Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action

Kyoung Shim Kim, Ko Woon Lee, Kang Woo Lee, Joo Young Im, Ji Yeoun Yoo, Seung Woo Kim, Ja Kyeong Lee, Eric J. Nestler, Pyung Lim Han

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked μ, δ, and κ opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective μ or δ opioid receptor agonists are lost in AC5-/- mice, whereas the behavioral effects of selective κ opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a μ or δ opioid receptor agonist to suppress adenylyl cyclase activity was absent in striatum of AC5-/- mice. Together, these results establish AC5 as an important component of μ and δ opioid receptor signal transduction mechanisms in vivo and provide further support for the importance of the cAMP pathway as a critical mediator of opioid action.

Original languageEnglish
Pages (from-to)3908-3913
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - 7 Mar 2006


  • Addiction
  • Analgesia
  • Opioid receptors
  • Striatum
  • cAMP


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