Processes such as memory acquisition, drug tolerance and dependence, and chronic pain are known to be impacted significantly by ACs. Although ACs are expressed ubiquitously throughout the body, certain isoforms have distinct tissue expression patterns. 9 AC1 and AC8 are primarily expressed in the central nervous system (CNS) within regions such as, but not limited to, the hippocampus and the anterior cingulate cortex (ACC); regions of the brain associated with learning, memory and the development of chronic pain. Evidence suggests AC1 is responsible for propagation of inflammatory pain stimuli. In vivo studies indicate that injury leads to increased postsynaptic Ca 2+ influx in the ACC, where Ca 2+ forms a complex with CaM that, in turn, binds and subsequently activates AC1 to produce cAMP. In chronic pain, it is suggested that persistent Ca 2+ influx causes hyperactivation of AC1 and downstream pain sensitization. Moreover, AC1 knockout (AC1 -/-) and AC1/8 double knockout (DKO) mice exhibit nearly complete abrogation of behavioral pain response when treated with an inflammatory cocktail, complete Freund's adjuvant (CFA), and display a lack of pain sensitization in a muscle pain model. However, both AC1 and AC8 are implicated to play a role in long-term memory and long-term potentiation in these brain regions. In mouse knockout models, DKO mice displayed severe impairment to spatial memory acquisition; however, this impairment was mostly absent in the AC1 -/-mice. Additionally, ACs propagate signals downstream from the µ-opioid receptor (MOR), a well characterized target for analgesic pharmacological therapy. MOR agonists act, in part, by negatively regulating AC1. Upon agonist stimulation the MOR activates and induces dissociation of a heterotrimeric G protein complex comprised of G protein αi (Gαi) and Gβγ subunits. The Gαi subunit can then translocate to a membrane bound AC, in this case AC1, and subsequently inhibit catalysis and reduce intracellular cAMP levels. Additionally, chronic opioid administration leads to compensatory neuroadaptation, including upregulation of AC1 to offset the reduced cAMP signal and ultimately leading to tolerance and dependence. Moreover, activation of the MOR signaling pathway has several undesired side effects, some of which are mediated by recruitment of β-arrestins and the release of Gβγ, which can lead to the development of physiological tolerance and may also contribute to opioid-induced respiratory depression, respectively. Furthermore, MOR expression is not limited to the brain but is also expressed peripherally, leading to other common side effects such as opioid-induced constipation. One potential approach under investigation to limit these side effects is the development of biased MOR agonists that favor signaling through the G protein pathway and reduce the β-arrestin pathway signal. Alternatively, our group and others have shown it is possible to target the activity of the downstream AC directly, bypassing the MOR entirely. This strategy would allow for effective inhibition of chronic pain through AC inhibition, while avoiding negative side-effects induced by clinically used MOR agonists; thus, increasing the therapeutic index. Taken together, the promising genetic evaluation coupled with the tissue localization at the key pain center of the brain and its role in analgesic response to opioid agonists all suggest AC1 is a promising target for development of novel pharmacological modulators for the treatment of chronic pain.