Ca2+/Calmodulin-Dependent Protein Kinase IIα Is Required for the Initiation and Maintenance of Opioid-Induced Hyperalgesia

Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca2+/calmodulin-depent protein kinase II (CaMKII alpha) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKII alpha activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose- and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKII alpha by using small interfering RNA and demonstrated that knockdown of spinal CaMKII alpha attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKII alpha(T286A) point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKII alpha as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.