyclazocine. These opioids also caused a dose-related decrease in the length of the tonic component and, in the largest doses, the tonic component of the convulsion was completely blocked. Naloxone, in doses as large as 10 mg/kg, did not appreciably reverse the action of either drug.

Vanilloids. 1. Analogs of capsaicin with antinociceptive and antiinflammatory activity.

As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion of the parent structure (and related compounds derived from homovanillic acid) was varied. In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active. Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin. In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin. The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.

Demonstration of cell sidedness in hepatic transfer of morphine and morphine glucuronide in the rat.

The purpose of this study was to demonstrate hepatic cell sidedness for the transfer of [14C]morphine and [14C]morphine glucuronide. A tracer dose of [14C]morphine was administered by segmented retrograde intrabiliary injection into the bile duct cannula of the urethane-anesthetized rat or the in situ isolated perfused liver preparation. The bile from the first, and the single pass perfusate from the second preparation, respectively, were analyzed for the radioactive components. Various doses of morphine were given intraportally in these preparations 5 min before the [14C]morphine to influence the recovery of the radioactive components. As the dose of morphine increased, the recovery in bile of [14C]morphine glucuronide decreased while [14C]morphine remained unchanged. In the perfusate, the morphine loading increased the recovery of [14C]morphine, but the [14C]morphine glucuronide content was unchanged. These sets of results indicated that morphine loading inhibited the formation of morphine glucuronide by isotope dilution, which should have led to an increase in [14C]morphine in the cell. Because of the presence of cell sidedness, the increased intracellular [14C]morphine was directed toward the perfusate and not toward the bile. The decrease in [14C]morphine glucuronide synthesis was manifested by a decrease in its excretion into bile, but not into perfusate. Further demonstration of cell sidedness was obtained by manipulation of these systems by chlordecone and trans-stilbene oxide pretreatment of the rats. The directionality of flow of [14C]morphine and [14C]morphine glucuronide out of the liver emanates from liver cell sidedness.

The antinociceptive effect and pharmacokinetics of olvanil following oral and subcutaneous dosing in the mouse.

Mice were tested for response latency on a 55 degrees C hot plate after subcutaneous (S.C.) or oral administration of olvanil (dose level 200 and 300 mg/kg, respectively). Only the S.C. injection of olvanil produced antinociception. A pharmacokinetics experiment with radiolabeled olvanil (200 mg/kg) was conducted to determine whether this antinociception difference was related to a difference in plasma concentration of olvanil following the two routes of administration. The results indicate that concentrations of radioactivity (olvanil plus metabolites) in plasma reach a peak higher and faster after oral dosing than after S.C. injection. However, the area under the concentration-time curve (AUC) for recovery of radioactivity was slightly higher after the S.C. injection than after the oral dose of olvanil. In contrast, intact olvanil is barely measurable (10 to 30 ng/g) in plasma following an oral dose but is present in high concentration (100 to 2000 ng/g) following S.C. injection. The AUC for olvanil was also higher following a S.C. dose. These data indicate that olvanil fails to produce antinociception after oral dosing in mice not due to lack of absorption, but because it undergoes first pass metabolism.

Comparison of the inhibition of biliary excretion produced by certain inducing agents including 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Rats were treated with chlordecone, mirex, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and respective solvent vehicle. Under urethane or pentobarbital anesthesia, the bile duct was cannulated and radioactive morphine, imipramine, or ouabain was given by segmented retrograde intrabiliary injection. The spectrum of inhibition of biliary excretion by chlordecone and mirex were similar in that morphine glucuronide and in part polar imipramine metabolite recoveries in bile were decreased; ouabain recovery was unaffected. TCDD was different in that it markedly decreased the recovery of ouabain. Thus, it appears that chlordecone, mirex, and TCDD inhibit the canalicular transport of the glucuronide metabolites of morphine and imipramine into bile, and TCDD affects in addition the canalicular transport of ouabain into bile.