The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Apr 2012
Comparative StudyActivation of protein kinase C (PKC)α or PKCε as an approach to increase morphine tolerance in respiratory depression and lethal overdose.
Long-term use of opioids is hindered by respiratory depression and the possibility for fatal overdose in drug abusers. This is attributed to higher levels of tolerance that develops against antinociception than to respiratory depression. Identifying important mechanisms that would increase morphine respiratory depression and overdose tolerance could lead to the safer use of opioids. ⋯ CAPKCε-expressing rats developed the highest level of respiratory depression tolerance. Furthermore, when CAPKCε lentivirus was injected into the vlPAG, rats were able to develop significant antinociceptive tolerance at low doses of morphine that normally do not cause tolerance. The approach of increasing morphine respiratory depression and lethality tolerance by increasing PKCα or ε activity at preBötC could be used to make opioids safer for long-term use.