The midbrain periaqueductal gray and fear extinction: Opioid receptor subtype and roles of cyclic AMP, protein kinase A, and mitogen-activated protein kinase

Four experiments studied the opioid receptor subtype and signal transduction mechanisms mediating fear extinction in the ventrolateral quadrant of the midbrain periaqueductal gray (vIPAG). Microinjection of a mu- but not a delta- or kappa-opioid receptor antagonist into the v1PAG retarded extinction. Extinction was also dose-dependently retarded by vIPAG infusions of a cyclic AMP (cAMP) analog but was unaffected by infusions of a protein kinase A activator or a mitogen-activated protein kinase inhibitor across wide dose ranges. The results show that fear extinction occurs via activation of v1PAG mu-opioid receptors and involves reductions in cAMP. These mechanisms are different from the cellular mechanisms for extinction in the amygdala and from the known cellular mechanisms for opioid analgesia in the v1PAG.