EFFECTS OF SPINAL VERSUS SUPRASPINAL ADMINISTRATION OF CYCLIC NUCLEOTIDE-DEPENDENT PROTEIN-KINASE INHIBITORS ON MORPHINE-TOLERANCE IN MICE

The consequences of becoming tolerant to the analgesic effects of morp hine include increased risk of unwanted side effects, such as respirat ory depression, because the patient is required to take larger doses o f the opioid to get the same relief from pain. Many studies suggest th at phosphorylation plays a role in the neuroplasticity associated with opioid tolerance. This study examines the effect of inhibiting cyclic nucleotide-dependent protein kinase activity in the brain or spinal c ord of morphine-tolerant mice. KT5720, a cyclic adenosine monophosphat e (cAMP)-dependent protein kinase inhibitor, or KT5823, a cyclic guano sine monophosphate (cGMP)-dependent protein kinase inhibitor, was cent rally administered in morphine-tolerant and placebo-treated mice prior to a systemically administered challenge dose of morphine. KT5720 com pletely reversed morphine tolerance in the tail-flick assay when the p retreatment was administered intracerebroventricularly (i.c.v.); KT582 3 had no effect on morphine via this route. When either of these drugs was administered intrathecally (i.t.), the activity of morphine was g reatly diminished in the tolerant animals, with no effect on morphine antinociception in the placebo group. These data suggest that cAMP-dep endent protein kinase activity may be upregulated in the brain with mo rphine tolerance, and that this upregulation is critical to the expres sion of tolerance to the antinociceptive effects of morphine. In the s pinal cord, however, the activity of cyclic nucleotide-dependent prote in kinases, and possibly their substrate proteins, may be affected by chronic morphine exposure such that inhibition of these kinases produc es hyperalgesia. Copyright (C) 1997 Elsevier Science Ireland Ltd.