Chronic treatment with cannabinoids and opiates results in tolerance to their analgesic effects through a mechanism that is mediated by PKA. Inhibition of PKA can restore analgesic sensitivity in tolerant animals. In mice tolerant to THC analgesia, intracerebroventricular injections of the PKA inhibitor KT5720 restore analgesic sensitivity.107 In rats tolerant to morphine analgesia, intracerebroventricular injection of PKA antisense oligonucleotides blocks the development of tolerance.108 Intracerebroventricular injections of the PKA inhibitors KT-5720 or 4-cyano-3-methylisoquinoline restore analgesic sensitivity.109
