Aiko Sawa

Evidence that dynorphin-(1–13) acts as an agonist on opioid κ-receptors

Abstract The study concerned the opioid-receptor subtype on which dynorphin-(1–13) acts in in vitro isolated preparations. The potency of dynorphin-(1–13) relative to that of ethylketocyclazocine (Mr 2266), a representative κ-receptor agonist, in inhibiting the electrically evoked contractions of the guinea-pig ileum was found to be similar to that found with either mouse vas deferens or rabbit ileum. Moreover, Mr 2266 was found to be several-fold more effective than naloxone to antagonize the agonist actions of both κ-receptor agonists such as ethylketocyclazocine, ketocyclazocine and bremazocine, and dynorphin-(1–13) either in the guinea-pig ileum, mouse vas deferens, or in rabbit ileum. Additionally, dynorphin-(1–13) was found to have a significant inhibitory action on the rabbit vas deferens which had been shown to contain κ-receptors exclusively. The data indicate that dynorphin-(1–13) acts as an endogenous agonist on κ-receptors.

Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents

The effects of rolipram, a cAMP-specific phosphodiesterase (phosphodiesterase 4) inhibitor, on experimentally-induced amnesia were examined using a 3-panel runway paradigm in rats and a passive avoidance task in mice. Scopolamine, cerebral ischemia induced by four-vessel occlusion and electric convulsive shock impaired working memory in the 3-panel runway task. Rolipram at 0.1 mg/kg reduced the increase in errors induced by scopolamine or cerebral ischemia. Rolipram at 0.32 mg/kg also reduced the increase in errors induced by electric convulsive shock. Dibutyryl cAMP also had similar effects in 3-panel runway experiments. In the passive avoidance task, rolipram reversed the impairments of the avoidance response induced by scopolamine, cycloheximide and electric convulsive shock at 10, 10 and 3 mg/kg, respectively. These results indicate that rolipram ameliorates impairments of learning and memory in rats and mice, and suggest that rolipram might ameliorate the impairments of learning and memory by elevating cAMP levels.

Phosphodiesterase type 4 that regulates cAMP level in cortical neurons shows high sensitivity to rolipram

To characterize the role of phosphodiesterase type 4 (a cAMP-specific and rolipram-sensitive phosphodiesterase) among phosphodiesterases in the regulation of the intracellular cAMP level in cortical neurons, we investigated the effects of phosphodiesterase inhibitors on the intracellular cAMP levels in primary cultured rat cortical neurons. Selective inhibitors of phosphodiesterase type 4 and type 2 significantly enhanced beta-adrenoceptor-mediated cAMP increase. Selective inhibitors of phosphodiesterase type 1, type 3 and type 5/6 had no effect on the cAMP level. Rolipram enhanced the beta-adrenoceptor-mediated cAMP increase in cortical neurons, astrocytes and vascular smooth muscle cells at different minimum effective concentrations (10, 100 and 1000 nM, respectively). These findings indicate that phosphodiesterase type 4, showing a high-sensitivity to rolipram, plays a major role in regulating cAMP in the cortical neurons, and that rolipram at low doses enhances the intracellular cAMP increase in the cortical neurons selectively.

CALCIUM REQUIREMENTS FOR ELECTRICALLY‐INDUCED RELEASE OF AN ENDOGENOUS OPIATE RECEPTOR LIGAND FROM THE GUINEA‐PIG ILEUM

Calcium requirements for electrically‐induced release of an endogenous opiate receptor ligand in the myenteric plexus‐longitudinal muscle strip of the guinea‐pig ileum were studied. The naloxone‐reversible depression of the electrically evoked contraction caused by stimulation at 10 Hz in normal Krebs solution was markedly reduced by decreasing the calcium concentration in the solution. The depression was greatly diminished by increasing the magnesium concentration in the solution. These results show that the electrically‐induced release of an opiate‐like material requires calcium ions.