Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase‐5

Abstract

Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.

Adenylate cyclase 5 coordinates the action of ADP, P2Y1, P2Y13 and ATP-gated P2X7 receptors on axonal elongation

“…Moreover, loss of AC5 compromises the ability of both contextual and discrete cues to modulate instrumental behavior (Kheirbek et al, 2010;Kheirbek et al, 2009), and the AC5 knockout mice show striking anxiolytic and antidepressant phenotypes in standard behavioral assays (Krishnan et al, 2008). Finally, AC5-knockout mice have markedly attenuated pain-like responses in neuropathic pain models (Kim et al, 2007), in accordance with the proposed roles of P2Y1 and P2Y13 in pain (Malin and Molliver, 2010). Our results demonstrate that AC5 protein is found in the soma and shows an increasing distal gradient along the axon and axonal growth cone.…”

Adenylyl Cyclase–A-kinase Anchoring Protein Complexes: The Next Dimension in cAMP Signaling

“…For example, both AKAP150⌬36 mice and AC5 knockouts show reduced inflammatory thermal hypersensitivity in response to prostaglandin E2 or formalin, respectively (Kim et al, 2007;Schnizler et al, 2008). These effects correlate with the loss of transient receptor potential vanilloid receptor 1 regulation by PKA in AKAP150⌬36 dorsal root ganglia.…”

Scaffolding by A-Kinase Anchoring Protein Enhances Functional Coupling between Adenylyl Cyclase and TRPV1 Channel

“…Deletion of AC1 has significantly reduced behavioral nociceptive responses in acute muscle pain and chronic muscle inflammatory pain (49). Deletion of AC5 strongly attenuates acute thermal pain, thermal allodynia, and chronic inflammatory pain (50) and attenuates the behavioral responses to morphine (51). AC8 does not have a role in formalin-mediated inflammatory pain (49); roles for additional AC isoforms have not been examined.…”