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Activation of PKCα or PKCε as an approach to increase morphine tolerance in respiratory depression and lethal overdose
Author(s) -
Lin Hong-Yiou,
Law Ping-Yee,
Loh Horace H.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.839.6
Subject(s) - morphine , respiratory system , pharmacology , drug tolerance , protein kinase c , medicine , anesthesia , biology , phosphorylation , microbiology and biotechnology
Identifying mechanisms that increase morphine respiratory depression and overdose tolerance could lead to the safer use of opioids. Since PKC activity mediates morphine antinociceptive tolerance, we hypothesized that activating PKCα or ε at the pre‐Bötzinger complex (preBötC) can increase morphine tolerance in respiration and overdose. Laser microdissection and qRT‐PCR were used to compare the relative mRNA abundances of PKCα, γ, and ε between vlPAG vs. preBötC. To test whether PKCα or ε could enhance tolerance in respiratory depression and overdose, lentivirus carrying the wild type (WT), constitutively activated mutants (CA), and siRNA against PKCα or ε were microinjected into the preBötC. Expressing CAPKCα or ε, but not WTPKCα or ε, at the preBötC allowed rats to develop tolerance to morphine respiratory depression. In terms of lethality, expressing either WTPKCε, CAPKCα, or CAPKCε at preBötC increased morphine tolerance to lethal overdose. 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 make opioids safer for chronic use. This research was supported by NIH grant [DA000564].