PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice.

Male Swiss Webster mice exhibited antinociception, hypothermia and Straub tail 3h following a 75mg morphine pellet implantation. These signs disappeared by 72h, and the morphine-pelleted mice were indistinguishable from placebo-pelleted ones, although brain morphine concentrations ranged from 200 to 400ng/gm. We previously demonstrated that chemical inhibitors of protein kinase C (PKC) and A (PKA) are able to reverse morphine tolerance in acutely morphine-challenged mice.

PKC and PKA inhibitors reverse tolerance to morphine-induced hypothermia and supraspinal analgesia in mice.

Morphine antinociceptive tolerance in the tail-flick test is completely reversed by inhibitors of protein kinase C (PKC) or cAMP-dependent protein kinase (PKA). The effects of these inhibitors on tolerance to supraspinally mediated antinociception, such as the hot-plate test was unknown, as well as their effects in tests of mechanical nociception. The PKC inhibitors bisinolylmaleimide I ((2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) and Gö-7874 [2[1[(3-Dimethylaminopropyl)-5-methozyindol-3-yl]-3-(1H-indol-3-yl) hydrochloride] completely reversed the tolerance to morphine in both the hot-plate and tail-pinch tests.

Effects of mGlu1 and mGlu5 metabotropic glutamate antagonists to reverse morphine tolerance in mice.

Intracerebroventricular (i.c.v.

The expression of a high level of morphine antinociceptive tolerance in mice involves both PKC and PKA.

We have previously reported that intracerebroventricular (i.c.v.

Prolonged reversal of morphine tolerance with no reversal of dependence by protein kinase C inhibitors.

The phosphatidylinositol (PI) cascade plays a pivotal role in mediating behavioral tolerance to the antinociceptive effects of morphine. Earlier we reported that antinociceptive tolerance was completely reversed 30 min after the administration of inhibitors of each step in the PI cascade. The aim of this study was to determine whether injection of a single dose of protein kinase C (PKC) inhibitor would elicit a prolonged reversal of morphine tolerance for up to 24 h.