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 morphine include increased risk of unwanted side effects, such as respiratory depression, because the patient is required to take larger doses of the opioid to get the same relief from pain. Many studies suggest that 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 cord of morphine-tolerant mice. KT5720, a cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor, or KT5823, a cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor, was centrally administered in morphine-tolerant and placebo-treated mice prior to a systemically administered challenge dose of morphine. KT5720 completely reversed morphine tolerance in the tail-flick assay when the pretreatment was administered intracerebroventricularly (i.c.v.); KT5823 had no effect on morphine via this route. When either of these drugs was administered intrathecally (i.t.), the activity of morphine was greatly diminished in the tolerant animals, with no effect on morphine antinociception in the placebo group. These data suggest that cAMP-dependent protein kinase activity may be upregulated in the brain with morphine tolerance, and that this upregulation is critical to the expression of tolerance to the antinociceptive effects of morphine. In the spinal cord, however, the activity of cyclic nucleotide dependent protein kinases, and possibly their substrate proteins, may be affected by chronic morphine exposure such that inhibition of these kinases produces hyperalgesia.