In rats, the development of tolerance to morphine analgesia is attenuated by intrahippocampal injections of the CaMKII inhibitors KN62 and KN93, or CaMKII antisense oligonucleotides.255 This is similar to the attenuation of tolerance to morphine analgesia by PKA inhibition with intracerebroventircular injection of PKA antisense oligonucleotides108 or of Cdk5 inhibition by intrathecal injection of roscovitine.154 These parallel results indicate that tolerance to morphine analgesia is mediated by several protein kinases and all are necessary for its expression.
